Overview¶

Cardiac G2P is an evidence-based dataset for inherited cardiac condition gene disease pairs. Each entry annotates a disease-associated gene with information about the gene-disease relationship, including the inheritance mode and allelic requirement, information pertaining to disease mechanism (represented as a disease-associated variant consequence), and known disease-relevant variant classes at a defined locus.

How to use¶

The Cardiac G2P Gene Panel can be downloaded in a csv file format here This dataset is also available through the official G2P website https://www.ebi.ac.uk/gene2phenotype.

Citation¶

Josephs, K.S., Roberts, A.M., Theotokis, P. et al. Beyond gene-disease validity: capturing structured data on inheritance, allelic requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions. Genome Med 15, 86 (2023). https://doi.org/10.1186/s13073-023-01246-8

Brugada Syndrome (BrS)¶

Brugada Syndrome¶

SCN5A - BrS - Autosomal dominant¶

Gene symbol	SCN5A
Gene mim	600163
Indication	BrS
Referral indication	Brugada Syndrome (BrS)
Disease grouping	Brugada Syndrome
Disease name	SCN5A-related Brugada syndrome
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	Typified by incomplete penetrance
Disease-associated variant consequence	altered gene product sequence; decreased gene product level
Mechanism	NA
Mutation consequence flag	restricted repertoire of mutations
Restricted repertoire of pathogenic variants	Intronic variants with functional evidence: NM_000335.5(SCN5A):c.3228+551T\>G (p.?)
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	splice_region_variant; splice_acceptor_variant; splice_donor_variant; missense_variant; inframe_deletion; inframe_insertion; stop_gained_NMD_triggering; frameshift_variant_NMD_triggering
PMIDs	32850980; 9521325; 20564468; 32533946; 20031634; 17075016; 17442746; 25905440; 11748104; 20129283; 29959160; 33164571; 33131149; 25829473; 30203441; 32893267; 29798782; 39391988
Disease accession	MONDO:0011001
Curated date	29.01.2021
Expert panel review date	21.07.2021
Expert panel	Channelopathy expert panel

Narrative

SCN5A-related Brugada syndrome is caused by decreased gene product level or altered gene product sequence due to a variety of mechanisms (e.g. decreased expression of cardiac sodium channel, Nav1.5 in the sarcolemma, expression of non-functional channels, or altered gating properties leading to a decreased INa sodium current (e.g., delayed activation or earlier or faster inactivation)) (PMID: 29798782). The disease mechanism is loss of function.

To date, SCN5A is the only gene classified as having definitive evidence as a cause of monogenic Brugada syndrome (BrS) by ClinGen (PMID: 29959160). SCN5A pathogenic variants are identified in approx. 20- 30% of cases of European ancestry (PMID: 30139433; PMID 33164571). This contribution may differ in other populations.

SCN5A-related Brugada syndrome is characterized by autosomal dominant inheritance with incomplete penetrance (PMID 9521325; 11748104; 25905440; 20031634; 33164571; NBK1517).

Hundreds of variants, both truncating and non-truncating, have been described in association with Brugada syndrome. Kapplinger et al 2010 (PMID: 20129283) identified 293 distinct variants in SCN5A: 193 missense, 32 nonsense, 38 frameshift, 21 splice-site, and 9 inframe deletions/insertions. Walsh et al 2020 (PMID: 32893267) found that non truncating variants were highly enriched in European cases in the SCN5A transmembrane regions.
More recently, a rare non-coding variant in an SCN5A intronic enhancer region has been identified in 9 patients with Brugada syndrome in Thailand (3.9% of the patient cohort). The variant is highly enriched compared to population matched controls and has been functionally validated. It causes significantly reduced SCN5A expression and a reduction in Nav1.5-mediated sodium current density. Authors describe a severe phenotype associated with this variant, 8/9 (89%) of the patients had experienced a cardiac arrest. The variant is in the RE5 enhancer region, 3-38580380-A-C (GRCh38) (PMID: 39391988).

Gain of function variants are associated with Long QT syndrome. Although loss of function appears to be the accepted mechanism in Brugada syndrome the SCN5A genotype/phenotype association is still not completely understood. Uncommonly, a single variant can cause both loss of peak current and gain of late current and can lead to a mixed phenotype of LQTS and BrS (PMID: 29806494).

Catecholaminergic polymorphic ventricular tachycardia (CPVT)¶

Atypical CPVT phenotype¶

CALM1 - CPVT - Autosomal dominant¶

Gene symbol	CALM1
Gene mim	114180
Indication	CPVT
Referral indication	Catecholaminergic polymorphic ventricular tachycardia (CPVT)
Disease grouping	Atypical CPVT phenotype
Disease name	CALM1-related Catecholaminergic polymorphic ventricular tachycardia
Gene disease validity (ClinGen)	MODERATE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	Typically de novo
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant
PMIDs	31170290; 26309258; 31983240; 24563457; 23040497; 25557436; 32929985
Disease accession	MONDO:0013966
Curated date	08.01.2021
Expert panel review date	19.05.2021
Expert panel	Channelopathy expert panel

Narrative

The disease mechanism in CALM1-related CPVT is likely a dominant negative effect caused by altered gene product sequence which reduces the calcium dependent inactivation of the calcium channel CaV1.2, resulting in increased inward calcium channel current (ICaL) and repolarization delay.

The three CALM genes encode an identical 149aa protein, calmodulin. The CALM1 gene is located on chromosome 14, CALM2 on chromosome 2 and CALM3 on chromosome 19. Calmodulin protein is involved in many calcium-dependent intracellular processes. All three CALM genes have been classified as Definitive for LQTS and Moderate for CPVT, certain variants are only associated with one or other phenotype, whereas others are associated with a mixed or variable phenotypes.

All variants with evidence of pathogenicity identified in the CALM genes are missense: at least 35 distinct missense variants have been identified and reported in the International Calmodulinopathy Registry including 11 (31%) in CALM1, 16 (46%) in CALM2, and 8 (23%) in CALM3. The majority of variants across the CALM genes affect amino acid residues in the EF-hand Ca2+ binding loop III and IV. Some variants have additional evidence in that the same substitution has been seen in paralogous CALM genes, or that the same substitution has been seen in a related phenotype (LQT). Most variants are unique, but 9 were present in more than one index case and among these, three (p.Asn98Ser, p.Asp130Gly, and p.Phe142Leu, identified in 10, 5, and 4 families, respectively.) appear to be recurrent. While p.Asp130Gly and p.Phe142Leu have always been reported as associated with the LQTS phenotype, the p.Asn98Ser has phenotypic variability, including LQTS, CPVT, idiopathic VF and sudden death. The majority of CALM variants are de novo.

Pathogenic variants in the CALM genes have been associated with: presentation in infancy or early childhood (up to 5 years); marked sinus bradycardia or atrioventricular block and QT prolongation; and, predominantly with CALM1 variants, a mild-to-severe neurological impairment, including seizures, development delay, motor and/or cognitive disability.

The phenotype most frequently shown by patients with CALM variants is LQTS, but some patients display other phenotypes including CPVT, idiopathic VF and sudden unexplained death. Some variants have been associated with both LQTS and CPVT, however Crotti et al (PMID: 31170290) report that ‘despite the relatively small numbers of cases, a significant association (P = 0.001) was observed between location of mutation and phenotype (Supplementary material online, Figure S1). Indeed, a pathogenic variant in EF-hand IV Ca2+ binding loop was found in the majority (17/32, 53%) of CALM-LQTS index cases but in only one of the nine CALM-CPVTs (11%). Conversely, variants identified in CALM-CPVT index cases were mostly located either in EF-hand III (n = 5, 56%), or in the inter-EF hand I-II linker (n = 3, 33%).’

For the ClinGen CPVT curation, CALM1 scored in the moderate range based on two reported variants in patients with CPVT or mixed CPVT/LQT phenotypes (p.Asn54Ile and p.Asn98Ser) and associated functional data. However, due to the unique characteristics of the calmodulin genes and their gene-disease associations, it was agreed by the expert panel to include them in this curation. The reasons were: 1) all three genes have already been established as disease-causing for an inherited arrhythmia syndrome (LQTS), 2) there are multiple examples of patients presenting with a phenotype indistinguishable from CPVT for each, either de novo or supported by functional evidence and 3) the genes encode for identical proteins, are all expressed in the heart and equivalent de novo variants in the three genes have been shown to lead to similar phenotypes, highlighting the functional equivalence of these genes.

CALM2 - CPVT - Autosomal dominant¶

Gene symbol	CALM2
Gene mim	114182
Indication	CPVT
Referral indication	Catecholaminergic polymorphic ventricular tachycardia (CPVT)
Disease grouping	Atypical CPVT phenotype
Disease name	CALM2-related Catecholaminergic polymorphic ventricular tachycardia
Gene disease validity (ClinGen)	MODERATE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	Typically de novo
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant
PMIDs	31170290; 26309258; 24917665; 31983240; 25557436; 27100291
Disease accession	MONDO:0017990
Curated date	08.01.2021
Expert panel review date	19.05.2021
Expert panel	Channelopathy expert panel

Narrative

The disease mechanism in CALM2-related CPVT is likely a dominant negative effect caused by altered gene product sequence which reduces the calcium dependent inactivation of the calcium channel CaV1.2, resulting in increased inward calcium channel current (ICaL) and repolarization delay.

The three CALM genes encode an identical 149aa protein, calmodulin. The CALM1 gene is located on chromosome 14, CALM2 on chromosome 2 and CALM3 on chromosome 19. Calmodulin protein is involved in many calcium-dependent intracellular processes. All three CALM genes have been classified as Definitive for LQTS and Moderate for CPVT, certain variants are only associated with one or other phenotype, whereas others are associated with a mixed or variable phenotypes.

All variants with evidence of pathogenicity identified in the CALM genes are missense: at least 35 distinct missense variants have been identified and reported in the International Calmodulinopathy Registry including 11 (31%) in CALM1, 16 (46%) in CALM2, and 8 (23%) in CALM3. The majority of variants across the CALM genes affect amino acid residues in the EF-hand Ca2+ binding loop III and IV. Some variants have additional evidence in that the same substitution has been seen in paralogous CALM genes, or that the same substitution has been seen in a related phenotype (LQTS). Most variants are unique, but 9 were present in more than one index case and among these, three (p.Asn98Ser, p.Asp130Gly, and p.Phe142Leu, identified in 10, 5, and 4 families, respectively.) appear to be recurrent. While variants p.Asp130Gly and p.Phe142Leu have always been reported as associated with the LQTS phenotype, the p.Asn98Ser has phenotypic variability, including LQTS, CPVT, idiopathic VF and sudden death. The majority of CALM variants are de novo.

Pathogenic variants in the CALM genes have been associated with: presentation in infancy or early childhood (up to 5 years); marked sinus bradycardia or atrioventricular block and QT prolongation; and, predominantly with CALM1 variants, a mild-to-severe neurological impairment, including seizures, development delay, motor and/or cognitive disability.

The phenotype most frequently shown by patients with CALM variants is LQTS, but some patients display other phenotypes including CPVT, idiopathic VF and sudden unexplained death. Some variants have been associated with both LQTS and CPVT, however Crotti et al (PMID: 31170290) report that ‘despite the relatively small numbers of cases, a significant association (P = 0.001) was observed between location of mutation and phenotype (Supplementary material online, Figure S1). Indeed, a pathogenic variant in EF-hand IV Ca2+ binding loop was found in the majority (17/32, 53%) of CALM-LQTS index cases but in only one of the nine CALM-CPVTs (11%). Conversely, variants identified in CALM-CPVT index cases were mostly located either in EF-hand III (n = 5, 56%), or in the inter-EF hand I-II linker (n = 3, 33%).’

For the ClinGen CPVT curation,CALM2 scored in the moderate range based on four reported variants in patients with CPVT or mixed CPVT/LQT phenotypes (p.Glu46Lys in two de novo cases, p.Asn98Ser and p.Asp132Glu) and associated functional data. However, due to the unique characteristics of the calmodulin genes and their gene-disease associations, it was agreed by the expert panel to include them in this curation. The reasons were: 1) all three genes have already been established as disease-causing for an inherited arrhythmia syndrome (LQTS), 2) there are multiple examples of patients presenting with a phenotype indistinguishable from CPVT for each, either de novo or supported by functional evidence and 3) the genes encode for identical proteins, are all expressed in the heart and equivalent de novo variants in the three genes have been shown to lead to similar phenotypes, highlighting the functional equivalence of these genes.

CALM3 - CPVT - Autosomal dominant¶

Gene symbol	CALM3
Gene mim	114183
Indication	CPVT
Referral indication	Catecholaminergic polymorphic ventricular tachycardia (CPVT)
Disease grouping	Atypical CPVT phenotype
Disease name	CALM3-related Catecholaminergic polymorphic ventricular tachycardia
Gene disease validity (ClinGen)	MODERATE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	Typically de novo
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant
PMIDs	31170290; 31983240; 27516456
Disease accession	MONDO:0017990
Curated date	08.01.2021
Expert panel review date	19.05.2021
Expert panel	Channelopathy expert panel

Narrative

The disease mechanism in CALM3-related CPVT is likely a dominant negative effect caused by altered gene product sequence which reduces the calcium dependent inactivation of the calcium channel CaV1.2, resulting in increased inward calcium channel current (ICaL) and repolarization delay.

The three CALM genes encode an identical 149aa protein, calmodulin. The CALM1 gene is located on chromosome 14, CALM2 on chromosome 2 and CALM3 on chromosome 19. Calmodulin protein is involved in many calcium-dependent intracellular processes. All three CALM genes have been classified as Definitive for LQTS and Moderate for CPVT, certain variants are only associated with one or other phenotype, whereas others are associated with a mixed or variable phenotypes.

All variants with evidence of pathogenicity identified in the CALM genes are missense: at least 35 distinct missense variants have been identified and reported in the International Calmodulinopathy Registry including 11 (31%) in CALM1, 16 (46%) in CALM2, and 8 (23%) in CALM3. The majority of variants across the CALM genes affect amino acid residues in the EF-hand Ca2+ binding loop III and IV. Some variants have additional evidence in that the same substitution has been seen in paralogous CALM genes, or that the same substitution has been seen in a related phenotype (LQTS). Most variants are unique, but 9 were present in more than one index case and among these, three (p.Asn98Ser, p.Asp130Gly, and p.Phe142Leu, identified in 10, 5, and 4 families, respectively.) appear to be recurrent. While variants p.Asp130Gly and p.Phe142Leu have always been reported as associated with the LQTS phenotype, the p.Asn98Ser has phenotypic variability, including LQTS, CPVT, idiopathic VF and sudden death. The majority of CALM variants are de novo.

Pathogenic variants in the CALM genes have been associated with: presentation in infancy or early childhood (up to 5 years); marked sinus bradycardia or atrioventricular block and QT prolongation; and, predominantly with CALM1 variants, a mild-to-severe neurological impairment, including seizures, development delay, motor and/or cognitive disability.

The phenotype most frequently shown by patients with CALM variants is LQTS, but some patients display other phenotypes including CPVT, idiopathic VF and sudden unexplained death. Some variants have been associated with both LQTS and CPVT, however Crotti et al (PMID: 31170290) report that ‘despite the relatively small numbers of cases, a significant association (P = 0.001) was observed between location of mutation and phenotype (Supplementary material online, Figure S1). Indeed, a pathogenic variant in EF-hand IV Ca2+ binding loop was found in the majority (17/32, 53%) of CALM-LQTS index cases but in only one of the nine CALM-CPVTs (11%). Conversely, variants identified in CALM-CPVT index cases were mostly located either in EF-hand III (n = 5, 56%), or in the inter-EF hand I-II linker (n = 3, 33%).’

For the ClinGen CPVT curation, CALM3 scored in the moderate range based on four reported variants in patients with CPVT or mixed CPVT/LQT phenotypes (p.Glu46Lys in two de novo cases, p.Asn98Ser and p.Asp132Glu) and associated functional data. However, due to the unique characteristics of the calmodulin genes and their gene-disease associations, it was agreed by the expert panel to include them in this curation. The reasons were: 1) all three genes have already been established as disease-causing for an inherited arrhythmia syndrome (LQTS), 2) there are multiple examples of patients presenting with a phenotype indistinguishable from CPVT for each, either de novo or supported by functional evidence and 3) the genes encode for identical proteins, are all expressed in the heart and equivalent de novo variants in the three genes have been shown to lead to similar phenotypes, highlighting the functional equivalence of these genes.

TECRL - CPVT - Autosomal recessive¶

Gene symbol	TECRL
Gene mim	617242
Indication	CPVT
Referral indication	Catecholaminergic polymorphic ventricular tachycardia (CPVT)
Disease grouping	Atypical CPVT phenotype
Disease name	TECRL-related Catecholaminergic polymorphic ventricular tachycardia
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	biallelic_autosomal
Inheritance	Autosomal recessive
Inheritance modifiers	NA
Disease-associated variant consequence	absent gene product; altered gene product sequence
Mechanism	loss of function
Mutation consequence flag	restricted repertoire of mutations
Restricted repertoire of pathogenic variants	Exon 2 deletion
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant; stop_gained_NMD_triggering; splice_donor_variant_NMD_triggering; exon_loss_variant
PMIDs	33367594; 30790670; 32173957; 27861123
Disease accession	MONDO:0013529
Curated date	08.01.2021
Expert panel review date	19.05.2021
Expert panel	Channelopathy expert panel

Narrative

Absent gene product level and altered gene product sequence of TECRL is associated with CPVT. The disease mechanism appears to be loss of function.
TECRL is rarely associated with CPVT, but several reports have described biallelic loss of function variants in cases. These include both homozygous and compound heterozygous inheritance, with a variety of variant types described, splice donor variant, stop gained, exon deletion (exon 2), missense variants (including homozygous p.Arg196Gln detected in 2 patients with exome sequencing), and a large duplication encompassing all of the TECRL gene with an uncertain consequence.

These cases presented with phenotypic features typical of CPVT, including exercise and emotion induced syncope and cardiac arrest and ventricular arrhythmias during exercise testing. A mild prolonged QT interval was observed in several cases, especially after stimulation by epinephrine or exercise, although overall the phenotypes are much more typical of CPVT than LQTS.

TRDN - CPVT - Autosomal recessive¶

Gene symbol	TRDN
Gene mim	603283
Indication	CPVT
Referral indication	Catecholaminergic polymorphic ventricular tachycardia (CPVT)
Disease grouping	Atypical CPVT phenotype
Disease name	TRDN-related Catecholaminergic polymorphic ventricular tachycardia
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	biallelic_autosomal
Inheritance	Autosomal recessive
Inheritance modifiers	NA
Disease-associated variant consequence	absent gene product; altered gene product sequence
Mechanism	loss of function
Mutation consequence flag	restricted repertoire of mutations
Restricted repertoire of pathogenic variants	Exon 2 deletion
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant; stop_gained_NMD_triggering; frameshift_variant_NMD_triggering; exon_loss_variant
PMIDs	25922419; 26768964; 22422768; 30479949; 26200674
Disease accession	MONDO:0014191
Curated date	08.01.2021
Expert panel review date	19.05.2021
Expert panel	Channelopathy expert panel

Narrative

Absent gene product level and altered gene product sequence of TRDN is associated with CPVT. The disease mechanism appears to be loss of function.
TRDN is rarely associated with CPVT, but several reports have described biallelic loss of function variants in cases. These include both homozygous and compound heterozygous variants, with a variety of variant types described - stop gained, frameshift, exon deletion (exon 2), intronic variants (with proven effect on splicing) and missense variants (proven to lead to degraded protein).
Biallelic loss of function variants in TRDN have also been associated with LQTS with an atypical presentation (ClinGen: strong evidence). This, ‘triadin knockout syndrome’ can lead to variable phenotypes.

Classic CPVT phenotype¶

CASQ2 - CPVT - Autosomal dominant¶

Gene symbol	CASQ2
Gene mim	114251
Indication	CPVT
Referral indication	Catecholaminergic polymorphic ventricular tachycardia (CPVT)
Disease grouping	Classic CPVT phenotype
Disease name	CASQ2-related Catecholaminergic polymorphic ventricular tachycardia
Gene disease validity (ClinGen)	MODERATE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	Typified by incomplete penetrance
Disease-associated variant consequence	altered gene product sequence; decreased gene product level
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	splice_region_variant; missense_variant; stop_gained_NMD_triggering; splice_donor_variant_NMD_triggering; frameshift_variant_NMD_triggering; splice_acceptor_variant_NMD_triggering
PMIDs	16908766; 32693635; 12386154; 15176429; 21618644; 27157848
Disease accession	MONDO:0012762
Curated date	08.01.2021
Expert panel review date	19.05.2021
Expert panel	Channelopathy expert panel

Narrative

CASQ2 is an established gene for autosomal recessive CPVT (the second most common genetic cause of the disease, responsible for up to 5% of cases).
Recent reports have also associated monoallelic or heterozygous CASQ2 variants with CPVT. Although the evidence for this association is not definitive, available data suggests that disease is likely due to decreased gene product level or altered gene product sequence. The main evidence for autosomal dominant CASQ2 association comes from an international multi-centre study describing CPVT patients with CASQ2 variants (Ng et al, 2020, PMID: 32693635). This study included 12 probands with heterozygous variants in CASQ2, as well as an assessment of heterozygous relatives of probands with homozygous/compound heterozygous CASQ2 variants (8/37 of these heterozygous relatives had a positive CPVT phenotype). While this study provides a substantive body of evidence to support autosomal dominant CASQ2 association with CPVT, the data should be cautiously interpreted. The multi-centre nature of the study precluded standardised phenotyping of the probands and relatives and therefore not every phenotype-positive individual may have a definitive diagnosis of CPVT. Additionally, several of the variants described have a gnomAD population minor allele frequency that is incompatible with being a penetrant autosomal dominant variant for a disease with the prevalence of CPVT (>1x10-5). The variants also included presumed nonsense mediated decay-escaping C-terminal truncating variants and a splice region variant without a proven effect on splicing. In contrast to 97% penetrance for homozygous/compound heterozygous individuals, penetrance for heterozygotes was only 33% although it is expected that the population level penetrance of CASQ2 heterozygous variants will be lower still.
Further support for the pathogenicity of heterozygous CASQ2 variants comes from a study that described the heterozygous p.Lys180Arg variant segregating with disease in a family (the published LOD score was 3.0 although there were only five meioses between genotype and phenotype positive individuals) (Gray et al, 2016, PMID: 27157848).

CASQ2 - CPVT - Autosomal recessive¶

Gene symbol	CASQ2
Gene mim	114251
Indication	CPVT
Referral indication	Catecholaminergic polymorphic ventricular tachycardia (CPVT)
Disease grouping	Classic CPVT phenotype
Disease name	CASQ2-related Catecholaminergic polymorphic ventricular tachycardia
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	biallelic_autosomal
Inheritance	Autosomal recessive
Inheritance modifiers	NA
Disease-associated variant consequence	absent gene product; altered gene product sequence
Mechanism	loss of function
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	splice_region_variant; missense_variant; stop_gained_NMD_triggering; splice_donor_variant_NMD_triggering; frameshift_variant_NMD_triggering; splice_acceptor_variant_NMD_triggering
PMIDs	16908766; 32693635; 12386154; 15176429; 21618644; 27157848
Disease accession	MONDO:0012762
Curated date	08.01.2021
Expert panel review date	19.05.2021
Expert panel	Channelopathy expert panel

Narrative

CASQ2 is an established gene for autosomal recessive CPVT (the second most common genetic cause of the disease, responsible for up to 5% of cases); disease is due to absent gene product level or altered gene product sequence. For the ClinGen curation, the maximum points were achieved with only a small subset of initial genetic and experimental reports leading to a definitive classification.

Biallelic loss-of-function variants in CASQ2 (both homozygous and compound heterozygous) have been reported in numerous CPVT probands, including frameshift, nonsense and splice donor/acceptor variants, as well as other splice region variants with verified effects on splicing, and missense variants with verified loss-of-function effects.

RYR2 - CPVT - Autosomal dominant¶

Gene symbol	RYR2
Gene mim	180902
Indication	CPVT
Referral indication	Catecholaminergic polymorphic ventricular tachycardia (CPVT)
Disease grouping	Classic CPVT phenotype
Disease name	RYR2-related Catecholaminergic polymorphic ventricular tachycardia
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	Typified by incomplete penetrance
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	restricted repertoire of mutations
Restricted repertoire of pathogenic variants	Exon 3 deletion
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant; exon_loss_variant
PMIDs	31112425; 30696458; 11208676; 24394973; 17081562; 12093772; 17875969; 29453246; 19216760; 23479668; 26018045
Disease accession	MONDO:0017990
Curated date	08.01.2021
Expert panel review date	19.05.2021
Expert panel	Channelopathy expert panel

Narrative

RYR2 is associated with CPVT with autosomal dominant inheritance. The allelic requirement for pathogenicity is monoallelic autosomal, and the disease is typified by incomplete penetrance. Disease is due to an altered gene product sequence.

The first reports of RYR2 variants in CPVT included numerous examples of de novo inheritance (Priori et al, 2001, PMID: 11208676; Priori et al, 2002, PMID: 12093772), although RYR2 missense variants often occur through familial autosomal dominant inheritance.

The predicted functional consequence of RYR2 pathogenic variants is altered gene product sequence. The majority of causative RYR2 variants in CPVT patients are heterozygous missense variants which are detected in up to 60% of cases with a definitive CPVT diagnosis (Kapplinger et al, 2018, PMID: 29453246) and act through a gain-of-function mechanism. Pathogenic variants in CPVT cases tend to be clustered in a number of regions in the RYR2 gene/protein:
- Original exon hotspots: 3-15, 44-50, 83-90 and 93-105 (George et al, 2007, PMID: 17081562).
- Updated exon hotspots: 3, 8, 14, 43, 47-49, 81, 83, 88-90, 93, 95, 97-101, 103, 105 (Kapplinger et al, 2018, PMID: 29453246).
- Hotspots based on unsupervised clustering algorithm (not restricted to exon boundaries): amino acid residues 2138-2538, 3935-4196 and 4721-4959 (Walsh et al, 2019, PMID: 30696458).

Rare cases of whole exon deletions of RYR2 exon 3 have been described that can lead to a CPVT and/or left ventricular non-compaction phenotype (Bhuiyan et al, 2007, PMID: 17875969; Marjamaa et al, 2009, PMID: 19216760; Szentpali et al, 2013, PMID: 23479668; Onho et al, 2014, PMID: 24394973; Campbell et al, 2015, PMID: 26018045; Mazzarotto et al, 2021, PMID: 33500567).

Long QT Syndrome (LQTS)¶

Familial Long QT Syndrome¶

KCNH2 - LQTS - Autosomal dominant¶

Gene symbol	KCNH2
Gene mim	152427
Indication	LQTS
Referral indication	Long QT Syndrome (LQTS)
Disease grouping	Familial Long QT Syndrome
Disease name	KCNH2-related Long QT syndrome
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	Typified by incomplete penetrance
Disease-associated variant consequence	altered gene product sequence; decreased gene product level
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	splice_acceptor_variant; splice_donor_variant; frameshift_variant; stop_gained; missense_variant; inframe_deletion; inframe_insertion; stop_gained_NMD_triggering; frameshift_variant_NMD_triggering; exon_loss_variant; duplication
PMIDs	21185501; 18774102; 22995932; 10841244; 27262388; 29504689; 19841300; 31983240; 24932360; 15840476; 25417810; 26320108; 19926013; 21185499; 29650123; 32893267; 27761161; 10491368; 12621127; 21787999; 19716085; 9927399
Disease accession	MONDO:0013367
Curated date	14.10.2020
Expert panel review date	16.06.2021
Expert panel	Channelopathy expert panel

Narrative

KCNH2-related LQTS is due to decreased gene product level or altered gene product sequence. The disease mechanism is loss of function due to a variety of mechanisms including disruption of synthesis of channel subunits, reduction in intracellular transport or trafficking, defects in ion permeation or channel gating.

Both haploinsufficiency and a dominant negative effect are proposed mechanisms causing loss of function of KCNH2. About 60% of LQT2 mutations are missense variants, the remaining 40% are nonsense, frameshift, insertions, deletions, duplications (intragenic tandem duplication), or involve a splice site.

KCNH2 variants account for approximately 30% of LQTS cases (PMID: 24932360).
Walsh et al showed that non truncating variants in KCNH2 are enriched in ion channel transmembrane regions and specific N-terminus and C-terminus domains and have >95% probability of pathogenicity (PMID: 32893267).
Shimizu et al report correlations between specific variant types and location and clinical phenotype (PMID: 19926013). Patients with missense variants in the transmembrane pore region have significantly higher cardiac event rates than those with missense variants in either N-terminus, transmembrane non-pore, or C-terminus regions.

It has been noted that approximately 10% of genotype positive LQT patients have more than 1 pathogenic variant in >=1 gene. Biallelic pathogenic variants or digenic pathogenic variants appear to be generally associated with a more severe phenotype with longer QTc interval and a higher incidence of cardiac events.

KCNQ1 - LQTS - Autosomal dominant¶

Gene symbol	KCNQ1
Gene mim	607542
Indication	LQTS
Referral indication	Long QT Syndrome (LQTS)
Disease grouping	Familial Long QT Syndrome
Disease name	KCNQ1-related Long QT syndrome
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	Typified by incomplete penetrance
Disease-associated variant consequence	altered gene product sequence; decreased gene product level
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	splice_acceptor_variant; splice_donor_variant; frameshift_variant; stop_gained; missense_variant; inframe_deletion; inframe_insertion; stop_gained_NMD_triggering; frameshift_variant_NMD_triggering; exon_loss_variant; tandem_duplication
PMIDs	27041150; 23591039; 9020846; 27868350; 23392653; 31983240; 11226272; 25187895
Disease accession	MONDO:0100316
Curated date	01.11.2020
Expert panel review date	16.06.2021
Expert panel	Channelopathy expert panel

Narrative

Pathogenic variants in KCNQ1 cause LQTS due to decreased gene product level or altered gene product sequence. This leads to loss of function due to a variety of mechanisms including defects in ion permeation, channel gating and trafficking.
KCNQ1 variants account for approx. 30%-45% of LQTS cases (PMID: 22456477; 21787999; 27262388; 29504689).

KCNQ1-related LQTS is typically inherited as an autosomal dominant trait characterised by incomplete penetrance. Rarely biallelic KCNQ1 variants can cause autosomal recessive LQTS or Jervell and Lange-Nielsen syndrome (JLNS) (severe cardiac phenotype and sensorineural hearing loss). JLNS results when there is complete absence of IKs (slowly activating delayed rectifier potassium channel/current) (PMID: 23591039).

It has been noted that approximately 10% of genotype positive LQT patients have more than 1 pathogenic variant in >=1 LQTS-related gene (PMID: 15840476; 19716085). Biallelic disease appears to be more penetrant with a more severe phenotype.

Missense variants are responsible for the majority of KCNQ1-related LQTS cases although truncating variants including nonsense, frameshift, splice site and structural variants (multi exon deletions and a multi exon duplication (inframe tandem repeat of exons 3-6, leading to duplication of the second to fifth transmembrane domains of the channel)) are also reported (PMID: 19716085; 18774102; 25174857).

ClinGen have concluded there is sufficient evidence for haploinsufficiency. Variants conferring a dominant negative effect have also been described. Moss et al (PMID: 17470695) reported that dominant-negative variants are associated with a more severe phenotype than variants conferring haploinsufficiency.

Phenotypes can differ according to regionality with some regions associated with more malignant phenotypes e.g. C-loop variants are associated with higher risk of sudden cardiac death (PMID: 22456477). In addition, there are gene regions where there is a high confidence for pathogenicity e.g. transmembrane regions and C-terminus domains (PMID: 32893267; 19841300).

KCNQ1 - LQTS - Autosomal recessive¶

Gene symbol	KCNQ1
Gene mim	607542
Indication	LQTS
Referral indication	Long QT Syndrome (LQTS)
Disease grouping	Familial Long QT Syndrome
Disease name	KCNQ1-related Long QT syndrome
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	biallelic_autosomal
Inheritance	Autosomal recessive
Inheritance modifiers	Typified by incomplete penetrance
Disease-associated variant consequence	altered gene product sequence; decreased gene product level
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	splice_acceptor_variant; splice_donor_variant; frameshift_variant; stop_gained; missense_variant; inframe_deletion; inframe_insertion; stop_gained_NMD_triggering; frameshift_variant_NMD_triggering; exon_loss_variant; tandem_duplication
PMIDs	27041150; 23591039; 9020846; 27868350; 23392653; 31983240; 11226272; 25187895
Disease accession	MONDO:0100316
Curated date	01.11.2020
Expert panel review date	16.06.2021
Expert panel	Channelopathy expert panel

Narrative

Pathogenic variants in KCNQ1 cause LQTS due to decreased gene product level or altered gene product sequence. This leads to loss of function due to a variety of mechanisms including defects in ion permeation, channel gating and trafficking.
KCNQ1 variants account for approx. 30%-45% of LQTS cases (PMID: 22456477; 21787999; 27262388; 29504689).

KCNQ1-related LQTS is typically inherited as an autosomal dominant trait characterised by incomplete penetrance. Rarely biallelic KCNQ1 variants can cause autosomal recessive LQTS or Jervell and Lange-Nielsen syndrome (JLNS) (severe cardiac phenotype and sensorineural hearing loss). JLNS results when there is complete absence of IKs (slowly activating delayed rectifier potassium channel/current) (PMID: 23591039).

It has been noted that approximately 10% of genotype positive LQT patients have more than 1 pathogenic variant in >=1 LQTS-related gene (PMID: 15840476; 19716085). Biallelic disease appears to be more penetrant with a more severe phenotype.

Missense variants are responsible for the majority of KCNQ1-related LQTS cases although truncating variants including nonsense, frameshift, splice site and structural variants (multi exon deletions and a multi exon duplication (inframe tandem repeat of exons 3-6, leading to duplication of the second to fifth transmembrane domains of the channel)) are also reported (PMID: 19716085; 18774102; 25174857).

ClinGen have concluded there is sufficient evidence for haploinsufficiency. Variants conferring a dominant negative effect have also been described. Moss et al (PMID: 17470695) reported that dominant-negative variants are associated with a more severe phenotype than variants conferring haploinsufficiency.

Phenotypes can differ according to regionality with some regions associated with more malignant phenotypes e.g. C-loop variants are associated with higher risk of sudden cardiac death (PMID: 22456477). In addition, there are gene regions where there is a high confidence for pathogenicity e.g. transmembrane regions and C-terminus domains (PMID: 32893267; 19841300).

SCN5A - LQTS - Autosomal dominant¶

Gene symbol	SCN5A
Gene mim	600163
Indication	LQTS
Referral indication	Long QT Syndrome (LQTS)
Disease grouping	Familial Long QT Syndrome
Disease name	SCN5A-related Long QT syndrome
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	Typified by incomplete penetrance
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant; inframe_deletion; inframe_insertion
PMIDs	21185501; 15840476; 27566755; 26320108; 22995932; 7889574; 29650123; 31983240; 32893267; 11463728; 29798782; 21787999; 9927399; 29806494; 19716085
Disease accession	MONDO:0011377
Curated date	14.10.2020
Expert panel review date	16.06.2021
Expert panel	Channelopathy expert panel

Narrative

Altered gene product sequence of SCN5A causes long QT syndrome. The likely disease mechanism is gain of function.
Over 200 pathogenic missense variants and inframe deletions or insertions have been reported. The sodium current mediated by Nav1.5 consists of peak and late components (INa-P and INa-L). It is thought that gain-of-function SCN5A pathogenic variants lead to enhanced INa-P and INa-L, which can trigger life-threating arrhythmias.
SCN5A-related LQTS accounts for 5-10% of LQTS cases (PMID: 27566755).
Rare missense variants are estimated to occur in around 2% of healthy White and 5% of healthy non-White subjects so collectively missense variants are not rare in the healthy population.

SCN5A-related LQTS can present with specific features: patients may have marked resting bradycardia, QT interval prolongation more pronounced during slow heart rate (which might explain why arrhythmic events occur more frequently at rest), a first cardiac event that is lethal, and onset after puberty (PMID: 29798782).

It has been noted that approximately 10% of genotype positive LQT patients have more than 1 mutation in >=1 gene. Biallelic pathogenic variants or digenic pathogenic variants appear to be generally associated with a more severe phenotype with longer QTc interval and a higher incidence of cardiac events.

Note: loss of function variants in SCN5A are associated with Brugada syndrome and individual variants can have hybrid loss of function and gain of function effects causing a mixed phenotype.

CACNA1C - LQTS - Autosomal dominant¶

Gene symbol	CACNA1C
Gene mim	114205
Indication	LQTS
Referral indication	Long QT Syndrome (LQTS)
Disease grouping	Familial Long QT Syndrome
Disease name	CACNA1C-related Long QT syndrome
Gene disease validity (ClinGen)	MODERATE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	NA
Disease-associated variant consequence	NA
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	NA
PMIDs	NA
Disease accession	NA
Curated date	NA
Expert panel review date	NA
Expert panel	NA

Narrative

The gene disease validity assertion is ‘moderate’ from ClinGen. No inheritance or mechanism curations have been done in the absence of an established gene disease relationship.

Long QT syndrome with an atypical presentation¶

CALM1 - LQTS - Autosomal dominant¶

Gene symbol	CALM1
Gene mim	114180
Indication	LQTS
Referral indication	Long QT Syndrome (LQTS)
Disease grouping	Long QT syndrome with an atypical presentation
Disease name	CALM1-related Long QT syndrome
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	Typically de novo
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant
PMIDs	31170290; 31983240; 23388215; 26969752
Disease accession	MONDO:0014548
Curated date	14.10.2020
Expert panel review date	16.06.2021
Expert panel	Channelopathy expert panel

Narrative

CALM1-related LQTS is caused by an altered gene product sequence. Reduction in the calcium dependent inactivation of the calcium channel CaV1.2 results in increased inward calcium channel current (ICaL) and repolarization delay. The disease mechanism is likely a dominant negative effect.

The three CALM genes encode an identical 149aa protein, calmodulin. The CALM1 gene is located on chromosome 14, CALM2 on chromosome 2 and CALM3 on chromosome 19. Calmodulin protein is involved in many calcium-dependent intracellular processes. All three CALM genes have been classified as Definitive for LQTS and Moderate for CPVT, certain variants are only associated with one or other phenotype, whereas others are associated with a mixed or variable phenotypes.

All variants with evidence of pathogenicity identified in the CALM genes are missense: at least 35 distinct missense variants have been identified and reported in the International Calmodulinopathy Registry including 11 (31%) in CALM1, 16 (46%) in CALM2, and 8 (23%) in CALM3. The majority of variants across the CALM genes affect amino acid residues in the EF-hand Ca2+ binding loop III and IV. Some variants have additional evidence in that the same substitution has been seen in paralogous CALM genes, or that the same substitution has been seen in a related phenotype (LQTS). Most variants are unique, but 9 were present in more than one index case and among these, three (p.Asn98Ser, p.Asp130Gly, and p.Phe142Leu, identified in 10, 5, and 4 families, respectively.) appear to be recurrent. While variants p.Asp130Gly and p.Phe142Leu have always been reported as associated with the LQTS phenotype, the variant p.Asn98Ser has phenotypic variability, including LQTS, CPVT, idiopathic VF and sudden death. The majority of CALM variants are de novo.

Pathogenic variants in the CALM genes have been associated with: presentation in infancy or early childhood (up to 5 years); marked sinus bradycardia or atrioventricular block and QT prolongation; and, predominantly with CALM1 variants, a mild-to-severe neurological impairment, including seizures, development delay, motor and/or cognitive disability.

The phenotype most frequently shown by patients with CALM variants is LQTS, but some patients display other phenotypes including CPVT, idiopathic VF and sudden unexplained death. Some variants have been associated with both LQTS and CPVT, however Crotti et al (PMID: 31170290) report that ‘despite the relatively small numbers of cases, a significant association (P = 0.001) was observed between location of mutation and phenotype (Supplementary material online, Figure S1). Indeed, a pathogenic variant in EF-hand IV Ca2+ binding loop was found in the majority (17/32, 53%) of CALM-LQTS index cases but in only one of the nine CALM-CPVTs (11%). Conversely, variants identified in CALM-CPVT index cases were mostly located either in EF-hand III (n = 5, 56%), or in the inter-EF hand I-II linker (n = 3, 33%).’

CALM2 - LQTS - Autosomal dominant¶

Gene symbol	CALM2
Gene mim	114182
Indication	LQTS
Referral indication	Long QT Syndrome (LQTS)
Disease grouping	Long QT syndrome with an atypical presentation
Disease name	CALM2-related Long QT syndrome
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	Typically de novo
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant
PMIDs	31170290; 27765793; 31983240; 23388215; 26969752
Disease accession	MONDO:0014550
Curated date	14.10.2020
Expert panel review date	16.06.2021
Expert panel	Channelopathy expert panel

Narrative

CALM2-related LQTS is caused by analtered gene product sequence which reduces the calcium dependent inactivation of the calcium channel CaV1.2, resulting in increased inward calcium channel current (ICaL) and repolarization delay. The disease mechanism is likely a dominant negative effect.

The three CALM genes encode an identical 149aa protein, calmodulin. The CALM1 gene is located on chromosome 14, CALM2 on chromosome 2 and CALM3 on chromosome 19. Calmodulin protein is involved in many calcium-dependent intracellular processes. All three CALM genes have been classified as Definitive for LQTS and Moderate for CPVT, certain variants are only associated with one or other phenotype, whereas others are associated with a mixed or variable phenotypes.

All variants with evidence of pathogenicity identified in the CALM genes are missense: at least 35 distinct missense variants have been identified and reported in the International Calmodulinopathy Registry including 11 (31%) in CALM1, 16 (46%) in CALM2, and 8 (23%) in CALM3. The majority of variants across the CALM genes affect amino acid residues in the EF-hand Ca2+ binding loop III and IV. Some variants have additional evidence in that the same substitution has been seen in paralogous CALM genes, or that the same substitution has been seen in a related phenotype (LQTS). Most variants are unique, but 9 were present in more than one index case and among these, three (p.Asn98Ser, p.Asp130Gly, and p.Phe142Leu, identified in 10, 5, and 4 families, respectively.) appear to be recurrent. While variants p.Asp130Gly and p.Phe142Leu have always been reported as associated with the LQTS phenotype, the variant p.Asn98Ser has phenotypic variability, including LQTS, CPVT, idiopathic VF and sudden death. The majority of CALM variants are de novo.

Pathogenic variants in the CALM genes have been associated with: presentation in infancy or early childhood (up to 5 years); marked sinus bradycardia or atrioventricular block and QT prolongation; and, predominantly with CALM1 variants, a mild-to-severe neurological impairment, including seizures, development delay, motor and/or cognitive disability.

The phenotype most frequently shown by patients with CALM variants is LQTS, but some patients display other phenotypes including CPVT, idiopathic VF and sudden unexplained death. Some variants have been associated with both LQTS and CPVT, however Crotti et al (PMID: 31170290) report that ‘despite the relatively small numbers of cases, a significant association (P = 0.001) was observed between location of mutation and phenotype (Supplementary material online, Figure S1). Indeed, a pathogenic variant in EF-hand IV Ca2+ binding loop was found in the majority (17/32, 53%) of CALM-LQTS index cases but in only one of the nine CALM-CPVTs (11%). Conversely, variants identified in CALM-CPVT index cases were mostly located either in EF-hand III (n = 5, 56%), or in the inter-EF hand I-II linker (n = 3, 33%).’

CALM3 - LQTS - Autosomal dominant¶

Gene symbol	CALM3
Gene mim	114183
Indication	LQTS
Referral indication	Long QT Syndrome (LQTS)
Disease grouping	Long QT syndrome with an atypical presentation
Disease name	CALM3-related Long QT syndrome
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	Typically de novo
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant
PMIDs	31170290; 31983240; 23388215; 26969752
Disease accession	MONDO:0019171
Curated date	14.10.2020
Expert panel review date	16.06.2021
Expert panel	Channelopathy expert panel

Narrative

For LQTS, CALM3 variants lead to an altered gene product sequence. The disease mechanism is likely a dominant negative effect which reduces the calcium dependent inactivation of the calcium channel CaV1.2, resulting in increased inward calcium channel current (ICaL) and repolarization delay.

The three CALM genes encode an identical 149aa protein, calmodulin. The CALM1 gene is located on chromosome 14, CALM2 on chromosome 2 and CALM3 on chromosome 19. Calmodulin protein is involved in many calcium-dependent intracellular processes. All three CALM genes have been classified as Definitive for LQTS and Moderate for CPVT, certain variants are only associated with one or other phenotype, whereas others are associated with a mixed or variable phenotypes.

All variants with evidence of pathogenicity identified in the CALM genes are missense: at least 35 distinct missense variants have been identified and reported in the International Calmodulinopathy Registry including 11 (31%) in CALM1, 16 (46%) in CALM2, and 8 (23%) in CALM3. The majority of variants across the CALM genes affect amino acid residues in the EF-hand Ca2+ binding loop III and IV. Some variants have additional evidence in that the same substitution has been seen in paralogous CALM genes, or that the same substitution has been seen in a related phenotype (LQTS). Most variants are unique, but 9 were present in more than one index case and among these, three (p.Asn98Ser, p.Asp130Gly, and p.Phe142Leu, identified in 10, 5, and 4 families, respectively.) appear to be recurrent. While variants p.Asp130Gly and p.Phe142Leu have always been reported as associated with the LQTS phenotype, the variant p.Asn98Ser has phenotypic variability, including LQTS, CPVT, idiopathic VF and sudden death. The majority of CALM variants are de novo.

Pathogenic variants in the CALM genes have been associated with: presentation in infancy or early childhood (up to 5 years); marked sinus bradycardia or atrioventricular block and QT prolongation; and, predominantly with CALM1 variants, a mild-to-severe neurological impairment, including seizures, development delay, motor and/or cognitive disability.

The phenotype most frequently shown by patients with CALM variants is LQTS, but some patients display other phenotypes including CPVT, idiopathic VF and sudden unexplained death. Some variants have been associated with both LQTS and CPVT, however Crotti et al (PMID: 31170290) report that ‘despite the relatively small numbers of cases, a significant association (P = 0.001) was observed between location of mutation and phenotype (Supplementary material online, Figure S1). Indeed, a pathogenic variant in EF-hand IV Ca2+ binding loop was found in the majority (17/32, 53%) of CALM-LQTS index cases but in only one of the nine CALM-CPVTs (11%). Conversely, variants identified in CALM-CPVT index cases were mostly located either in EF-hand III (n = 5, 56%), or in the inter-EF hand I-II linker (n = 3, 33%).’

TRDN - LQTS - Autosomal recessive¶

Gene symbol	TRDN
Gene mim	603283
Indication	LQTS
Referral indication	Long QT Syndrome (LQTS)
Disease grouping	Long QT syndrome with an atypical presentation
Disease name	TRDN-related Long QT syndrome
Gene disease validity (ClinGen)	STRONG
Allelic requirement	biallelic_autosomal
Inheritance	Autosomal recessive
Inheritance modifiers	NA
Disease-associated variant consequence	absent gene product
Mechanism	loss of function
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	frameshift_variant_NMD_triggering
PMIDs	30649896; 22422768; 32402482; 25922419; 26768964; 31983240; 30479949; 31437535; 26200674
Disease accession	MONDO:0019171
Curated date	04.11..2020
Expert panel review date	16.06.2021
Expert panel	Channelopathy expert panel

Narrative

TRDN-related LQTS is due to an absent gene product level. The disease mechanism is loss of function (LoF).
TRDN is rarely associated with LQTS with an atypical presentation. Following identification of a homozygous frameshift variant in TRDN, 4 other patients with homozygous or compound heterozygous frameshift variants were identified in a cohort of 33 unrelated genotype-negative LQTS patients.
The atypical LQTS phenotype described: extensive T-wave inversions in precordial leads V1 through V4, persistent or transient QT prolongation and severe disease expression of exercise-induced cardiac arrest in early childhood (less than or equal to 3 years of age).

Biallelic loss of function variants in TRDN have also been associated with catecholaminergic polymorphic ventricular tachycardia (CPVT). As patients can have overlapping phenotypes, there is a term ‘triadin knockout syndrome’. The Triadin Knock Out Syndrome (TKOS) registry had 21 patients in 2019. All were homozygous or compound heterozygous for TRDN variants. The majority were frameshift or nonsense. There were a small number of missense or splice altering variants.
TRDN is expressed in both cardiac and skeletal muscle and undergoes extensive alternative splicing to produce several isoforms. Only biallelic LoF variants affecting cardiac isoforms should be considered as pathogenic for LQTS.

Syndromic QT prolongation and cardiac arrhythmias¶

CACNA1C - LQTS - Autosomal dominant¶

Gene symbol	CACNA1C
Gene mim	114205
Indication	LQTS
Referral indication	Long QT Syndrome (LQTS)
Disease grouping	Syndromic QT prolongation and cardiac arrhythmias
Disease name	CACNA1C-related Timothy syndrome
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	Typically de novo
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	restricted repertoire of mutations; activating
Restricted repertoire of pathogenic variants	A recurrent, de novo missense_variant causing Classic Timothy Syndrome has been described: NM_001167623.2(CACNA1C):c.1216G\>C (p.Gly406Arg)
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant
PMIDs	15863612; 15454078; 22106044; 26253506; 4728418; 31983240; NBK1403; 30681346; 33797204; 16360093
Disease accession	MONDO:0010979
Curated date	11.11.2020
Expert panel review date	16.06.2021
Expert panel	Channelopathy expert panel

Narrative

CACNA1C-related Timothy syndrome is caused by variants leading to altered gene product sequence. A recurrent, de novo, missense variant in CACNA1C was described in 13 Timothy syndrome patients, p.Gly406Arg in exon 8A (PMID 15454078; 15863612). The disease mechanism appears to be gain-of-function through failed channel inactivation.

Classic Timothy syndrome (TS1) is a very rare multisystem disorder characterized by marked QT prolongation, syndactyly, immune deficiency, seizures, congenital heart defects, cognitive abnormalities, learning difficulties, and intermittent hypoglycaemia (PMID: 28211989).

CACNA1C has a complex genomic structure that undergoes extensive alternative splicing. Splawski et al identified 2 patients with de novo missense variants in exon 8 of an alternate splice form (p.Gly406Arg, analogous to the exon 8a variant, and p.Gly402Ser). This splice form represents 80% of all cardiac mRNAs. The patients were described as having atypical Timothy syndrome (TS2), presenting with a more severe cardiac phenotype and without syndactyly (PMID: 15863612; 25633834).
Other missense variants in CACNA1C have been reported in association with isolated LQTS (PMID: 26253506; 25633834; 24728418). However as of 2020, the ClinGen Cardiovascular Domain Working Group have classified the strength of evidence supporting an association between CACNA1C and LQTS as moderate (PMID: 31983240).

KCNE1 - LQTS - Autosomal recessive¶

Gene symbol	KCNE1
Gene mim	176261
Indication	LQTS
Referral indication	Long QT Syndrome (LQTS)
Disease grouping	Syndromic QT prolongation and cardiac arrhythmias
Disease name	KCNE1-related Jervell and Lange-Nielsen syndrome 2
Gene disease validity (ClinGen)	MODERATE
Allelic requirement	biallelic_autosomal
Inheritance	Autosomal recessive
Inheritance modifiers	NA
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant; inframe_deletion; inframe_insertion; stop_gained_NMD_escaping
PMIDs	30461122; 9354783; NBK1405; 31941373; 9445165; 9328483; 10973849; 19716085; 16461811
Disease accession	MONDO:0012871
Curated date	01.08.2021
Expert panel review date	30.08.2021
Expert panel	Channelopathy expert panel

Narrative

KCNE1-related JLNS is due to altered gene product sequence. Inheritance is autosomal recessive. Homozygous or compound heterozygous KCNE1 variants cause JLNS through loss of function (PMID: 9354783). The majority of JLNS patients have biallelic KCNQ1 variants (JLNS1), only a minority have JLNS2 caused by biallelic KCNE1 variants (PMID: 16461811).
The KCNE1 protein (previous names LQT5, mink, IsK) functions as a regulatory subunit of KCNQ1. It has 7 annotated exons but only one is protein coding (PMID: 30461122).

A small number of variants have been reported, mainly missense and inframe indels. In more recent studies, 4 nonsense variants have also been reported (PMID: 30461122; 31941373). However, in one of these studies (PMID: 30461122), patients were ascertained for deafness and QT prolongation is either variable or not reported in some family members. The authors did not carry out functional studies to determine the effect of these variants on mRNA but suggest that given there is only one coding exon, these nonsense variants would be unlikely to result in nonsense mediated decay.
The phenotype of KCNE1-related JLNS2 appears to be milder than JLNS1 (caused by biallelic KCNQ1 variants) (PMID: 16461811; 31941373)
Heterozygous variants in KCNE1 have been associated with LQT syndrome without deafness. However, Roberts et al observed a low ECG penetrance in these individuals with the majority not manifesting clinically (PMID: 31941373).
ClinGen classified the gene disease association, KCNE1 and JLNS2, as Moderate stating that although there was a large amount of experimental evidence and no contradictory evidence, more case level evidence was required to reach a Definitive classification.

KCNJ2 - LQTS - Autosomal dominant¶

Gene symbol	KCNJ2
Gene mim	600681
Indication	LQTS
Referral indication	Long QT Syndrome (LQTS)
Disease grouping	Syndromic QT prolongation and cardiac arrhythmias
Disease name	KCNJ2-related Andersen-related Tawil syndrome
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	NA
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant; inframe_deletion; inframe_insertion; stop_gained_NMD_escaping
PMIDs	12163457; 16217063; 11371347; 32299589; 21493816; 31983240; 21148745; 32947483; 32499698; 32843460
Disease accession	MONDO:0008222
Curated date	01.05.2021
Expert panel review date	16.06.2021
Expert panel	Channelopathy expert panel

Narrative

KCNJ2 pathogenic variants cause Andersen Tawil syndrome (ATS) through altered gene product sequence. Most of the pathogenic variants cause Kir2.1 (inwardly-rectifying potassium channel) loss-of-function, either via trafficking or gating defects.
Kir2.1, encoded by KCNJ2, contributes a major component of the cardiac action potential repolarization phase. Pathogenic variants of KCNJ2 gene account for 60-70% of clinical ATS cases, termed type-1 ATS.

The cardiac manifestation includes QT-U abnormalities but not typical QT prolongation. Ventricular arrhythmias also differ from typical LQTS with frequent premature ventricular complexes and polymorphic non-sustained ventricular tachycardia but only rarely torsades de pointes. Extracardiac manifestations include dysmorphic features and periodic paralysis with hypo- and hyperkalemic episodes in some patients.

The majority of pathogenic variants in KCNJ2 are missense changes. A small number of inframe deletions, insertions and stop gained variants predicted to escape nonsense mediated decay (NMD) have also been reported in this single-exon gene.
The p.Arg218Trp pathogenic variant is considered a potential mutational hot spot (Davies et al 2005 PMID: 16217063).
Penetrance in families appears high, with estimates of greater or equal to 80%.

KCNQ1 - LQTS - Autosomal recessive¶

Gene symbol	KCNQ1
Gene mim	607542
Indication	LQTS
Referral indication	Long QT Syndrome (LQTS)
Disease grouping	Syndromic QT prolongation and cardiac arrhythmias
Disease name	KCNQ1-related Jervell and Lange-Nielsen syndrome
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	biallelic_autosomal
Inheritance	Autosomal recessive
Inheritance modifiers	NA
Disease-associated variant consequence	absent gene product; altered gene product sequence
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	splice_acceptor_variant; splice_donor_variant; frameshift_variant; stop_gained; missense_variant; stop_gained_NMD_triggering; frameshift_variant_NMD_triggering; exon_loss_variant; complex_structural_alteration
PMIDs	27041150; 23591039; 9020846; 27868350; 23392653; 31983240; 11226272; 25187895
Disease accession	MONDO:0024540
Curated date	01.05.2021
Expert panel review date	16.06.2021
Expert panel	Channelopathy expert panel

Narrative

Biallelic pathogenic variants in KCNQ1 cause JLNS due to absent gene product level or altered gene product sequence.
Both homozygous and compound heterozygous pathogenic variants in KCNQ1 have been reported in JLNS. Nonsense, frameshift, splice site, whole exon deletions, missense variants and complex rearrangements have been reported as pathogenic.

Bhuiyan and Wilde (PMID: 23591039) compared two groups of patients with homozygous variants in KCNQ1. Those patients where there was residual IKs (slowly activating delayed rectifier potassium channel/current) even as little as 10%, had QT prolongation but no hearing loss (autosomal recessive LQTS), whereas those patients with complete absence of IKs had both QT prolongation and hearing loss (JLNS).
They concluded that homozygous or compound heterozygous nonsense, frameshift or exon skipping variants resulting in 100% loss of IKs would result in JLNS. In addition, biallelic missense mutations that lead to a protein product that does not traffic to the cell membrane (or is subject to nonsense mediated decay) will lead to JLNS.
Note: heterozygous variants in KCNQ1 lead to dominant LQTS.

Short QT Syndrome (SQTS)¶

Classic SQTS¶

KCNH2 - SQTS - Autosomal dominant¶

Gene symbol	KCNH2
Gene mim	152427
Indication	SQTS
Referral indication	Short QT Syndrome (SQTS)
Disease grouping	Classic SQTS
Disease name	KCNH2-related Short QT syndrome
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	NA
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant
PMIDs	29876509; 21130771; 30582453; 30175559; 29759541; 29016797; 9547387; 18692916; 14676148; 25974115; 7889573; 30947366; 30496390; 19088443; 30571592; 7736582; 29574456; 21310316; 15673388; 15828882; 31049424; 28491588; 25335996; 19340359; 31072576
Disease accession	MONDO:0012312
Curated date	21.07.2021
Expert panel review date	21.07.2021
Expert panel	Channelopathy expert panel

Narrative

SQTS is a rare (\< 1/10,000) AD inherited arrhythmia syndrome associated with atrial fibrillation, ventricular arrhythmia, and risk of sudden cardiac arrest. Diagnosis is based on a diagnostic scorecard (PMID: 21310316), similar to LQTS. Approximately 20% of diagnosed cases will have a genetic cause, and KCNH2 is the most common identified gene.
It is noteworthy that of the 18 probands with SQTS in whom KCNH2 variants have been identified, 13 had one of 2 variants; 7 with p.Thr618Ile variant (ClinVar Variation ID# 67297) and 6 with p.Asn588Lys (ClinVar Variation ID# 14436; NM_172056.2). There is high penetrance for these recurrent variants.
Experimental evidence derived from non-patient cells, human-induced pluripotent stem cell-derived cells and a rabbit animal model (PMID: 30496390) all support this gene’s relationship with SQTS, with a gain-of-function mechanism. These experimental studies demonstrate that genetic variants identified in SQTS patients lead to potassium current perturbations concordant with SQTS phenotype and shortening of the QT interval.

Note loss-of-function variants in KCNH2 are associated with Long QT Syndrome (LQTS).

KCNJ2 - SQTS - Autosomal dominant¶

Gene symbol	KCNJ2
Gene mim	600681
Indication	SQTS
Referral indication	Short QT Syndrome (SQTS)
Disease grouping	Classic SQTS
Disease name	KCNJ2 relared Short QT syndrome
Gene disease validity (ClinGen)	MODERATE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	NA
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant
PMIDs	19710529; 23440193; 24794859; 11410627; 15761194; 22155372; 29615871; 19285083; 2479485
Disease accession	MONDO:0012314
Curated date	21.07.2021
Expert panel review date	21.07.2021
Expert panel	Channelopathy expert panel

Narrative

Genetic variants in KCNJ2 have been identified in 6 patients from 5 families with unique variants, including at least 2 probands with a de-novo variant (paternity not confirmed). Experimental evidence demonstrated these variants lead to gain-of-function of the late repolarizing, KCNJ2-encoded Ik1 current in the heart, and abbreviation of the action potential duration. The ClinGen GCEP reviewing gene-disease validity considered these data sufficient for classifying the gene-disease relationship of KCNJ2 as ‘Moderate’ but, in the absence of segregation or case-control data, the genetic evidence was not sufficient for a stronger classification. Further information on ClinGen gene-disease validity can be found here: https://search.clinicalgenome.org/kb/genes/HGNC:6263

KCNQ1 - SQTS - Autosomal dominant¶

Gene symbol	KCNQ1
Gene mim	607542
Indication	SQTS
Referral indication	Short QT Syndrome (SQTS)
Disease grouping	Classic SQTS
Disease name	KCNQ1-related Short QT syndrome
Gene disease validity (ClinGen)	STRONG
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	NA
Disease-associated variant consequence	altered gene product sequence
Mechanism	gain of function
Mutation consequence flag	restricted repertoire of mutations
Restricted repertoire of pathogenic variants	Almost all evidence derived from: NM_000218.3(KCNQ1):c.421G\>A (p.Val141Met); NM_000218.3(KCNQ1):c.919G\>C (p.Val307Leu)
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant
PMIDs	28491751; 16109388; 24380499; 26279191; 29213224; 15159330; 26168993; 25974115; 8900283; 28491547; 26346102; 8528244
Disease accession	MONDO:0012313
Curated date	21.07.2021
Expert panel review date	21.07.2021
Expert panel	Channelopathy expert panel

Narrative

Almost all evidence for KCNQ1 as a cause of SQTS is derived from a single variant (p.Val141Met) identified in 9 unrelated probands. All 9 cases presented with severe bradycardia in-utero or at birth and in 6 atrial fibrillation was also reported. In one case complete atrioventricular block was documented. (PMIDs: 24818999; 26279191; 16109388; 24380499; 25974115; 28491547).

Five other variants have been reported for SQTS, but the phenotypic features of SQTS for 4 of these have been unclear or functional data supporting the mechanism of disease lacking in the published manuscripts. For the fifth additionally reported variant, 70-year-old patient presented with ‘idiopathic VF’ and a short QT interval, a KCNQ1 variant, p.Val307Leu, was reported as the likely genetic culprit, with in vitro studies reporting a gain-of-function effect of the mutant (Bellocq et al, Circ 2004).

Functional characterisation in cell models confirms a gain of function mechanism for Val141Met and Val307Leu.
Four cases of Val141Met are reported as de novo without noted confirmed paternity. Importantly, in none of the p.Val141Met cases was cardiac arrest or sudden cardiac death described.
Note: loss-of-function variants in KCNQ1 are associated with Long QT Syndrome (LQTS).

SLC4A3 - SQTS - Autosomal dominant¶

Gene symbol	SLC4A3
Gene mim	106195
Indication	SQTS
Referral indication	Short QT Syndrome (SQTS)
Disease grouping	Classic SQTS
Disease name	SLC4A3-related Short QT syndrome
Gene disease validity (ClinGen)	MODERATE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	NA
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	restricted repertoire of mutations
Restricted repertoire of pathogenic variants	NM_201574(SLC4A3):c.1109G\>A (p.Arg370His)
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant
PMIDs	29167417
Disease accession	MONDO:0000453
Curated date	21.07.2021
Expert panel review date	21.07.2021
Expert panel	Channelopathy expert panel

Narrative

SLC4A3 encodes a plasma membrane anion exchange protein. Genetic evidence supporting SLC4A3 as a SQTS-causing gene is derived from a single publication in which exome sequencing was performed in 2 families, including one large pedigree (PMID: 29167417). The same rare genetic variant (p.Arg370His, c.1109G>A) was identified in both families, suggesting they are possibly distantly related. Experimental evidence from in vitro and zebrafish models suggests reduced membrane localization of the mutated protein leads to intracellular alkalinization and shortening of the cardiomyocyte action potential duration. The genetic evidence, including the unbiased gene discovery approach of whole exome sequencing and segregation of the identified genetic variant with a large number of affected individuals within the presented pedigree, was considered relatively strong by the ClinGen GCEP. However, lack of other publications supporting this gene-disease relationship led to a score in the ‘Moderate’ range (for gene-disease validity). Further information on ClinGen gene-disease validity can be found here: https://search.clinicalgenome.org/kb/genes/HGNC:11029

Syndrome including shortened QT and cardiac arrhythmias¶

SLC22A5 - SQTS - Autosomal recessive¶

Gene symbol	SLC22A5
Gene mim	603377
Indication	SQTS
Referral indication	Short QT Syndrome (SQTS)
Disease grouping	Syndrome including shortened QT and cardiac arrhythmias
Disease name	SLC22A5-related primary systemic carnitine deficiency
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	biallelic_autosomal
Inheritance	Autosomal recessive
Inheritance modifiers	NA
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant
PMIDs	31472821; 3009296; 26190315
Disease accession	MONDO:0008919
Curated date	21.07.2021
Expert panel review date	21.07.2021
Expert panel	Channelopathy expert panel

Narrative

Variants in SLC22A5 cause autosomal recessive primary systemic carnitine deficiency (PSCD), a syndrome characterized by hypoketotic hypoglycemia, hyperammonemia, liver dysfunction, hypotonia and cardiomyopathy (PMID: 26190315).
Homozygote or compound heterozygote variants have been identified in unexplained sudden cardiac death or resuscitated cardiac arrest cases without overt extra-cardiac manifestations (PMIDs: 31472821; 3009296). Furthermore, a short QT interval has been demonstrated in a carnitine deficient mouse model (PMID: 31472821) as well as in patients with PSCD (PMID: 31472821; 3009296). Importantly, however, the QT interval in these patients returns to normal with carnitine supplementation treatment.
Information on ClinGen gene-disease validity conclusion: the ClinGen GCEP conclude that PSCD is a metabolic and reversible SQTS-mimic.
While there is no robust evidence of a relationship between SLC22A5 and true SQTS [ClinGen ‘disputed’ classification], there is ‘definitive’ evidence for a relationship between SLC22A5 and PSCD which may justify testing in individuals being investigated for possible SQTS. Further information on ClinGen gene-disease validity can be found here: https://search.clinicalgenome.org/kb/genes/HGNC:10969

Arrhythmogenic right ventricular cardiomyopathy (ARVC)¶

Familial isolated arrhythmogenic cardiomyopathy¶

DSC2 - ARVC - Autosomal dominant¶

Gene symbol	DSC2
Gene mim	125645
Indication	ARVC
Referral indication	Arrhythmogenic right ventricular cardiomyopathy (ARVC)
Disease grouping	Familial isolated arrhythmogenic cardiomyopathy
Disease name	DSC2-related Arrhythmogenic right ventricular cardiomyopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	Typified by incomplete penetrance
Disease-associated variant consequence	altered gene product sequence; decreased gene product level
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	splice_region_variant; splice_acceptor_variant; splice_donor_variant; frameshift_variant; stop_gained; missense_variant; inframe_deletion; inframe_insertion; NMD_triggering
PMIDs	17963498; 33831308; 24070718; 17186466; 19863551; 24793512; 20031616; 21636032; 23911551; 17033975; 34400560; 31028357; 23863954; 31402444; 26310507
Disease accession	MONDO:0012506
Curated date	25.11.2021
Expert panel review date	05.01.2022
Expert panel	Cardiomyopathy expert panel

Narrative

DSC2-related ARVC is due to decreased gene product level or altered gene product sequence due to a variety of mechanisms (e.g. null alleles, trafficking defects, impaired proteolytic processing, absence of or impaired protein-protein interactions) (PMID: 31028357; 23911551; NBK1131).
Loss of function is the likely disease mechanism. ClinGen found there was some evidence to support haploinsufficiency as a mechanism. https://search.clinicalgenome.org/kb/gene-dosage/HGNC:3036.
Autosomal dominant inheritance with incomplete penetrance is the most common mode of transmission (PMID: 21636032; 33831308). Homozygous and compound heterozygous variants have also been described in association with ARVC with or without cutaneous features (PMID: 26310507; 23863954; 24793512; 24070718; 34400560). In some cases, these appear to reflect autosomal recessive inheritance (PMID 24793512; 23863954, 33831308). Instances of digenic inheritance have been identified with DSC2 variants along with other desmosomal gene pathogenic variants (PMID: 24070718).
A number of DSC2 variants have been reported in the literature including nonsense, frameshift, splice, missense and inframe insertions and deletions (NBK1131; 17033975; 17963498; 17186466; 20031616; 19863551; 31402444).
DSC2-related ARVC appears to be characterised by an increased risk of biventricular involvement and heart failure when compared to PKP2-related ARVC (PMID: 34400560).

DSC2 - ARVC - Autosomal recessive¶

Gene symbol	DSC2
Gene mim	125645
Indication	ARVC
Referral indication	Arrhythmogenic right ventricular cardiomyopathy (ARVC)
Disease grouping	Familial isolated arrhythmogenic cardiomyopathy
Disease name	DSC2-related Arrhythmogenic right ventricular cardiomyopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	biallelic_autosomal
Inheritance	Autosomal recessive
Inheritance modifiers	Typified by incomplete penetrance
Disease-associated variant consequence	altered gene product sequence; decreased gene product level
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	splice_region_variant; splice_acceptor_variant; splice_donor_variant; frameshift_variant; stop_gained; missense_variant; inframe_deletion; inframe_insertion; NMD_triggering
PMIDs	17963498; 33831308; 24070718; 17186466; 19863551; 24793512; 20031616; 21636032; 23911551; 17033975; 34400560; 31028357; 23863954; 31402444; 26310507
Disease accession	MONDO:0012506
Curated date	25.11.2021
Expert panel review date	05.01.2022
Expert panel	Cardiomyopathy expert panel

Narrative

DSC2-related ARVC is due to decreased gene product level or altered gene product sequence due to a variety of mechanisms (e.g. null alleles, trafficking defects, impaired proteolytic processing, absence of or impaired protein-protein interactions) (PMID: 31028357; 23911551; NBK1131).
Loss of function is the likely disease mechanism. ClinGen found there was some evidence to support haploinsufficiency as a mechanism. https://search.clinicalgenome.org/kb/gene-dosage/HGNC:3036.
Autosomal dominant inheritance with incomplete penetrance is the most common mode of transmission (PMID: 21636032; 33831308). Homozygous and compound heterozygous variants have also been described in association with ARVC with or without cutaneous features (PMID: 26310507; 23863954; 24793512; 24070718; 34400560). In some cases, these appear to reflect autosomal recessive inheritance (PMID 24793512; 23863954, 33831308). Instances of digenic inheritance have been identified with DSC2 variants along with other desmosomal gene pathogenic variants (PMID: 24070718).
A number of DSC2 variants have been reported in the literature including nonsense, frameshift, splice, missense and inframe insertions and deletions (NBK1131; 17033975; 17963498; 17186466; 20031616; 19863551; 31402444).
DSC2-related ARVC appears to be characterised by an increased risk of biventricular involvement and heart failure when compared to PKP2-related ARVC (PMID: 34400560).

DSG2 - ARVC - Autosomal dominant¶

Gene symbol	DSG2
Gene mim	125671
Indication	ARVC
Referral indication	Arrhythmogenic right ventricular cardiomyopathy (ARVC)
Disease grouping	Familial isolated arrhythmogenic cardiomyopathy
Disease name	DSG2-related Arrhythmogenic right ventricular cardiomyopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	Typified by incomplete penetrance
Disease-associated variant consequence	altered gene product sequence; decreased gene product level
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	splice_acceptor_variant; splice_donor_variant; frameshift_variant; stop_gained; missense_variant; inframe_deletion; inframe_insertion
PMIDs	25616645; 33831308; 33917638; 24070718; 27532257; 30790397; 21636032; 16505173; 34400560; 30454721; 27170944; 16823493
Disease accession	MONDO:0012434
Curated date	12.12.2021
Expert panel review date	05.01.2022
Expert panel	Cardiomyopathy expert panel

Narrative

DSG2-related ARVC is due to decreased gene product level or altered gene product sequence due to a variety of mechanisms. Much of the underlying pathogenesis of DSG2 pathogenic variants is still unknown; it is believed that loss of DSG2 compromises cell-to-cell adhesion between cardiomyocytes (PMID: 26085008; NBK1131). There is also work revealing that desmosomal variants can reduce canonical Wnt signaling and activating Wnt with a GSK3B inhibitor can block disease pathogenesis (PMID: 16823493; PMID: 27170944).
The usual mode of inheritance is autosomal dominant characterized by incomplete penetrance (PMID: 21636032; 33831308). Compound heterozygous and homozygous variants have been described. In some families, heterozygous carriers of these variants were not affected suggesting autosomal recessive inheritance (PMID: 33917638; 34400560; 24070718; 33831308; 30454721). Patients with >1 variant appear to have a more severe phenotype (PMID: 25616645; PMID: 30790397).

The majority of DSG2 variants are rare missense variants with unknown significance/unknown mechanism of pathogenicity. In addition, nonsense, frameshift, insertions, deletions, and splice site variants have all been described (PMID: 16505173; NBK1131; 30790397; 27532257; 33917638).
DSG2-related ARVC appears to be characterised by an increased risk of biventricular involvement and heart failure when compared to PKP2-related ARVC (PMID: 34400560; 30790397).

DSG2 - ARVC - Autosomal recessive¶

Gene symbol	DSG2
Gene mim	125671
Indication	ARVC
Referral indication	Arrhythmogenic right ventricular cardiomyopathy (ARVC)
Disease grouping	Familial isolated arrhythmogenic cardiomyopathy
Disease name	DSG2-related Arrhythmogenic right ventricular cardiomyopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	biallelic_autosomal
Inheritance	Autosomal recessive
Inheritance modifiers	Typified by incomplete penetrance
Disease-associated variant consequence	altered gene product sequence; decreased gene product level
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	splice_acceptor_variant; splice_donor_variant; frameshift_variant; stop_gained; missense_variant; inframe_deletion; inframe_insertion
PMIDs	25616645; 33831308; 33917638; 24070718; 27532257; 30790397; 21636032; 16505173; 34400560; 30454721; 27170944; 16823493
Disease accession	MONDO:0012434
Curated date	12.12.2021
Expert panel review date	05.01.2022
Expert panel	Cardiomyopathy expert panel

Narrative

DSG2-related ARVC is due to decreased gene product level or altered gene product sequence due to a variety of mechanisms. Much of the underlying pathogenesis of DSG2 pathogenic variants is still unknown; it is believed that loss of DSG2 compromises cell-to-cell adhesion between cardiomyocytes (PMID: 26085008; NBK1131). There is also work revealing that desmosomal variants can reduce canonical Wnt signaling and activating Wnt with a GSK3B inhibitor can block disease pathogenesis (PMID: 16823493; PMID: 27170944).
The usual mode of inheritance is autosomal dominant characterized by incomplete penetrance (PMID: 21636032; 33831308). Compound heterozygous and homozygous variants have been described. In some families, heterozygous carriers of these variants were not affected suggesting autosomal recessive inheritance (PMID: 33917638; 34400560; 24070718; 33831308; 30454721). Patients with >1 variant appear to have a more severe phenotype (PMID: 25616645; PMID: 30790397).

The majority of DSG2 variants are rare missense variants with unknown significance/unknown mechanism of pathogenicity. In addition, nonsense, frameshift, insertions, deletions, and splice site variants have all been described (PMID: 16505173; NBK1131; 30790397; 27532257; 33917638).
DSG2-related ARVC appears to be characterised by an increased risk of biventricular involvement and heart failure when compared to PKP2-related ARVC (PMID: 34400560; 30790397).

DSP - ARVC - Autosomal dominant¶

Gene symbol	DSP
Gene mim	125647
Indication	ARVC
Referral indication	Arrhythmogenic right ventricular cardiomyopathy (ARVC)
Disease grouping	Familial isolated arrhythmogenic cardiomyopathy
Disease name	DSP-related Arrhythmogenic right ventricular cardiomyopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	Typified by incomplete penetrance
Disease-associated variant consequence	altered gene product sequence; decreased gene product level
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	splice_acceptor_variant; splice_donor_variant; frameshift_variant; stop_gained; missense_variant; inframe_deletion; inframe_insertion
PMIDs	33831308; 20716751; 27532257; 33275305; 27761164; 21636032; 31319917; 32372669; 31514951; 23810894; 20940358; 22795705; 24503780; 26604139; 23137101; 11063735; 32808748; 30382575
Disease accession	MONDO:0011831
Curated date	12.12.2021
Expert panel review date	05.01.2022
Expert panel	Cardiomyopathy expert panel

Narrative

DSP-related ARVC is due to decreased gene product level or altered gene product sequence.
The disease mechanism is loss of function via haploinsufficiency, dominant negative or both (PMID 32372669; 23137101; 16917092; NBK1131).
DSP-related ARVC is inherited in an autosomal dominant manner characterized by incomplete penetrance (PMID: 21636032; 33831308). However, DSP is associated with multiple phenotypes which are heterogeneous and overlapping (including DCM, DCM with cutaneous features, ARVC, and Carvajal syndrome) and autosomal recessive inheritance has been reported. There does not appear to be distinct mechanisms leading to different phenotypes https://search.clinicalgenome.org/kb/gene-dosage/HGNC:3052.

The initial variant description in DSP was in Carvajal syndrome characterized by woolly hair, keratoderma and ARVC. In 2000 three families from Ecuador were found to be homozygous for the variant 7901delG in DSP which produces a premature stop codon leading to a truncated desmoplakin protein missing the C domain of the tail region (PMID 11063735). Since then both autosomal dominant and autosomal recessive patterns of inheritance have been described in Carvajal syndrome (PMID: 27761164; 20940358; 22795705; 26604139; 23137101). This was followed by the description of a heterozygous variant in DSP in an Italian family with ARVC with co-segregation of the variant with disease. There have been reports of digenic inheritance with other desmosomal pathogenic variants.

In a retrospective multicentre study, curly hair and/or thick skin on the palms or soles (palmoplantar keratoderma) was commonly present in DSP patients (54/98, 55%) but not in PKP2 patients (1/46, 2%) (PMID: 32372669). Maruthappu et al 2019 also describe 38 patients with arrhythmogenic cardiomyopathy who were carriers of a dominant loss-of-function (nonsense or frameshift) variants in DSP. Nearly all were found to have curly hair and palmoplantar keratoderma. However, there was one family described where the majority did not demonstrate a curly hair/cutaneous phenotype. The variant in this family was located in a fragment (c.3585-5379, (p.1195-1793)) only included in isoform 1 of DSP (it has previously been shown that isoform 2 is the major isoform regulating keratinocyte adhesion (PMID: 30382575).

Both truncating (stop gained, frame shift, splice site) and non-truncating variants in DSP have been reported in the literature associated with ARVC (PMID 31319917; 20716751; 23810894; 24503780; 27532257; 31514951; 27761164; 21636032; 32808748). Pathogenic truncating variants are more common.
Grondin et al 2020 re-evaluated reported missense variants and found an enrichment localizing to the spectrin repeat domain (SRD) in cases vs gnomAD. A similar hot spot location (amino acid residues 250-604) was reported by Kapplinger et al in 2011 (PMID: 32808748; 21636032).
Smith E et al 2020 report that DSP variants are associated with a distinct type of cardiomyopathy with a high prevalence of LV inflammation, fibrosis, and systolic dysfunction, and DSP cardiomyopathy should be considered in the differential diagnosis for myocarditis and sarcoidosis (PMID: 32372669).

DSP - ARVC - Autosomal recessive¶

Gene symbol	DSP
Gene mim	125647
Indication	ARVC
Referral indication	Arrhythmogenic right ventricular cardiomyopathy (ARVC)
Disease grouping	Familial isolated arrhythmogenic cardiomyopathy
Disease name	DSP-related Arrhythmogenic right ventricular cardiomyopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	biallelic_autosomal
Inheritance	Autosomal recessive
Inheritance modifiers	Typified by incomplete penetrance
Disease-associated variant consequence	altered gene product sequence; decreased gene product level
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	splice_acceptor_variant; splice_donor_variant; frameshift_variant; stop_gained; missense_variant; inframe_deletion; inframe_insertion
PMIDs	33831308; 20716751; 27532257; 33275305; 27761164; 21636032; 31319917; 32372669; 31514951; 23810894; 20940358; 22795705; 24503780; 26604139; 23137101; 11063735; 32808748; 30382575
Disease accession	MONDO:0011831
Curated date	12.12.2021
Expert panel review date	05.01.2022
Expert panel	Cardiomyopathy expert panel

Narrative

DSP-related ARVC is due to decreased gene product level or altered gene product sequence.
The disease mechanism is loss of function via haploinsufficiency, dominant negative or both (PMID 32372669; 23137101; 16917092; NBK1131).
DSP-related ARVC is inherited in an autosomal dominant manner characterized by incomplete penetrance (PMID: 21636032; 33831308). However, DSP is associated with multiple phenotypes which are heterogeneous and overlapping (including DCM, DCM with cutaneous features, ARVC, and Carvajal syndrome) and autosomal recessive inheritance has been reported. There does not appear to be distinct mechanisms leading to different phenotypes https://search.clinicalgenome.org/kb/gene-dosage/HGNC:3052.

The initial variant description in DSP was in Carvajal syndrome characterized by woolly hair, keratoderma and ARVC. In 2000 three families from Ecuador were found to be homozygous for the variant 7901delG in DSP which produces a premature stop codon leading to a truncated desmoplakin protein missing the C domain of the tail region (PMID 11063735). Since then both autosomal dominant and autosomal recessive patterns of inheritance have been described in Carvajal syndrome (PMID: 27761164; 20940358; 22795705; 26604139; 23137101). This was followed by the description of a heterozygous variant in DSP in an Italian family with ARVC with co-segregation of the variant with disease. There have been reports of digenic inheritance with other desmosomal pathogenic variants.

In a retrospective multicentre study, curly hair and/or thick skin on the palms or soles (palmoplantar keratoderma) was commonly present in DSP patients (54/98, 55%) but not in PKP2 patients (1/46, 2%) (PMID: 32372669). Maruthappu et al 2019 also describe 38 patients with arrhythmogenic cardiomyopathy who were carriers of a dominant loss-of-function (nonsense or frameshift) variants in DSP. Nearly all were found to have curly hair and palmoplantar keratoderma. However, there was one family described where the majority did not demonstrate a curly hair/cutaneous phenotype. The variant in this family was located in a fragment (c.3585-5379, (p.1195-1793)) only included in isoform 1 of DSP (it has previously been shown that isoform 2 is the major isoform regulating keratinocyte adhesion (PMID: 30382575).

Both truncating (stop gained, frame shift, splice site) and non-truncating variants in DSP have been reported in the literature associated with ARVC (PMID 31319917; 20716751; 23810894; 24503780; 27532257; 31514951; 27761164; 21636032; 32808748). Pathogenic truncating variants are more common.
Grondin et al 2020 re-evaluated reported missense variants and found an enrichment localizing to the spectrin repeat domain (SRD) in cases vs gnomAD. A similar hot spot location (amino acid residues 250-604) was reported by Kapplinger et al in 2011 (PMID: 32808748; 21636032).
Smith E et al 2020 report that DSP variants are associated with a distinct type of cardiomyopathy with a high prevalence of LV inflammation, fibrosis, and systolic dysfunction, and DSP cardiomyopathy should be considered in the differential diagnosis for myocarditis and sarcoidosis (PMID: 32372669).

PKP2 - ARVC - Autosomal dominant¶

Gene symbol	PKP2
Gene mim	602861
Indication	ARVC
Referral indication	Arrhythmogenic right ventricular cardiomyopathy (ARVC)
Disease grouping	Familial isolated arrhythmogenic cardiomyopathy
Disease name	PKP2-related Arrhythmogenic right ventricular cardiomyopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	Typified by incomplete penetrance
Disease-associated variant consequence	altered gene product sequence; decreased gene product level
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	splice_region_variant; splice_acceptor_variant; splice_donor_variant; frameshift_variant; stop_gained; missense_variant; deletion; duplication
PMIDs	17041889; 25616645; 33831308; 23736219; 24070718; 22781308; 20301310; 24704780; 30619891; 28740174; 17010805; 21636032; 30830208; 34120153
Disease accession	MONDO:0012180
Curated date	14.12.2021
Expert panel review date	05.01.2022
Expert panel	Cardiomyopathy expert panel

Narrative

PKP2 pathogenic variants cause ARVC through decreased gene product level or altered gene product sequence. PKP2 encodes plakophilin-2 which is a protein of the desmosome and provides structural and functional integrity to adjacent cells. The disease mechanism in ARVC is loss of function (LoF). Rasmussen et al showed that truncating variants in PKP2 resulted in PKP2 transcript and protein levels reduced to approx 50% (PMID: 24704780). Cerrone et al showed that loss of PKP2 in adult myocytes was sufficient to generate an arrhythmogenic cardiomyopathy of right ventricle predominance in mice (PMID: 28740174).

PKP2 is the major causative gene for ARVC and accounts for 34%-74% of cases (PMID: 20301310). Inheritance is predominantly autosomal dominant characterised by variable expression and incomplete penetrance (PMID: 34120153; 21636032; 17010805).

Both recessive and digenic inheritance (with one pathogenic variant in PKP2 and a second in another desmosomal gene) have been reported (including a recessive cryptic splice variant PMID 17041889) and appear to confer a more severe phenotype (PMID: 30830208; 25616645; 24070718; NBK1131). The expert panel noted instances where PKP2 LoF variants on both alleles had resulted in neonatal lethality.

There are over 250 PKP2 variants listed in ClinVar for ARVC (nonsense, frameshift, splice, missense, deletions, duplications, and complex rearrangements (PMID: 30619891; 25616645; 21636032; 34120153). Dries et al report that PKP2 truncating variants explain a large proportion of ARVC cases but there is no clear relationship between their transcript position and their likelihood of disease association (PMID: 30619891). Although missense variants are associated with disease and validated with functional studies (PMID 22781308), their mechanism and overall impact in ARVC is not completely understood. The majority of missense variants in ClinVar are classified as variants of uncertain significance.

TMEM43 - ARVC - Autosomal dominant¶

Gene symbol	TMEM43
Gene mim	612048
Indication	ARVC
Referral indication	Arrhythmogenic right ventricular cardiomyopathy (ARVC)
Disease grouping	Familial isolated arrhythmogenic cardiomyopathy
Disease name	TMEM43-related Arrhythmogenic right ventricular cardiomyopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	NA
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	restricted repertoire of mutations
Restricted repertoire of pathogenic variants	NM_024334.3(TMEM43):c.1073C\>T (p.Ser358Leu)
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant
PMIDs	25343256; 29980933; 33831308; 32062046; 20301310; 22725725; 18313022; 23812740; 21214875; 24598986; 21391237
Disease accession	MONDO:0011459
Curated date	14.12.2021
Expert panel review date	05.01.2022
Expert panel	Cardiomyopathy expert panel

Narrative

TMEM43-related ARVC is due to altered gene product sequence.
Pathogenic variants in TMEM43 are a rare cause of ARVC (PMID: 20301310).
The majority of genetic evidence comes from one founder missense variant, (NM_024334.3, c.1073C>T (p.S358L)) (PMID 18313022; 21214875; 23812740; 20301310; 24598986; 33831308). This was originally identified in Newfoundland and has subsequently been found in patients from other countries including USA, Germany, and Denmark (PMID: 33831308; 18313022; 23812740). It is reported that ‘[the variant occurs on] a common haplotype with those from Newfoundland, USA, and Denmark, suggesting that the mutation originated from a common founder. Examination of 40 control chromosomes revealed an estimated age of 1300-1500 years for the mutation, which proves the European origin of the Newfoundland mutation.’ (PMID: 24598986)
The disease mechanism is largely unknown. There is no evidence currently for haploinsufficiency (https://search.clinicalgenome.org/kb/gene-dosage/HGNC:28472).

Although ARVC is known to display incomplete penetrance, this particular founder variant appears to be more penetrant.
TMEM43-related ARVC is associated with a high risk of sudden cardiac death and characteristic clinical and electrocardiographic features (PMID: 32062046). Ventricular ectopy on Holter monitoring is commonly seen and can occur early in the natural history (PMID: 22725725).
PMID 21391237 described two patients with TMEM43 heterozygous missense variants in Emery Dreifuss Muscular Dystrophy Related Myopathy. Other missense variants have been reported but their pathogenicity is debated.

DES - ARVC - Autosomal dominant¶

Gene symbol	DES
Gene mim	125660
Indication	ARVC
Referral indication	Arrhythmogenic right ventricular cardiomyopathy (ARVC)
Disease grouping	Familial isolated arrhythmogenic cardiomyopathy
Disease name	DES-related Arrhythmogenic right ventricular cardiomyopathy
Gene disease validity (ClinGen)	MODERATE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	NA
Disease-associated variant consequence	NA
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	NA
PMIDs	NA
Disease accession	NA
Curated date	NA
Expert panel review date	NA
Expert panel	NA

Narrative

The gene disease validity assertion is ‘moderate’ from ClinGen. No inheritance or mechanism curations have been done in the absence of an established gene disease relationship.

PLN - ARVC - Autosomal dominant¶

Gene symbol	PLN
Gene mim	172405
Indication	ARVC
Referral indication	Arrhythmogenic right ventricular cardiomyopathy (ARVC)
Disease grouping	Familial isolated arrhythmogenic cardiomyopathy
Disease name	PLN -related Arrhythmogenic right ventricular cardiomyopathy
Gene disease validity (ClinGen)	MODERATE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	NA
Disease-associated variant consequence	NA
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	NA
PMIDs	NA
Disease accession	NA
Curated date	NA
Expert panel review date	NA
Expert panel	NA

Narrative

The gene disease validity assertion is ‘moderate’ from ClinGen. No inheritance or mechanism curations have been done in the absence of an established gene disease relationship.

Rare familial disorder with ARVC¶

JUP - ARVC - Autosomal recessive¶

Gene symbol	JUP
Gene mim	173325
Indication	ARVC
Referral indication	Arrhythmogenic right ventricular cardiomyopathy (ARVC)
Disease grouping	Rare familial disorder with ARVC
Disease name	JUP-related Naxos disease
Gene disease validity (ClinGen)	STRONG
Allelic requirement	biallelic_autosomal
Inheritance	Autosomal recessive
Inheritance modifiers	NA
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant; inframe_deletion; frameshift_variant_NMD_escaping
PMIDs	25820315; 21320868; 25705887; 17924338; 10902626; 11691526; 20031617; 21673311; 32966140; 8858175; 20130592; 28098346; 15851108; 8954745; 31402444
Disease accession	MONDO:0011017
Curated date	12.12.2021
Expert panel review date	05.01.2022
Expert panel	Cardiomyopathy expert panel

Narrative

JUP-related Naxos disease (ARVC, woolly hair and palmoplantar keratoderma) is due to altered gene product sequence causing loss of function of JUP (PMID: 25705887; 21673311; 11691526; 10902626). JUP encodes the protein plakoglobin. Kaplan et al found that in 4 Naxos patients, Connexin43 expression at intercellular junctions was significantly reduced and mutant plakoglobin was expressed but failed to localize normally at intercellular junctions (PMID: 15851108).
Inheritance is autosomal recessive.
The initial nine patients described ranged in age from 7 to 41 years. Since then, more patients have been discovered carrying the disease with an estimate of 1:1000 in the population of the Greek islands. The disease has also been diagnosed in other countries (PMID: 32966140).
A homozygous 2bp deletion in plakoglobin (JUP), c.2157delTG, causing a frameshift and premature termination of the protein and expression of a truncated plakoglobin lacking 56 residues from the C terminus was described in 2000 (PMID: 10902626). The truncated protein was identified on western blot.
In 2017, a homozygous missense variant was described in 7 unrelated French-Canadian individuals. All had typical hair and skin findings; 4/7 had ARVC presenting after 28 years (PMID: 28098346). The effect of this variant in the heterozygous state was not investigated.
Two siblings of consanguineous parents were found to have a homozygous 3bp deletion in JUP c.901903delGAG (p.Glu301del). Both had woolly hair and skin findings, only the older sister had ARVC and neither had palmoplantar keratoderma (PMID: 28098346).
In OMIM there have been reports of other types of homozygous variants (nonsense, splice, missense) in JUP causing overlapping phenotypes and segregating with disease. Data on biallelic LoF variants are sparse. In mice, generation of a null mutation of the plakoglobin gene by homologous recombination results in embryonic lethality (PMID: 8954745; 8858175). There are 2 reports in humans who had skin features but no obvious cardiomyopathy (PMID: 20130592; 21320868). In one, JUP expression in the skin was absent. Cardiac JUP expression was not directly measured to establish the consequence in the heart - it is not known whether variant allele was expressed, degraded, or rescued by alternate splicing.

To note dominant pathogenic variants in JUP have also been rarely described in association with ARVC. Asimaki et al reported a dominant variant in JUP in a German family with ARVC and no obvious cutaneous abnormalities (PMID: 17924338). Other studies have identified heterozygous missense variants however their pathogenicity is still debated (PMID: 25820315; 20031617; 31402444).

Dilated Cardiomyopathy (DCM)¶

Familial dilated cardiomyopathy¶

BAG3 - DCM - Autosomal dominant¶

Gene symbol	BAG3
Gene mim	603883
Indication	DCM
Referral indication	Dilated Cardiomyopathy (DCM)
Disease grouping	Familial dilated cardiomyopathy
Disease name	BAG3-related Dilated cardiomyopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	Typified by incomplete penetrance
Disease-associated variant consequence	altered gene product sequence; decreased gene product level
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	splice_acceptor_variant; splice_donor_variant; frameshift_variant; missense_variant; stop_gained_NMD_triggering; exon_loss_variant; transcript_ablation
PMIDs	25008357; 21353195; 21898660; 23518596; 31808029; 30442290; 26796036; 31983221; 27391596; 32160020; 28737513; 20884878
Disease accession	MONDO:0013479
Curated date	31.03.2021
Expert panel review date	08.12.2021
Expert panel	Cardiomyopathy expert panel

Narrative

Pathogenic variants in BAG3 cause an estimated 2-4% of familial DCM due to decreased gene product level or altered gene product sequence. This likely leads to loss of function causing several pathological effects on cardiomyocytes including direct destabilization of the Z-disc, impaired protein homeostasis leading to proteotoxicity and increased susceptibility to apoptosis.
Truncating variants are responsible for most BAG3-related DCM cases, the majority of which are nonsense and frameshift, and include several single, multi-exon, and whole gene deletions. ClinGen have concluded there is good evidence for haploinsufficiency. There is not yet evidence for dominant-negative effects.
There is no apparent enrichment for non-truncating mutations in any specific domain, and it should be noted that different missense variants in similar domains can lead to different phenotypes (e.g., p.Pro209Leu leading to myofibrillar myopathy, and p.Arg218Trp leading to DCM).
BAG3-related DCM is inherited as an autosomal dominant trait, characterised by incomplete penetrance.

DES - DCM - Autosomal dominant¶

Gene symbol	DES
Gene mim	125660
Indication	DCM
Referral indication	Dilated Cardiomyopathy (DCM)
Disease grouping	Familial dilated cardiomyopathy
Disease name	DES-related Dilated cardiomyopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	NA
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant; splice_acceptor_variant_NMD_escaping
PMIDs	23349452; 23300193; 10430757; 17626518; 26724190; 11728149; 17325244
Disease accession	MONDO:0011482
Curated date	31.03.2021
Expert panel review date	08.12.2021
Expert panel	Cardiomyopathy expert panel

Narrative

Pathogenic variants in DES cause DCM due to altered gene product sequence.
Only missense variants in DES have been confidently reported as pathogenic in DCM. There are no reports of truncating variants; DES is yet to undergo ClinGen Dosage Haploinsufficiency investigations. DES has a pLI of 0.01 in gnomAD (o/e = 0.33 (0.19 - 0.6)).

There is some indication that truncating variants in DES are associated with myofibrillar myopathy rather than DCM. There is a report of a splice site variant in a DCM case, however, it causes exon 3 skipping to produce an inframe transcript (PMID: 17626518).

DES-related DCM is inherited in an autosomal dominant manner, and disease is generally highly penetrant. DES missense variants account for a very small proportion (estimated 2%) of genetically-explained DCM (PMID: 17325244).

DSP - DCM - Autosomal dominant¶

Gene symbol	DSP
Gene mim	125647
Indication	DCM
Referral indication	Dilated Cardiomyopathy (DCM)
Disease grouping	Familial dilated cardiomyopathy
Disease name	DSP-related Dilated cardiomyopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	NA
Disease-associated variant consequence	altered gene product sequence; decreased gene product level
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	frameshift_variant; missense_variant; stop_gained_NMD_triggering; splice_donor_variant_NMD_triggering; splice_acceptor_variant_NMD_triggering
PMIDs	20716751; 27532257; 31317183; 32005173; 24503780; 23022708; 31983221; 32013205
Disease accession	MONDO:0005021
Curated date	06.08.2021
Expert panel review date	01.02.2022
Expert panel	Cardiomyopathy expert panel

Narrative

Pathogenic variants in DSP cause DCM due to decreased gene product level or altered gene product sequence due to a variety of mechanisms.

Both missense and truncating mutations have been reported in DCM cases, however, there is significantly more evidence in support of truncating variants being pathogenic.

DSP-related DCM is inherited in an autosomal dominant manner, and disease is generally penetrant in families with an increased burden of left ventricular fibrosis and ventricular tachyarrhythmia. Pathogenic DSP variants are likely to account for approximately 2-3% of familial DCM cases (PMID: 24503780; 23022708).
Of note DSP is associated with multiple phenotypes which are heterogeneous and overlapping (including DCM, DCM with cutaneous features, ARVC, and Carvajal syndrome). There does not appear to be distinct mechanisms leading to different phenotypes https://search.clinicalgenome.org/kb/gene-dosage/HGNC:3052.

FLNC - DCM - Autosomal dominant¶

Gene symbol	FLNC
Gene mim	102565
Indication	DCM
Referral indication	Dilated Cardiomyopathy (DCM)
Disease grouping	Familial dilated cardiomyopathy
Disease name	FLNC-related Dilated cardiomyopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	Typified by incomplete penetrance
Disease-associated variant consequence	decreased gene product level
Mechanism	loss of function
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	splice_acceptor_variant; splice_donor_variant; frameshift_variant; stop_gained; stop_gained_NMD_triggering; frameshift_variant_NMD_triggering
PMIDs	27601210; 31627847; 27206985; 22020047; 30067491; 27908349; 2843697; 32154132; 32160020; 32150467
Disease accession	MONDO:0005021
Curated date	31.03.2021
Expert panel review date	08.12.2021
Expert panel	Cardiomyopathy expert panel

Narrative

Pathogenic variants in FLNC account for approximately 2-4% of familial DCM due to decreased gene product level. The mechanism is likely loss of function, leading to Z-disc disarray and weakened cell-cell adhesion, promoting arrhythmogenesis and fibrosis.
Truncating variants (stop-gained, frameshift and splicing) are responsible for almost all reported cases of FLNC-related DCM to date. It is possible that some loss-of-function missense variants could cause DCM and experts commented on their experience of families with missense variants segregating with disease. However, there is limited evidence for this. Xiao et al 2020 report an infant girl presenting with DCM and a paternally inherited missense variant, p.Arg441Ile in FLNC identified on exome sequencing. No functional studies were carried out (PMID: 32154132).
The FLNC-related DCM phenotype is frequently arrhythmogenic, characterized by a high burden of ventricular arrhythmias and myocardial fibrosis.
FLNC-related DCM is inherited as an autosomal dominant trait, penetrance in close relatives of an affected proband is generally high, although not complete, with mean age of onset in the late 4th or early 5th decade, +/- 10-15 years.

LMNA - DCM - Autosomal dominant¶

Gene symbol	LMNA
Gene mim	150330
Indication	DCM
Referral indication	Dilated Cardiomyopathy (DCM)
Disease grouping	Familial dilated cardiomyopathy
Disease name	LMNA-related Dilated cardiomyopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	Typified by age-related onset
Disease-associated variant consequence	altered gene product sequence; decreased gene product level
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	frameshift_variant; missense_variant; stop_gained_NMD_triggering; splice_donor_variant_NMD_triggering; splice_acceptor_variant_NMD_triggering; exon_loss_variant
PMIDs	11897440; 20127487; 29367541; 28912180; 10662742; 12854972; 10580070; 31983221; 18926329; 29095976; 12920062
Disease accession	MONDO:0007269
Curated date	30.03.2021
Expert panel review date	08.12.2021
Expert panel	Cardiomyopathy expert panel

Narrative

Pathogenic variants in LMNA cause DCM due to decreased gene product level or altered gene product sequence, likely due to a variety of mechanisms. Missense variants are more prevalent, and are responsible for a larger proportion of DCM cases, but truncating variants (nonsense, frameshift, and splice variants) are also associated with disease, most probably through loss of function mechanisms. Single and multi-exon deletions have also been reported.
LMNA has a ClinGen Dosage sensitivity score of 2, indicating there is some evidence for dosage pathogenicity. Non-missense variants are reported to convey a higher risk of life-threatening arrhythmia (PMID: 31155932).

LMNA-related DCM is inherited in an autosomal dominant manner, and disease is generally a highly penetrant and aggressive arrhythmogenic phenotype with high rates of heart failure and sudden cardiac death. LMNA missense and truncating variants account for ~5-8% of genetic DCM.

Of note LMNA is also associated with several other conditions (the laminopathies) including muscular dystrophies and Hutchinson-Gilford progeria. Some of these conditions are autosomal recessive and some dominant. There is evidence of clustering of variants to specific regions of the gene. However, DCM causing variants have been recorded across the gene and are so far all reported with dominant inheritance.

MYH7 - DCM - Autosomal dominant¶

Gene symbol	MYH7
Gene mim	160760
Indication	DCM
Referral indication	Dilated Cardiomyopathy (DCM)
Disease grouping	Familial dilated cardiomyopathy
Disease name	MYH7-related Dilated cardiomyopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	Typified by incomplete penetrance
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant
PMIDs	29093449; 29666183; 11106718; 31983221; 29300372
Disease accession	MONDO:0013262
Curated date	31.03.2021
Expert panel review date	08.12.2021
Expert panel	Cardiomyopathy expert panel

Narrative

MYH7 encodes the beta-myosin heavy chain, part of the sarcomere which plays a major role in cardiac muscle contraction.
Pathogenic variants in MYH7 cause DCM due to altered gene product sequence primarily due to decrease in sarcomere force generation.
Dominant-negative missense variants resulting in an altered protein with reduced function are responsible for most MYH7-associated DCM cases, and a small number of inframe indels have also been reported associated with disease. The likely disease mechanism is a reduction in the passive stiffness of myofibrils (PMID: 29093449) and deficit in force generation and force-holding capacity (PMID: 29666183). There is no good evidence that loss of function is a disease mechanism (e.g. PMID: 31983221), and MYH7 is not known to be haploinsufficient.
MYH7-related DCM is inherited in an autosomal dominant manner, and disease has incomplete penetrance, age-related onset, and variable expressivity. Pathogenic MYH7 variants are likely to account for approximately 5-6% of familial DCM cases. There is evidence that biallelic variants can have an additive effect resulting in more severe cardiomyopathic phenotypes.

PLN - DCM - Autosomal dominant¶

Gene symbol	PLN
Gene mim	172405
Indication	DCM
Referral indication	Dilated Cardiomyopathy (DCM)
Disease grouping	Familial dilated cardiomyopathy
Disease name	PLN-related Intrinsic Cardiomyopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	Typified by incomplete penetrance
Disease-associated variant consequence	altered gene product sequence; decreased gene product level
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	frameshift_variant; stop_gained; missense_variant; inframe_deletion; exon_loss_variant
PMIDs	16432188; 12639993; 33020536; 21167350
Disease accession	MONDO:0012362
Curated date	17.11.2021
Expert panel review date	24.11.2021
Expert panel	Cardiomyopathy expert panel

Narrative

Pathogenic variants in PLN cause cardiomyopathy by decreased gene product level or altered gene product sequence.
Inheritance is typically autosomal dominant with incomplete penetrance but biallelic variants have been described and appear to confer an earlier onset and more severe phenotype (PMID: 12639993).

PLN is encoded by one coding exon (52 amino acids). Schmitt et al described a missense variant (p.Arg9Cys) in a patient with DCM. The variant segregated with disease in the family; transgenic mice developed biventricular dilatation (PMID: 12610310). A stop gained variant and inframe deletion have also been described (PMID: 12639993; 16432188). There are 6 pathogenic/likely pathogenic variants reported on ClinVar: 1 missense, 2 stop gained, 2 frameshift and a large deletion all associated with dilated cardiomyopathy.
In the Netherlands there is a founder mutation p.Arg14del. Up to 10-15% of both dilated cardiomyopathy and arrhythmogenic cardiomyopathy patients are reported to be caused by PLN-R14del. (PMID: 33020536).

ClinGen found no difference in the molecular mechanism(s) underlying PLN-related DCM and HCM and observed that inter and intrafamilial variability in phenotype had been reported. Haghighi et al describe the same variant (p.Leu39X) in a family causing severe DCM in the homozygous state and both DCM and HCM phenotypes in the heterozygous state (PMID: 12639993). This variant has also been reported in other HCM families (PMID: 21167350). As a result, ClinGen curated PLN for an association with intrinsic cardiomyopathy and did not separately evaluate the evidence for the role in hypertrophic vs dilated phenotypes.

PLN is definitively associated with cardiomyopathy and the majority of variants reported appear to be associated with DCM. Experts commented that further investigation into PLN and HCM and the variant classes associated needs to be undertaken.

RBM20 - DCM - Autosomal dominant¶

Gene symbol	RBM20
Gene mim	613171
Indication	DCM
Referral indication	Dilated Cardiomyopathy (DCM)
Disease grouping	Familial dilated cardiomyopathy
Disease name	RBM20-related Dilated cardiomyopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	Typified by incomplete penetrance
Disease-associated variant consequence	altered gene product sequence; decreased gene product level
Mechanism	NA
Mutation consequence flag	restricted repertoire of mutations
Restricted repertoire of pathogenic variants	There is a mutation hotspot in exon 9 (amino acids 634-638)
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant; stop_gained_NMD_triggering
PMIDs	30871351; 25979592; 29367541; 19712804; 29895960; 32851336; 22466703; 29650543; 26084686; 20590677; 27496873; 30871348; 22004663; 21846512; 32789749
Disease accession	MONDO:0013168
Curated date	31.03.2021
Expert panel review date	08.12.2021
Expert panel	Cardiomyopathy expert panel

Narrative

Pathogenic variants in RBM20 cause DCM due to decreased gene product level or altered gene product sequence due to a variety of mechanisms including altered splicing of targets. A dominant negative effect causing disrupted RNA binding is also a possible/likely mechanism.

Missense variants are responsible for the majority of DCM cases although a small number of truncating variants (nonsense) have been reported. Of note, there are multiple ClinVar entries of truncating variants associated with DCM reported by diagnostic laboratories, comparing to the very low number of truncating variants detected in gnomAD.
Loss of function via truncating variants is not absolutely established, but highly likely.
RBM20-related DCM is inherited in an autosomal dominant manner, and disease is often an aggressive arrhythmogenic phenotype with high rates of heart failure and sudden cardiac death. Pathogenic RBM20 variants are likely to account for approximately 1.5-3% of familial DCM cases. There is a pathogenic variant hotspot in exon 9 (RS motif, amino acids 634-638).

SCN5A - DCM - Autosomal dominant¶

Gene symbol	SCN5A
Gene mim	600163
Indication	DCM
Referral indication	Dilated Cardiomyopathy (DCM)
Disease grouping	Familial dilated cardiomyopathy
Disease name	SCN5A-related Dilated cardiomyopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	NA
Disease-associated variant consequence	altered gene product sequence; decreased gene product level
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant; stop_gained_NMD_triggering
PMIDs	15671429; 27532257; 26916278; 15466643; 19808398; 21596231; 22675453; 22999724; 30847666
Disease accession	MONDO:0011003
Curated date	06.08.2021
Expert panel review date	01.02.2022
Expert panel	Cardiomyopathy expert panel

Narrative

Pathogenic variants in SCN5A cause DCM mainly due to altered gene product sequence leading to gain of function, and more rarely decreased/absent gene product level. The mechanism by which changes in sodium conductivity lead to cardiomyopathy is not fully understood; however, it is thought to be due to disruption of the voltage-sensing mechanism of this channel and subsequent disruption to action potential and cardiac contraction over time. It is unclear whether loss of function is a true disease mechanism (for DCM).

Pathogenic variants in SCN5A are likely to cause \<2% of familial DCM cases (PMID: 26916278, 21596231) and are associated with an arrhythmogenic phenotype with high rates of sudden cardiac death. There are no defined hotspot regions for SCN5A missense variants in DCM, however, they do appear to commonly lie within voltage sensing regions (S3 and S4 transmembrane segments) of the protein.

Of note SCN5A loss of function is generally more associated with Brugada syndrome (BrS); SCN5A is the only gene definitively associated with BrS. Gain of function variants are also associated with Long QT syndrome.

TNNC1 - DCM - Autosomal dominant¶

Gene symbol	TNNC1
Gene mim	191040
Indication	DCM
Referral indication	Dilated Cardiomyopathy (DCM)
Disease grouping	Familial dilated cardiomyopathy
Disease name	TNNC1-related Dilated cardiomyopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	NA
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant
PMIDs	18212018; 19808376; 32038292; 1554228; 27532257; 17021793; 17977476; 18803402; 20458010; 27604170
Disease accession	MONDO:0012745
Curated date	31.03.2021
Expert panel review date	08.12.2021
Expert panel	Cardiomyopathy expert panel

Narrative

Pathogenic variants in TNNC1 are a rare (\<1%) cause of familial DCM due to altered gene product sequence. This leads to a likely ‘poison peptide’ dominant negative effect, causing alteration of troponin interactions, and altered (decreased) calcium binding of myofilaments and resulting in decreased force production.

Missense variants are responsible for all reported cases of TNNC1-related DCM, with no evidence that truncating variants are causative of disease.
There is no apparent enrichment for non-truncating mutations in any specific domain, although exon 1-3 show regional constraint (gnomAD database).

TNNC1-related DCM is inherited as an autosomal dominant trait, with high penetrance observed in families. There is currently insufficient evidence for autosomal recessive inheritance, although there are some reports of early onset DCM and other cardiomyopathy associated with compound heterozygosity for TNNC1 variants (PMID: 27604170).

TNNT2 - DCM - Autosomal dominant¶

Gene symbol	TNNT2
Gene mim	191045
Indication	DCM
Referral indication	Dilated Cardiomyopathy (DCM)
Disease grouping	Familial dilated cardiomyopathy
Disease name	TNNT2-related Dilated cardiomyopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	NA
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant
PMIDs	11106718; 29367541; 27532257; 15542288; 20978592; 20031601
Disease accession	MONDO:0007267
Curated date	31.03.2021
Expert panel review date	08.12.2021
Expert panel	Cardiomyopathy expert panel

Narrative

Pathogenic variants in TNNT2 cause DCM due to altered gene product sequence.
Only missense variants have confidently been reported as pathogenic in TNNT2 DCM cases. There are no reports of truncating variants and TNNT2 has a ClinGen Dosage haploinsufficiency score of 0, and a PLi of 0 in gnomAD (19.6 expected and 20 observed).

TNNT2-related DCM is inherited in an autosomal dominant manner, and disease is often an aggressive arrhythmogenic phenotype with high rates of heart failure and sudden cardiac death. TNNT2 missense mutations account for 3% of genetic DCM (PMID: 27532257).
TNNT2 variants are associated with an early-onset and more severe form of DCM.
Of note pathogenic variants in TNNT2 are also associated hypertrophic and restrictive cardiomyopathies.

TTN - DCM - Autosomal dominant¶

Gene symbol	TTN
Gene mim	188840
Indication	DCM
Referral indication	Dilated Cardiomyopathy (DCM)
Disease grouping	Familial dilated cardiomyopathy
Disease name	TTN-related Dilated cardiomyopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	Typified by incomplete penetrance; Typified by age-related onset
Disease-associated variant consequence	altered gene product sequence; decreased gene product level
Mechanism	NA
Mutation consequence flag	restricted repertoire of mutations
Restricted repertoire of pathogenic variants	Variants must occur in A-band or \>90% percentage spliced in (PSI) exons. Pathogenic missense variants are very rare. Missense variants with segregation evidence: NM_001267550.2(TTN):c.2926T\>C (p.Trp976Arg); NM_001267550.2(TTN):c.533C\>A (p.Ala178Asp); NM_001267550.2(TTN):c.11674T\>A (p.Cys3892Ser)
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	splice_acceptor_variant; splice_donor_variant; frameshift_variant; stop_gained; missense_variant; stop_gained_NMD_triggering; frameshift_variant_NMD_triggering; exon_loss_variant
PMIDs	23418287; 9826585; 9817758; 25759365; 19789381; 25589632; 32160020; 31849696; 18765796; 28045975; 27625337; 11788824; 37253077; 29316444; 27869827; 29238064; 26084686; 32013205; 26315439; 22335739
Disease accession	MONDO:0011400
Curated date	31.03.2021
Expert panel review date	08.12.2021
Expert panel	Cardiomyopathy expert panel

Narrative

Pathogenic variants in TTN cause an estimated 15-20% of familial DCM due to decreased gene product level and altered gene product sequence. The likely disease mechanism is loss of function however, it is unclear whether this is due to haploinsufficiency or a dominant negative effect, and it is likely that both mechanisms contribute. It is likely that the reduced function has a direct effect on the sarcomere, leading to impaired contractility.
Truncating variants, specifically in exons constitutively expressed in cardiac tissue (percentage spliced in (PSI) >90%) see (PMID: 25589632; 27869827; 32160020), are responsible for the vast majority of TTN-related DCM cases. Missense variants are difficult to interpret, and generally not classified as disease-causing, although there are reports of at least three missense variants with evidence of pathogenicity.
TTN missense variants with segregation evidence:
p.Trp976Arg (PMID: 11788824)
p.Ala178Asp (PMID: 27625337)
p.Cys3575Ser (https://www.biorxiv.org/content/10.1101/2020.09.05.282913v1.full.pdf) - note not yet peer reviewed

TTN-related DCM is inherited as an autosomal dominant trait and displays incomplete and age-related onset. TTN truncating variants are present in ~1% of the general population, although these variants are more likely to reside in isoforms with lower functional expression in cardiac tissue.

ACTC1 - DCM - Autosomal dominant¶

Gene symbol	ACTC1
Gene mim	102540
Indication	DCM
Referral indication	Dilated Cardiomyopathy (DCM)
Disease grouping	Familial dilated cardiomyopathy
Disease name	ACTC1-related Dilated cardiomypathy
Gene disease validity (ClinGen)	MODERATE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	NA
Disease-associated variant consequence	NA
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	NA
PMIDs	NA
Disease accession	NA
Curated date	NA
Expert panel review date	NA
Expert panel	NA

Narrative

The gene disease validity assertion is ‘moderate’ from ClinGen. No inheritance or mechanism curations have been done in the absence of an established gene disease relationship.

JPH2 - DCM - Autosomal dominant¶

Gene symbol	JPH2
Gene mim	605267
Indication	DCM
Referral indication	Dilated Cardiomyopathy (DCM)
Disease grouping	Familial dilated cardiomyopathy
Disease name	JPH2-related Dilated cardiomyopathy
Gene disease validity (ClinGen)	MODERATE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	NA
Disease-associated variant consequence	NA
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	NA
PMIDs	NA
Disease accession	NA
Curated date	NA
Expert panel review date	NA
Expert panel	NA

Narrative

The gene disease validity assertion is ‘moderate’ from ClinGen. No inheritance or mechanism curations have been done in the absence of an established gene disease relationship.

NEXN - DCM - Autosomal dominant¶

Gene symbol	NEXN
Gene mim	613121
Indication	DCM
Referral indication	Dilated Cardiomyopathy (DCM)
Disease grouping	Familial dilated cardiomyopathy
Disease name	NEXN-related Dilated cardiomyopathy
Gene disease validity (ClinGen)	MODERATE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	NA
Disease-associated variant consequence	NA
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	NA
PMIDs	NA
Disease accession	NA
Curated date	NA
Expert panel review date	NA
Expert panel	NA

Narrative

The gene disease validity assertion is ‘moderate’ from ClinGen. No inheritance or mechanism curations have been done in the absence of an established gene disease relationship.

TNNI3 - DCM - Autosomal dominant¶

Gene symbol	TNNI3
Gene mim	191044
Indication	DCM
Referral indication	Dilated Cardiomyopathy (DCM)
Disease grouping	Familial dilated cardiomyopathy
Disease name	TNNI3-related Dilated cardiomyopathy
Gene disease validity (ClinGen)	MODERATE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	NA
Disease-associated variant consequence	NA
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	NA
PMIDs	NA
Disease accession	NA
Curated date	NA
Expert panel review date	NA
Expert panel	NA

Narrative

The gene disease validity assertion is ‘moderate’ from ClinGen. No inheritance or mechanism curations have been done in the absence of an established gene disease relationship.

TPM1 - DCM - Autosomal dominant¶

Gene symbol	TPM1
Gene mim	191010
Indication	DCM
Referral indication	Dilated Cardiomyopathy (DCM)
Disease grouping	Familial dilated cardiomyopathy
Disease name	TPM1-related Dilated cardiomyopathy
Gene disease validity (ClinGen)	MODERATE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	NA
Disease-associated variant consequence	NA
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	NA
PMIDs	NA
Disease accession	NA
Curated date	NA
Expert panel review date	NA
Expert panel	NA

Narrative

The gene disease validity assertion is ‘moderate’ from ClinGen. No inheritance or mechanism curations have been done in the absence of an established gene disease relationship.

VCL - DCM - Autosomal dominant¶

Gene symbol	VCL
Gene mim	193065
Indication	DCM
Referral indication	Dilated Cardiomyopathy (DCM)
Disease grouping	Familial dilated cardiomyopathy
Disease name	VCL-related Dilated cardiomyopathy
Gene disease validity (ClinGen)	MODERATE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	NA
Disease-associated variant consequence	NA
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	NA
PMIDs	NA
Disease accession	NA
Curated date	NA
Expert panel review date	NA
Expert panel	NA

Narrative

The gene disease validity assertion is ‘moderate’ from ClinGen. No inheritance or mechanism curations have been done in the absence of an established gene disease relationship.

Hypertrophic Cardiomyopathy (HCM)¶

Familial hypertrophic cardiomyopathy¶

ACTC1 - HCM - Autosomal dominant¶

Gene symbol	ACTC1
Gene mim	102540
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Familial hypertrophic cardiomyopathy
Disease name	ACTC1-related Hypertrophic cardiomyopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	NA
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant; inframe_deletion
PMIDs	10966831; 20031618; 17611253; 28972856; 27532257; 26061005; 10330430; 28007147; 23604709
Disease accession	MONDO:0012799
Curated date	10.10.2021
Expert panel review date	10.11.2021
Expert panel	Cardiomyopathy expert panel

Narrative

ACTC1 pathogenic variants cause HCM through altered gene product sequence. The disease mechanism is not definitively known but may involve impact on sarcomere force generation. There is currently little evidence to support haploinsufficiency as a mechanism.
Inheritance is autosomal dominant. There is limited information regarding penetrance. The initial missense variant identified by Mogensen et al was reported to be highly penetrant in family members but with a variable age of onset and severity (PMID: 10330430).
ACTC1 variants account for \<3-5% of HCM cases (NBK1768; 20031618).
Heterozygous missense variants are the major type of pathogenic variants found. One inframe deletion (a deletion of a single amino acid, Phe92del) has been reported in association with HCM (PMID: 20031618). This variant is classified as likely pathogenic on ClinVar. Liu et al suggest it may act to change the local structure and arrangement of amino acids in the actomyosin binding site (PMID: 28972856).
Large deletions or duplications have not been described.

ACTN2 - HCM - Autosomal dominant¶

Gene symbol	ACTN2
Gene mim	102573
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Familial hypertrophic cardiomyopathy
Disease name	ACTN2-related cardiac and skeletal myopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	NA
Disease-associated variant consequence	altered gene product sequence; decreased gene product level
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	frameshift_variant_NMD_triggering; stop_gained_NMD_triggering; missense_variant; inframe_deletion; deletion
PMIDs	34802252; 34526680; 20022194; 25224718; 25173926; 30630173; 31956495; 31680489; 17097056; 27532257; 31983221; 33500567; 32973354; 30701273; 30900782; 38311799; 39971408
Disease accession	MONDO:0000591
Curated date	10.10.2024
Expert panel review date	17.03.2025
Expert panel	ClinGen HCVD GCEP

Narrative

Pathogenic variants in ACTN2 are definitively associated with cardiac and skeletal myopathy. They can cause disease through decreased gene product level and altered gene product sequence.

ClinGen originally curated ACTN2 for intrinsic cardiomyopathy (hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM)) but this was re-evaluated and expanded to include other cardiomyopathy types and skeletal muscle phenotypes in December 2024 (PMID 39971408). ClinGen found no difference in the mechanisms underlying these different disease entities and therefore have grouped them together.

Individuals can show variable cardiomyopathy phenotypes, arrhythmias and sudden death (PMID: 34526680); the phenotype can vary between individuals in the same family. Pathogenic variants in this gene can give rise to isolated left ventricular hypertrophy (LVH). The inheritance pattern is autosomal dominant; however there has been a report of a homozygous ACTN2-truncating variant (in the terminal exon) with a recessive mode of inheritance leading to restrictive cardiomyopathy (RCM) (PMID: 34802252). The skeletal phenotype is also variable and includes distal myopathy and congenital myopathy. As per ClinGen ‘The skeletal muscle cases reported in different families carrying ACTN2 variants had homozygous and heterozygous missense variants reported. In the combined cases, where patients presented with both cardiac and skeletal muscle phenotypes, the proband showed frameshift and missense ACTN2 variants’ (PMID: 30701273, PMID: 30900782, PMID: 38311799).

Missense, nonsense, frameshift and larger deletions have all been reported in association with cardiomyopathy phenotypes. 4 missense variants have segregation data and 3 have functional data to support pathogenicity. Patients with these variants presented with atypical and diverse phenotypes. In their review, Walsh et al summarise what is known about ACTN2 variants and their role in cardiomyopathy (PMID: 34526680).

Missense variants with segregation evidence: NM_001103.4(ACTN2): c.355G>A (p.Ala119Thr) PMID: 20022194, PMID: 25224718; NM_001103.4(ACTN2): c.683T>C (p.Met228Thr) PMID: 25173926;
NM_001103.4(ACTN2): c.959T>G (p.Leu320Arg) PMID: 30630173;
NM_001103.4(ACTN2): c.1418A>G (p.Tyr473Cys) PMID: 31956495.

Missense variants with functional evidence:
NM_001103.4(ACTN2): c.740C>T (p.Thr247Met) PMID: 31680489;
NM_001103.4(ACTN2):c.332G>T (p.Gly111Val) PMID: 17097056;
NM_001103.4(ACTN2):c.355G>A (p.Ala119Thr) PMID: 20022194.

According to Genome Aggregation Database (gnomAD), loss of function variants are constrained in ACTN2. There have been reports of deletions in ACTN2 leading to disease. An exon 3-6 deletion leading to a frameshift was found in two families with left ventricular non compaction (LVNC) and HCM (PMID 32973354) and an exon 8-10 deletion leading to an in frame deletion was found in a family with LVNC and arrhythmias (PMID: 34802252, PMID: 34526680).
Truncating variants in ACTN2 have been identified in approximately 1% of patients previously classified as having LVNC. These variants were significantly enriched in individuals with an LVNC classification compared to controls (0.65% vs. 0.01%, p = 1.3E-06) (PMID 33500567). Of note, it is unclear whether these ‘LVNC’ individuals exhibited both hypertrabeculation and cardiomyopathy or only hypertrabeculation.

Overall, rare variants are not enriched for ACTN2 in HCM or DCM cohorts which suggests they are rarely causative of disease so should be interpreted with caution in cardiomyopathy patients (PMID: 27532257, PMID: 31983221).

Expert review panel: ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel. Review date: 17/03/2025

ALPK3 - HCM - Autosomal dominant¶

Gene symbol	ALPK3
Gene mim	617608
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Familial hypertrophic cardiomyopathy
Disease name	ALPK3-related Hypertrophic cardiomyopathy
Gene disease validity (ClinGen)	STRONG
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	NA
Disease-associated variant consequence	decreased gene product level
Mechanism	loss of function
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	stop_gained_variant; frameshift_variant; splice_donor_variant; splice_acceptor_variant
PMIDs	33191771; 34263907; 34526680; 32480058; 39971408
Disease accession	MONDO:0054838
Curated date	10.10.2024
Expert panel review date	17.03.2025
Expert panel	ClinGen HCVD GCEP

Narrative

Pathogenic variants in ALPK3 are strongly associated with hypertrophic cardiomyopathy (HCM) (PMID 39971408). They cause disease through decreased gene product level. The mechanism of disease is loss of function.

Heterozygous truncating variants in ALPK3 have been found to be enriched in HCM cohorts over population controls. They have been detected in 1.6% of patients with HCM in two separate cohorts (PMID: 34263907). There is also segregation data to support an association between heterozygous truncating variants and HCM (PMID: 33191771; 34263907). Pathogenic heterozygous missense/non-truncating variants have not been reported in association with cardiomyopathy (PMID: 34526680). The phenotype associated with autosomal dominant ALPK3 related HCM appears to be later onset disease in adulthood with a higher prevalence of apical or concentric hypertrophy. Severity was noted to be similar to those with sarcomeric HCM. No extra-cardiac features are reported (PMIDs: 34263907; 34526680). Age related penetrance was observed in genotype positive family members. Given the effect size is relatively modest compared to other causal variants in this context (Lopes et al found an odds ratio of 16 between cases and controls, PMIDs: 34263907), the penetrance in the population is expected to be very low. Therefore caution is required when interpreting these variants particularly as secondary findings. A research letter describing a case series of ALPK3 related AD HCM is available here, doi: https://doi.org/10.1101/2025.03.27.25324722.

ALPK3 is also definitively associated with autosomal recessive cardiomyopathy. Biallelic ALPK3 variants (both biallelic truncating and compound heterozygous missense and truncating variants) have been associated with early onset HCM and DCM. The phenotype is variable but several infants have been described as having DCM that progresses to HCM (PMID: 32480058). Extra-cardiac features have also been described in some individuals – see curation summary for ALPK3 recessively inherited HCM. Heterozygous relatives of these individuals were mostly described as unaffected but a minority, 10-15%, had adult onset HCM (PMID 34526680). Expert review panel: ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel. Review date: 17/03/2025

CSRP3 - HCM - Autosomal dominant¶

Gene symbol	CSRP3
Gene mim	600824
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Familial hypertrophic cardiomyopathy
Disease name	CSRP3-related Hypertrophic cardiomyopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	NA
Disease-associated variant consequence	altered gene product sequence; decreased gene product level
Mechanism	loss of function
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	frameshift_variant_NMD_triggering; stop_gained_NMD_triggering; splice_acceptor_variant; splice_donor_variant; missense_variant; inframe_deletion; inframe_insertion
PMIDs	30012424; 31919335; 30681346; 28082330; 18505755; 33035702; 34526680; 16352453; 15781201; 23396983; 26656175; 21425739; 12642359; 19035361; 25351510; 23861362; 20087448; 34558151; 33012304; 37431535; 39971408
Disease accession	MONDO:0012804
Curated date	10.10.2024
Expert panel review date	17.03.2025
Expert panel	ClinGen HCVD GCEP

Narrative

Pathogenic variants in CSRP3 are definitively associated with hypertrophic cardiomyopathy (HCM) (PMID 39971408). They can cause disease through decreased gene product level and altered gene product sequence. The mechanism is loss of function.

Both autosomal dominant and autosomal recessive inheritance have been reported.

Seven patients with biallelic truncating variants and HCM have been described (PMID: 30012424, PMID: 31919335, ). The pathogenicity of these variants in heterozygous relatives is not known. Separately, heterozygous CSRP3-truncating variants have been described in patients with HCM (PMID: 30681346).

Twenty-five unique variants (16 missense, 4 frameshift, 2 nonsense, 2 canonical splice site, and 1 indel) have been reported in humans (PMIDs: 16352453, 18505755, 15781201, 23396983, 26656175, 21425739, 12642359, 19035361, 25351510, 23861362, 20087448, 30012424, 34558151, 33035702, 31919335, 33012304, 37431535). A meta-analysis found a significant excess of rare variants in cases compared with general population controls (0.9% versus 0.3%) (PMID: 28082330). There is segregation evidence for the missense variant NM_003476.5(CSRP3) c.172T>G (p.Cys58Gly) (PMID: 18505755). And these recurrent variants are significantly enriched in HCM cases: NM_003476.5(CSRP3) c.131T>C (p.Leu44Pro) PMID: 28082330; NM_003476.5(CSRP3) c.449G>A (p.Cys150Tyr) PMID: 33035702.

Expert review panel: ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel. Review date: 17/03/2025

CSRP3 - HCM - Autosomal recessive¶

Gene symbol	CSRP3
Gene mim	600824
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Familial hypertrophic cardiomyopathy
Disease name	CSRP3-related Hypertrophic cardiomyopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	biallelic_autosomal
Inheritance	Autosomal recessive
Inheritance modifiers	NA
Disease-associated variant consequence	altered gene product sequence; decreased gene product level
Mechanism	loss of function
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	frameshift_variant_NMD_triggering; stop_gained_NMD_triggering; splice_acceptor_variant; splice_donor_variant; missense_variant; inframe_deletion; inframe_insertion
PMIDs	30012424; 31919335; 30681346; 28082330; 18505755; 33035702; 34526680; 16352453; 15781201; 23396983; 26656175; 21425739; 12642359; 19035361; 25351510; 23861362; 20087448; 34558151; 33012304; 37431535; 39971408
Disease accession	MONDO:0012804
Curated date	10.10.2024
Expert panel review date	17.03.2025
Expert panel	ClinGen HCVD GCEP

Narrative

Pathogenic variants in CSRP3 are definitively associated with hypertrophic cardiomyopathy (HCM) (PMID 39971408). They can cause disease through decreased gene product level and altered gene product sequence. The mechanism is loss of function.

Both autosomal dominant and autosomal recessive inheritance have been reported.

Seven patients with biallelic truncating variants and HCM have been described (PMID: 30012424, PMID: 31919335, ). The pathogenicity of these variants in heterozygous relatives is not known. Separately, heterozygous CSRP3-truncating variants have been described in patients with HCM (PMID: 30681346).

Twenty-five unique variants (16 missense, 4 frameshift, 2 nonsense, 2 canonical splice site, and 1 indel) have been reported in humans (PMIDs: 16352453, 18505755, 15781201, 23396983, 26656175, 21425739, 12642359, 19035361, 25351510, 23861362, 20087448, 30012424, 34558151, 33035702, 31919335, 33012304, 37431535). A meta-analysis found a significant excess of rare variants in cases compared with general population controls (0.9% versus 0.3%) (PMID: 28082330). There is segregation evidence for the missense variant NM_003476.5(CSRP3) c.172T>G (p.Cys58Gly) (PMID: 18505755). And these recurrent variants are significantly enriched in HCM cases: NM_003476.5(CSRP3) c.131T>C (p.Leu44Pro) PMID: 28082330; NM_003476.5(CSRP3) c.449G>A (p.Cys150Tyr) PMID: 33035702.

Expert review panel: ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel. Review date: 17/03/2025

FHOD3 - HCM - Autosomal dominant¶

Gene symbol	FHOD3
Gene mim	609691
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Familial hypertrophic cardiomyopathy
Disease name	FHOD3-related Hypertrophic cardiomyopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	NA
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	splice_acceptor_variant_NMD_escaping; splice_donor_variant_NMD_escaping; missense_variant; inframe_deletion; inframe_insertion; exon_loss_variant
PMIDs	19706596; 30442288; 29907873; 30898215; 31742804; 32335906; 33586461; 34526680; 35288587; 38051749; 39971408
Disease accession	MONDO:0005045
Curated date	10.10.2024
Expert panel review date	17.03.2025
Expert panel	ClinGen HCVD GCEP

Narrative

Pathogenic variants in FHOD3 are definitively associated with hypertrophic cardiomyopathy (HCM) (PMID 39971408). They can cause disease through altered gene product sequence. The mechanism of disease is not known. FHOD3 encodes FH1/FH2 domain-containing protein 3, a cardiac formin protein that plays a critical role in regulating sarcomere organisation in cardiomyocytes (PMID: 19706596).

The inheritance pattern is autosomal dominant. Ochoa et al demonstrated that patients with FHOD3 variants develop mild to moderate left ventricular hypertrophy (LVH), similar to that seen in general HCM cohorts (PMID: 30442288).

Disease-causing variants in FHOD3 are usually non-truncating (PMID 34526680), and they cluster in two regions in the diaphanous inhibitory domain: exon 12 and the coiled-coil domain (encoded by exons 15 and 16). There are recurrent pathogenic variants in exon 12: c.15781580del (p.Ser527del) (PMID: 30442288, 31742804) and c.1583A>G (p.Tyr528Cys) (PMID: 30442288, 34526680). Whole in frame deletions of exons 15 and 16 have also been reported (PMID: 32335906). Additionally, specific splice donor site variants in exon 11, c.1286+2delT (PMID: 33586461), and exon 12, c.1646+1G>A/C/T (PMID: 30898215; 35288587) and the Balkan founder variant c.1646+2T>C (PMID: 38051749), have been observed in multiple individuals with HCM. The exon 12 splice variant, c.1646+1G>A/C/T, is predicted to cause an inframe deletion of exon 12. ClinGen also noted two large CNVs, an 11kb deletion from c.1836-1527 in intron 14 to c.2022-2042 in intron 16 and an 11kb deletion c.1836-2543 in intron 14 to c.2021+2217 in intron 16 (PMID: 32335906, https://www.medrxiv.org/content/10.1101/2024.07.29.24311195v1.full-text).

Expert review panel: ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel. Review date: 17/03/2025

MYBPC3 - HCM - Autosomal dominant¶

Gene symbol	MYBPC3
Gene mim	600958
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Familial hypertrophic cardiomyopathy
Disease name	MYBPC3-related Hypertrophic cardiomyopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	Typified by incomplete penetrance
Disease-associated variant consequence	altered gene product sequence; decreased gene product level
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	splice_region_variant; splice_acceptor_variant; splice_donor_variant; frameshift_variant; stop_gained; missense_variant; inframe_deletion; intron_variant; inframe_insertion; stop_gained_NMD_triggering; splice_donor_variant_NMD_triggering; frameshift_variant_NMD_triggering; splice_acceptor_variant_NMD_triggering; exon_loss_variant
PMIDs	25611685; 32163302; 30696458; 28912181; 27532257; 7493025; 31877118; 17937428; 29300372; 32841044; 20624503; 28007147; 22057632; 12707239; 18467358; 32731933; 26573135; 32396390; 19151713
Disease accession	MONDO:0007268
Curated date	10.10.2021
Expert panel review date	10.11.2021
Expert panel	Cardiomyopathy expert panel

Narrative

MYBPC3 pathogenic variants cause HCM through decreased gene product level or altered gene product sequence either leading to a reduction in MyBP-C content in the sarcomere or altered function. The disease mechanism is loss of function; There is evidence of haploinsufficiency (PMID 31877118; 22057632; 32841044).
Variants in MYBPC3 and MYH7 collectively account for up to 50% of all clinically recognised cases of HCM and constitute at least 75% of probands where a variant is identified (PMID: 28007147; NBK1768).
Inheritance is usually autosomal dominant, typified by incomplete penetrance and variable expressivity.
Homozygous and compound heterozygous variants have been reported and can lead to severe, early onset phenotypes (PMID: 26573135; 25611685; PMID: 18467358; PMID: 17937428).

The majority of variants are heterozygous frameshift, nonsense, or splice site variants that result in premature termination codons (PMID: 25611685; 31877118). Missense and inframe indels are also frequently reported and a subset have been shown to cause loss of function through failure of myofilament incorporation and rapid degradation, further supporting haploinsufficiency as a mechanism (PMID: 32841044). Variants in MYBPC3 affecting canonical splice site dinucleotides are a well-characterised cause of HCM. Furthermore, recent work has identified more deeply intronic variants associated with disease (https://doi.org/10.3390/cardiogenetics11020009; PMID: 32396390). There are 39 pathogenic/likely pathogenic MYBPC3 intronic variants submitted on ClinVar.
The common 25 base pair intronic deletion detected in 4% to 8% of South Asian populations, is associated with cardiomyopathy as a risk allele (PMID: 19151713).
Although there is significant genetic and allelic heterogeneity in HCM, there are also several MYBPC3 founder variants (PMID: 28912181; 27532257).

MYH7 - HCM - Autosomal dominant¶

Gene symbol	MYH7
Gene mim	160760
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Familial hypertrophic cardiomyopathy
Disease name	MYH7-related Hypertrophic cardiomyopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	Typified by incomplete penetrance
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant; inframe_deletion; stop_gained_NMD_escaping
PMIDs	25611685; 20359594; 34460321; 30696458; 25209314; 27532257; 1552912; 29300372; 15856146; 1944483; 30924982; 1975517; 33500567; 12788380; 30681346; 32731933; 27247418
Disease accession	MONDO:0008647
Curated date	10.10.2021
Expert panel review date	10.11.2021
Expert panel	Cardiomyopathy expert panel

Narrative

MYH7 pathogenic variants cause HCM through altered gene product sequence leading to an increase in sarcomere force generation. Variants produce an abnormal activated protein that incorporates into the sarcomere as a ‘poison peptide’. Variants can either directly affect motor function or can impact on myosin ‘interacting head motif’ and therefore impair inactivation kinetics. There is currently no evidence to support haploinsufficiency as a disease mechanism.
Inheritance is autosomal dominant, typified by incomplete penetrance and variable expressivity.

Most pathogenic variants are missense. There are some inframe deletions reported.
A frameshift variant has been identified in 3.3% of Egyptian HCM patients. It is predicted to result in a premature termination codon downstream of the last exon-exon junction of the gene that is expected to escape nonsense-mediated decay (NMD). (PMID: 34460321).

MYH7 loss of function (LoF) variants are very rare and their contribution to inherited cardiomyopathy is incompletely understood. Notably in a study of left ventricular non-compaction (LVNC), MYH7 truncating variants, generally considered non-pathogenic for cardiomyopathies, were 20-fold enriched in LVNC cases over controls (PMID: 33500567). While there is currently no evidence for a disease-causing role in the heterozygous state in HCM, compound heterozygosity of LoF variants along with missense variants can lead to extremely severe presentations, mimicking recessive inheritance.

There is a clustering of HCM variants in the head region conferring a high probability of pathogenicity (amino acid residues 181-937). (PMID: 27247418; 27532257; 29300372; 30696458).
Kelly et al 2018 (PMID: 29300372) provide gene-specific adaptations of ACMG criteria for MYH7 and HCM.

MYL2 - HCM - Autosomal dominant¶

Gene symbol	MYL2
Gene mim	160781
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Familial hypertrophic cardiomyopathy
Disease name	MYL2-related Hypertrophic cardiomyopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	NA
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant
PMIDs	25611685; 25324513; 28912181; 30696458; 8673105; 32453731; 16076902; 12404107; 9535554; 32731933; 24111713; 16837010; 23365102; 28007147
Disease accession	MONDO:0012112
Curated date	10.10.2021
Expert panel review date	10.11.2021
Expert panel	Cardiomyopathy expert panel

Narrative

MYL2 pathogenic variants cause autosomal HCM through altered gene product sequence. The disease mechanism is not definitively known but may involve destabilization of the interacting heads motif (PMID: 28606303).
There is currently insufficient evidence to support haploinsufficiency (https://search.clinicalgenome.org/kb/gene-dosage/HGNC:7583).
MYL2 variants account for \<3% of HCM cases (NBK1768; 32731933).
Inheritance is typically autosomal dominant. There is limited information regarding penetrance.

Homozygous and compound heterozygous variants have been described in association with a lethal myosinopathy (PMID: 23365102). A study reported a homozygous frameshift variant causing infantile onset HCM. Heterozygous parents were unaffected. The authors suggest a molecular mechanism by which loss-of-function variants in MYL2 are recessive while missense variants are dominant in HCM. Several loss-of-function variants are reported in gnomAD suggesting MYL2 is not intolerant to LoF variants. (PMID: 32453731).

The majority of variants reported are missense (PMID: 8673105; 9535554; 12404107.)
On ClinVar, nearly all pathogenic variants are missense. There is one frameshift variant associated only with cardiomyopathy, not HCM specifically and a deletion encompassing exon 7 expected to result in a truncated protein - https://www.ncbi.nlm.nih.gov/clinvar/variation/417460/.
Walsh et al found the MYL2 gene to be significantly enriched for non-truncating variants, odds ratio 9.1 (6.2-13.3) (PMID: 30696458).

MYL3 - HCM - Autosomal dominant¶

Gene symbol	MYL3
Gene mim	160790
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Familial hypertrophic cardiomyopathy
Disease name	MYL3-related Hypertrophic cardiomyopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	NA
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant
PMIDs	25611685; 12021217; 20031618; 22957257; 8673105; 30696458; 26443374; 28369730; 33288880; 29914921
Disease accession	MONDO:0012111
Curated date	10.10.2021
Expert panel review date	24.11.2021
Expert panel	Cardiomyopathy expert panel

Narrative

MYL3 pathogenic variants cause HCM through altered gene product sequence. The disease mechanism is not definitively known but may involve impairing protein-protein interaction with components of the sarcomere and destabilizing the interacting heads motif (PMID: 30275503; 28606303). There is currently no evidence to support haploinsufficiency as a mechanism (https://search.clinicalgenome.org/kb/gene-dosage/HGNC:7584).
MYL3 variants account for \<3% of HCM cases (NBK1768; 20031618; 28369730).
Inheritance is primarily autosomal dominant. There is limited information regarding penetrance given small numbers of variants identified. In a large family where a missense variant was identified (p. Arg94His), penetrance was estimated at 88% (PMID: 26443374).
Osborn et al 2021 (PMID: 33288880) report a homozygous missense variant in a large family with HCM and sudden cardiac death. Heterozygous carriers were unaffected. Another biallelic variant was also described by Olson et al in 2002 (E143K) (PMID: 12021217), however this variant has also been associated with HCM variably in the heterozygous state.

Heterozygous missense variants are the major type of pathogenic variants found (PMID: 8673105; 20031618; 25611685). There are reports on ClinVar of frameshift and splice site variants, but these are classified as uncertain significance or conflicting. There is currently insufficient evidence to support loss of function as a mechanism.
Walsh et al reported a cluster of non-truncating MYL3 variants in HCM at amino acid residues 143-180 (PMID: 30696458).

PLN - HCM - Autosomal dominant¶

Gene symbol	PLN
Gene mim	172405
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Familial hypertrophic cardiomyopathy
Disease name	PLN-related Intrinsic Cardiomyopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	Typified by incomplete penetrance
Disease-associated variant consequence	altered gene product sequence; decreased gene product level
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	frameshift_variant; stop_gained; missense_variant; inframe_deletion; exon_loss_variant
PMIDs	16432188; 12639993; 33020536; 21167350
Disease accession	MONDO:0012362
Curated date	17.11.2021
Expert panel review date	24.11.2021
Expert panel	Cardiomyopathy expert panel

Narrative

Pathogenic variants in PLN cause cardiomyopathy by decreased gene product level or altered gene product sequence.
Inheritance is typically autosomal dominant with incomplete penetrance but biallelic variants have been described and appear to confer an earlier onset and more severe phenotype (PMID: 12639993).

PLN is encoded by one coding exon (52 amino acids). Schmitt et al described a missense variant (p.Arg9Cys) in a patient with DCM. The variant segregated with disease in the family; transgenic mice developed biventricular dilatation (PMID: 12610310). A stop gained variant and inframe deletion have also been described (PMID: 12639993; 16432188). There are 6 pathogenic/likely pathogenic variants reported on ClinVar: 1 missense, 2 stop gained, 2 frameshift and a large deletion all associated with dilated cardiomyopathy.
In the Netherlands there is a founder mutation p.Arg14del. Up to 10-15% of both dilated cardiomyopathy and arrhythmogenic cardiomyopathy patients are reported to be caused by PLN-R14del. (PMID: 33020536).

ClinGen found no difference in the molecular mechanism(s) underlying PLN-related DCM and HCM and observed that inter and intrafamilial variability in phenotype had been reported. Haghighi et al describe the same variant (p.Leu39X) in a family causing severe DCM in the homozygous state and both DCM and HCM phenotypes in the heterozygous state (PMID: 12639993). This variant has also been reported in other HCM families (PMID: 21167350). As a result, ClinGen curated PLN for an association with intrinsic cardiomyopathy and did not separately evaluate the evidence for the role in hypertrophic vs dilated phenotypes.

PLN is definitively associated with cardiomyopathy and the majority of variants reported appear to be associated with DCM. Experts commented that further investigation into PLN and HCM and the variant classes associated needs to be undertaken.

TNNC1 - HCM - Autosomal dominant¶

Gene symbol	TNNC1
Gene mim	191040
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Familial hypertrophic cardiomyopathy
Disease name	TNNC1-related Hypertrophic cardiomyopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	NA
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant; frameshift_NMD_escaping
PMIDs	11385718; 18572189; 21262074; 22815480; 26779504; 28771489; 29121657; 29255176; 30775854; 34317385; 33658040; 34488226; 39971408
Disease accession	MONDO:0013195
Curated date	12.10.2024
Expert panel review date	17.03.2025
Expert panel	ClinGen HCVD GCEP

Narrative

Pathogenic variants in TNNC1 are definitively associated with hypertrophic cardiomyopathy (HCM) (PMID 39971408). They can cause disease through altered gene product sequence. The mechanism of disease is not known. The inheritance pattern is autosomal dominant.

According to ClinGen, at least 11 unique variants have been reported, 10 missense and 1 frameshift variant predicted to escape nonsense mediated decay (NMD). PMIDs: 11385718; 18572189; 21262074; 22815480; 26779504; 28771489; 29121657; 29255176; 30775854; 34317385; 33658040; 34488226.

Although there is no apparent enrichment for non-truncating variants in any specific domain, exon 1-3 show regional missense constraint (gnomAD database).
TNNC1 is definitively associated with dilated cardiomyopathy (DCM). It has also been reported in association with left ventricular noncompaction (LVNC), and restrictive cardiomyopathy (RCM) but these gene disease relationships have not been curated by ClinGen.

Expert review panel: ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel. Review date: 17/03/2025

TNNI3 - HCM - Autosomal dominant¶

Gene symbol	TNNI3
Gene mim	191044
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Familial hypertrophic cardiomyopathy
Disease name	TNNI3-related Hypertrophic cardiomyopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	Typified by incomplete penetrance
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant; inframe_deletion
PMIDs	21415410; 25611685; 30696458; 28912181; 32731933; 23270746; 9241277; 21839045; 15607392; 26440512
Disease accession	MONDO:0013369
Curated date	10.10.2021
Expert panel review date	24.11.2021
Expert panel	Cardiomyopathy expert panel

Narrative

TNNI3 pathogenic variants cause HCM through altered gene product sequence. The disease mechanism is not definitively known but a review by Tardif et al reported functional studies on missense variants that found an increase in the Ca2+ sensitivity of myofilament activation (PMID: 21415410). ClinGen also conclude that ‘missense mutations have [been] shown to affect Ca2+ binding to myofilaments containing the mutant TNNI3 (PMIDs: 16531415 and 22675533) or result in an increased myofilament response to Ca2+ (PMID: 11735257).’ https://search.clinicalgenome.org/kb/genes/HGNC:11947.
TNNI3 variants account for approx. 3-5% of HCM cases (NBK1768; PMID: 15607392).

Inheritance is autosomal dominant characterised by incomplete penetrance (PMID: 26440512; 15607392; 9241277). Lorenzini et al found that subjects with TNNI3 variants had a lower penetrance than variants in MYBPC3, MYH7, and TNNT2 (PMID: 32731933). Experts commented that variants seen in TNNI3 in severe/early onset disease were more likely to be de novo in origin.
Maron et al 2012 describe 4 HCM probands with both pathogenic variants in TNNI3 and MYBPC3 (PMID: 21839045). In addition, 2 siblings have been reported with homozygous TNNI3 missense variants (Arg162Trp) and severe myocardial hypertrophy. Parents of the affected children are consanguineous and along with other family members harbouring the same variant in the heterozygous state, were unaffected (PMID: 23270746). Multiple disease-causing sarcomeric variants appear to be associated with more severe disease. There is not enough evidence to suggest biallelic variants in TNNI3 have a distinct mechanism compared to monoallelic variants. Of note both dominant and recessive modes of inheritance have been reported in TNNI3-related DCM (PMID: 26440512).

Heterozygous missense variants are the major type of pathogenic variants found. There are also reports of inframe deletions. In a systematic review, Mogensen et al reported 91% of all variants were missense variants. Six variants (Arg141Gln, Arg145Trp, Arg157Val, Arg162Gln, Ser166Phe, and Lys183Del) appeared with a particularly high frequency and were identified in 116 of the 256 probands (45%) (PMID: 26440512). There are reports on ClinVar of frameshift, splice site variants and nonsense variants but these are either classified as uncertain significance/conflicting, not associated with HCM specifically or have no functional evidence to demonstrate loss of function as a mechanism. ClinGen have concluded that there is currently limited evidence to support haploinsufficiency as a mechanism.
Mogensen et al found that 85% of variants were identified in exons 7 and 8 (amino acid residues 125 - 210). (PMID: 26440512).
Similarly, Walsh et al detected a cluster of non-truncating TNNI3 variants in HCM at amino acid residues 141-209 (PMID: 30696458).

TNNT2 - HCM - Autosomal dominant¶

Gene symbol	TNNT2
Gene mim	191045
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Familial hypertrophic cardiomyopathy
Disease name	TNNT2-related Hypertrophic cardiomyopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	Typified by incomplete penetrance
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant; inframe_deletion; stop_gained_NMD_escaping; splice_donor_variant_NMD_escaping
PMIDs	25611685; 22144547; 12707239; 28973951; 30696458; 28912181; 8205619; 30578328; 32731933; 7898523; 11034944; 28007147; 10965086
Disease accession	MONDO:0007266
Curated date	10.10.2021
Expert panel review date	24.11.2021
Expert panel	Cardiomyopathy expert panel

Narrative

TNNT2 pathogenic variants cause HCM through altered gene product sequence. Troponin T is a regulatory protein found in striated muscles that forms a complex with troponin I (TnI) and troponin C (TnC) that, together with tropomyosin (TM), is required for Ca2+ dependent regulation of muscle contraction.

The mechanism appears to be dominant negative rather than haploinsufficiency. The majority of pathogenic variants are missense. A functional study of a splice variant associated with HCM concluded that the resulting truncated protein does not function as a ‘null protein, but rather as a dominant-negative leading to reduction in the level of calcium activated force production’ (PMID: 8958207). Gangadharan et al suggest the primary reason by which TNNT2 variants between residues 92 and 144 cause cardiomyopathy is by changing the affinity of TnT for Tm within the N terminal part of Troponin T (PMID: 28973951).
TNNT2 variants account for \<5% of HCM cases (NBK1768; 12860912)
Inheritance is autosomal dominant characterised by incomplete penetrance (PMID: 32731933).
Homozygous TNNT2 variants causing HCM are rare and have been reported to be associated with more severe disease (PMID 30578328; 10965086; 11034944). Piroddi et al investigated a patient with severe, early onset HCM with a homozygous K280N variant. There was no family information available, however the authors demonstrated that it resulted in 100% mutant cTnT with no evidence of haploinsufficiency and suggested this supports the idea of a gene dose-dependent effect of HCM variants on the severity of the phenotype (PMID: 30578328).
Experts commented that variants seen in TNNT2 in severe/early onset disease were more likely to be de novo in origin.
Nearly all pathogenic variants are missense (PMID: 12707239; 22144547; 25611685). However, there are a few reports of inframe deletions, nonsense variants in the final exon which likely escape nonsense mediated decay and splice donor variants (PMID: 8958207; 12707239; 22144547; 25611685).
https://www.ncbi.nlm.nih.gov/clinvar/variation/43673/;
https://www.ncbi.nlm.nih.gov/clinvar/variation/177636/

Walsh et al found non truncating variants in the TNNT2 gene to be significantly enriched in HCM cases, odds ratio 11.4 (8.5 - 15.2). They found a clustering of non-truncating variants conveying a high probability of pathogenicity in the tropomyosin binding domain (amino acid residues 79 - 179) (PMID: 30696458).

TPM1 - HCM - Autosomal dominant¶

Gene symbol	TPM1
Gene mim	191010
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Familial hypertrophic cardiomyopathy
Disease name	TPM1-related Hypertrophic cardiomyopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	Typified by incomplete penetrance
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant
PMIDs	12860912; 7898523; 8205619; 24005378
Disease accession	MONDO:0007267
Curated date	10.10.2021
Expert panel review date	24.11.2021
Expert panel	Cardiomyopathy expert panel

Narrative

TPM1 pathogenic variants cause HCM through altered gene product sequence. TPM1 encodes alpha-tropomyosin which acts to place the troponin complex on cardiac actin. The mechanism is through altered function rather than haploinsufficiency - Bottinelli et al examined the Asp175Asn variant from 2 HCM patients and found equal expression of wild type and mutant alpha-tropomyosin proteins (PMID: 9440709). Gupte et al concluded that ‘TPM1 mutations cause differences in protein stability, actin binding, and Tn conformation. All of these differences could converge to change the Ca2+ dependence of myosin activity’ (PMID: 25548289).
TPM1 variants account for \<3% of HCM cases (NBK1768; PMID: 7898523; 12860912).
Inheritance is autosomal dominant characterised by incomplete penetrance (PMID: 32731933).
There are reports of homozygous or compound heterozygous variants in TPM1. (PMID: 33642254; 32744700).
A homozygous missense variant, (p.Gly3Arg), in exon 1 of TPM1 was identified in triplets (two had HCM and one patent ductus arteriosus). The parents were heterozygous for the variant and unaffected clinically and on echocardiogram (PMID: 32744700).

Pathogenic variants are nearly always heterozygous missense variants. There is one de novo inframe deletion (6bp, 2 amino acids) associated with HCM classified as likely pathogenic on ClinVar, no additional details are given.
Redwood and Robinson reviewed TPM1 variants in 2013 and reported ‘at least 15 described in the current literature (Table1). Most of these mutations are unique and have been reported in only a single family or individual. Each mutation is missense causing a single amino acid substitution, and no truncation or nonsense mutations have been reported.’ (PMID: 24005378).
Walsh et al found that in HCM non-truncating variants across the whole TPM1 gene showed a high probability of pathogenicity. (PMID: 30696458)

JPH2 - HCM - Autosomal dominant¶

Gene symbol	JPH2
Gene mim	605267
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Familial hypertrophic cardiomyopathy
Disease name	JPH2-related Hypertrophic cardiomyopathy
Gene disease validity (ClinGen)	MODERATE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	NA
Disease-associated variant consequence	NA
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	NA
PMIDs	NA
Disease accession	NA
Curated date	NA
Expert panel review date	NA
Expert panel	NA

Narrative

The gene disease validity assertion is ‘moderate’ from ClinGen. No inheritance or mechanism curations have been done in the absence of an established gene disease relationship.

TRIM63 - HCM - Autosomal recessive¶

Gene symbol	TRIM63
Gene mim	606131
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Familial hypertrophic cardiomyopathy
Disease name	TRIM63-related Hypertrophic cardiomyopathy
Gene disease validity (ClinGen)	MODERATE
Allelic requirement	biallelic_autosomal
Inheritance	Autosomal recessive
Inheritance modifiers	NA
Disease-associated variant consequence	NA
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	NA
PMIDs	NA
Disease accession	NA
Curated date	NA
Expert panel review date	NA
Expert panel	NA

Narrative

The gene disease validity assertion is ‘moderate’ from ClinGen. No inheritance or mechanism curations have been done in the absence of an established gene disease relationship.

MT-TI - HCM - Mitochondrial¶

Gene symbol	MT-TI
Gene mim	590045
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Familial hypertrophic cardiomyopathy
Disease name	MT-TI-related Hypertrophic cardiomyopathy
Gene disease validity (ClinGen)	MODERATE
Allelic requirement	mitochondrial
Inheritance	Mitochondrial
Inheritance modifiers	NA
Disease-associated variant consequence	NA
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	NA
PMIDs	NA
Disease accession	NA
Curated date	NA
Expert panel review date	NA
Expert panel	NA

Narrative

The gene disease validity assertion is ‘moderate’ from ClinGen. No inheritance or mechanism curations have been done in the absence of an established gene disease relationship.

KLHL24 - HCM - Autosomal recessive¶

Gene symbol	KLHL24
Gene mim	611295
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Familial hypertrophic cardiomyopathy
Disease name	KLHL24-related Hypertrophic cardiomyopathy
Gene disease validity (ClinGen)	MODERATE
Allelic requirement	biallelic_autosomal
Inheritance	Autosomal recessive
Inheritance modifiers	NA
Disease-associated variant consequence	NA
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	NA
PMIDs	NA
Disease accession	NA
Curated date	NA
Expert panel review date	NA
Expert panel	NA

Narrative

The gene disease validity assertion is ‘moderate’ from ClinGen. No inheritance or mechanism curations have been done in the absence of an established gene disease relationship.

Rare syndromic disorder with hypertrophic cardiomyopathy - isolated LVH¶

ALPK3 - HCM - Autosomal recessive¶

Gene symbol	ALPK3
Gene mim	617608
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Rare syndromic disorder with hypertrophic cardiomyopathy - isolated LVH
Disease name	ALPK3-related Hypertrophic cardiomyopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	biallelic_autosomal
Inheritance	Autosomal recessive
Inheritance modifiers	NA
Disease-associated variant consequence	altered gene product sequence; decreased gene product level
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	splice_acceptor_variant; splice_donor_variant; frameshift_variant; stop_gained; missense_variant
PMIDs	34263907; 21441111; 33191771; 34263911; 32480058; 31074094; 27106955; 26846950
Disease accession	MONDO:0054838
Curated date	11.11.2021
Expert panel review date	24.11.2021
Expert panel	Cardiomyopathy expert panel

Narrative

ALPK3 pathogenic variants cause hypertrophic cardiomyopathy through decreased gene product level or altered gene product sequence. Biallelic ALPK3 variants were first associated with a rare recessive form of cardiomyopathy by Almomani et al in 2016 (), with several other reports since (; PMID: 31074094; PMID: 32480058). Patients display variable phenotypes but often present at birth or early childhood (at least 4 patients have presented in utero) with dilated cardiomyopathy (DCM) that progressed to a HCM phenotype over time. Extra-cardiac features including musculoskeletal and craniofacial abnormalities are also commonly observed in these cases (PMID: 32480058; PMID: 34263911).
Herkert et al 2020 reviewed the variants and phenotype in 19 paediatric patients with biallelic ALPK3 variants (including 9 previously published cases) and identified 11 loss-of-function (LoF) variants (including nonsense, frameshift and intronic variants with predicted severe effect on splicing), seven compound LoF and deleterious missense variants, and one homozygous deleterious missense variant, c.5155G>C, p.(Ala1719Pro) (PMID: 32480058). The clinical manifestations associated with the missense variants were similar to those associated with other damaging ALPK3 variants.

To note heterozygous LoF ALPK3 variants have also been reported and are enriched in adults with cardiomyopathy (PMID: 34263907; PMID: 32480058; PMID: 33191771). Haploinsufficiency is the proposed mechanism. Herkert et al found notable differences between the clinical features associated with monoallelic and biallelic ALPK3 cardiomyopathy, including absence or undetected extracardiac phenotypes. ‘Whether these differences reflect graded dose-responses to ALPK3 deficits or distinct mechanisms by which monoallelic or biallelic variants cause disease remains unknown.’(PMID: 32480058).
There does not appear to be a distinct mechanism between monoallelic and biallelic variants. The disease mechanism is loss of function of ALPK3 likely due to creation of premature stop codons, leading to nonsense-mediated decay or truncated proteins with partial or complete removal of the kinase domain (; 27106955; 32480058; 21441111). Herkert et al predicted that missense variants could result in a conformational change that affects protein folding or flexibility, protein-protein or protein-DNA interaction, or the activity of the alpha-kinase domain (PMID: 32480058).

CACNA1C - HCM - Autosomal dominant¶

Gene symbol	CACNA1C
Gene mim	114205
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Rare syndromic disorder with hypertrophic cardiomyopathy - isolated LVH
Disease name	CACNA1C-related Timothy syndrome
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	Typically de novo
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	restricted repertoire of mutations; activating
Restricted repertoire of pathogenic variants	A recurrent, de novo missense_variant causing Classic Timothy Syndrome has been described: NM_001167623.2(CACNA1C):c.1216G\>C (p.Gly406Arg)
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant
PMIDs	28211989; 25633834; 15863612; 15454078; 22106044; 26253506; 4728418; 31983240; NBK1403; 30681346; 33797204; 16360093
Disease accession	MONDO:0010979
Curated date	11.11.2021
Expert panel review date	24.11.2021
Expert panel	Cardiomyopathy expert panel

Narrative

CACNA1C-related Timothy syndrome is caused by variants leading to altered gene product sequence.
Classic Timothy syndrome (TS1) is a very rare multisystem disorder characterized by marked QT prolongation, syndactyly, immune deficiency, seizures, congenital heart defects, hypertrophic cardiomyopathy, cognitive abnormalities, learning difficulties, and intermittent hypoglycaemia (PMID: 28211989; NBK1403). Infants can present with severe biventricular hypertrophy (PMID 30681346). In some individuals left ventricular hypertrophy (LVH) may be the presenting feature, without recognised syndromic features, fulfilling a clinical diagnosis of HCM.
A recurrent, de novo, missense variant in CACNA1C was described in 13 Timothy syndrome patients, p.Gly406Arg in exon 8A (PMID: 15454078; PMID: 15863612). The mechanism appears to be gain-of-function through failed channel inactivation. Boczek et al suggest Ca2+ mishandling may lead to ventricular hypertrophy (PMID: 26253506).

CACNA1C has a complex genomic structure that undergoes extensive alternative splicing. Splawski et al identified 2 patients with de novo missense variants in exon 8 of an alternate splice form (p.Gly406Arg, analogous to the exon 8a variant, and p.Gly402Ser). This splice form represents 80% of all cardiac mRNAs. The patients were described as having atypical Timothy syndrome (TS2), presenting with a more severe cardiac phenotype (biventricular hypertrophy, moderate biventricular dysfunction, more severe QT prolongation and multiple arrythmias) and without syndactyly (PMID: 15863612; PMID: 25633834).
Boczek et al describe a novel variant p.Arg518Cys as the probable pathogenic substrate for COTS [cardiac only Timothy syndrome]. The phenotype included LQTS, hypertrophic cardiomyopathy, congenital heart defects and sudden cardiac death. Follow-up cohort analysis revealed two additional pedigrees, with very similar phenotypes, having variants at the exact same amino acid positions p.Arg518Cys and p.Arg518His. (PMID: 26253506)

Other missense variants in CACNA1C have been reported in association with isolated LQT (PMID: 26253506; 25633834; 24728418). However as of 2020, the ClinGen Cardiovascular Domain Working Group have classified the strength of evidence supporting an association between CACNA1C and LQTS as moderate (PMID: 31983240).

DES - HCM - Autosomal dominant¶

Gene symbol	DES
Gene mim	125660
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Rare syndromic disorder with hypertrophic cardiomyopathy - isolated LVH
Disease name	DES-related Myofibrillar myopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	NA
Disease-associated variant consequence	absent gene product; altered gene product sequence
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant; inframe_deletion; stop_gained_NMD_triggering; stop_gained_NMD_escaping; frameshift_variant_NMD_triggering; splice_acceptor_variant_NMD_escaping; splice_donor_variant_NMD_escaping; frameshift_variant_NMD_escaping
PMIDs	20718792; 11073539; 29926427; 19433360; 9736733; 31718026; 30681346; 16217025; 23815709; 19181099
Disease accession	MONDO:0011076
Curated date	27.03.2021
Expert panel review date	12.01.2022
Expert panel	Cardiomyopathy expert panel

Narrative

DES-related myofibrillar myopathy is typically inherited as an autosomal dominant condition. Penetrance is incomplete with age-related onset, but simplex cases have often been found to be due to de novo heterozygous variants rather than recessive variants. Over 100 different variants have been reported, including missense variants, in-frame indels, and splice-site variants leading to exon skipping.
There is evidence for a possible genotype-phenotype correlation for heterozygous DES variants, with variants located in specific domains more likely to cause either a neurological or cardiac phenotype.
There is a wide range of cardiac phenotypes associated with DES, including hypertrophic cardiomyopathy, restrictive cardiomyopathy, dilated cardiomyopathy, arrhythmogenic cardiomyopathy, and left-ventricular non-compaction. Cardiac involvement can be the presenting feature, even without recognised syndromic features, fulfilling a clinical diagnosis of HCM.
The mechanism of autosomal dominant disease is likely a dominant-negative effect of protein-altering variants leading to abnormal intermediate filament aggregation. The autosomal recessive phenotype has been associated with an earlier age of onset, and has been linked with combinations of protein-altering variants and/or null variants. It has been suggested that biallelic loss of function leads to the autosomal recessive phenotype, indicating a distinct mechanism of disease to the dominant phenotype. The heterozygous parents of patients with the recessive phenotype are reported as being clinically unaffected, suggesting that heterozygous loss of function is tolerated.

DES - HCM - Autosomal recessive¶

Gene symbol	DES
Gene mim	125660
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Rare syndromic disorder with hypertrophic cardiomyopathy - isolated LVH
Disease name	DES-related Myofibrillar myopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	biallelic_autosomal
Inheritance	Autosomal recessive
Inheritance modifiers	Typified by incomplete penetrance; Typified by age-related onset
Disease-associated variant consequence	absent gene product; altered gene product sequence
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant; inframe_deletion; stop_gained_NMD_triggering; stop_gained_NMD_escaping; frameshift_variant_NMD_triggering; splice_acceptor_variant_NMD_escaping; splice_donor_variant_NMD_escaping; frameshift_variant_NMD_escaping
PMIDs	20718792; 11073539; 29926427; 19433360; 9736733; 31718026; 30681346; 16217025; 23815709; 19181099
Disease accession	MONDO:0011076
Curated date	27.03.2021
Expert panel review date	12.01.2022
Expert panel	Cardiomyopathy expert panel

Narrative

DES-related myofibrillar myopathy is typically inherited as an autosomal dominant condition. Penetrance is incomplete with age-related onset, but simplex cases have often been found to be due to de novo heterozygous variants rather than recessive variants. Over 100 different variants have been reported, including missense variants, in-frame indels, and splice-site variants leading to exon skipping.
There is evidence for a possible genotype-phenotype correlation for heterozygous DES variants, with variants located in specific domains more likely to cause either a neurological or cardiac phenotype.
There is a wide range of cardiac phenotypes associated with DES, including hypertrophic cardiomyopathy, restrictive cardiomyopathy, dilated cardiomyopathy, arrhythmogenic cardiomyopathy, and left-ventricular non-compaction. Cardiac involvement can be the presenting feature, even without recognised syndromic features, fulfilling a clinical diagnosis of HCM.
The mechanism of autosomal dominant disease is likely a dominant-negative effect of protein-altering variants leading to abnormal intermediate filament aggregation. The autosomal recessive phenotype has been associated with an earlier age of onset, and has been linked with combinations of protein-altering variants and/or null variants. It has been suggested that biallelic loss of function leads to the autosomal recessive phenotype, indicating a distinct mechanism of disease to the dominant phenotype. The heterozygous parents of patients with the recessive phenotype are reported as being clinically unaffected, suggesting that heterozygous loss of function is tolerated.

FHL1 - HCM - Autosomal dominant¶

Gene symbol	FHL1
Gene mim	300163
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Rare syndromic disorder with hypertrophic cardiomyopathy - isolated LVH
Disease name	FHL1-related Emery Dreifuss muscular dystrophy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	Typified by age-related onset
Disease-associated variant consequence	altered gene product sequence; decreased gene product level
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	splice_region_variant; stop_lost; missense_variant; stop_gained_NMD_escaping; frameshift_variant_NMD_escaping
PMIDs	22523091; 19716112; 32993534; 20186852; 30681346
Disease accession	MONDO:0010680
Curated date	27.03.2021
Expert panel review date	12.01.2022
Expert panel	Cardiomyopathy expert panel

Narrative

FHL1-related Emery-Dreifuss muscular dystrophy is inherited as an X-linked condition. Carrier females are usually unaffected, but some exhibit a cardiac and/or skeletal muscle phenotype.
The precise mechanism is unclear, but may be mediated by reduced function or dominant-negative effects of altered FHL1, associated with frameshift/truncating variants predicted to escape nonsense mediated decay (NMD), missense variants, or loss of the native stop codon.
FHL1 pathogenic variants are responsible for a minority of Emery-Dreifuss muscular dystrophy cases (~1.2% according to GeneReviews). Hypertrophic cardiomyopathy is more typical of FHL1-related Emery-Dreifuss muscular dystrophy, while LMNA and EMD Emery-Dreifuss muscular dystrophy are more commonly associated with dilated cardiomyopathy.
There are reports of FHL1 variants causing isolated hypertrophic cardiomyopathy, without skeletal myopathy.

FLNC - HCM - Autosomal dominant¶

Gene symbol	FLNC
Gene mim	102565
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Rare syndromic disorder with hypertrophic cardiomyopathy - isolated LVH
Disease name	FLNC-related Myofibrillar myopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	Typified by age-related onset
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant; inframe_deletion; stop_gained_NMD_escaping
PMIDs	31245841; 26666891; 21135393; 25351925; 15929027; 30681346; 27908349; 32022900; 32112656; 20697107; 19050726
Disease accession	MONDO:0012289
Curated date	27.03.2021
Expert panel review date	12.01.2022
Expert panel	Cardiomyopathy expert panel

Narrative

FLNC-related myofibrillar myopathy is inherited as an autosomal dominant condition with age-related onset. Myofibrillar myopathy and isolated hypertrophic cardiomyopathy have been associated with protein-altering variants in FLNC (missense, in-frame deletion, and nonsense predicted to escape nonsense mediated decay (NMD)).
The specific mechanism of disease for pathogenic missense variants is not clear, but there is a cluster of HCM-related variants in the ROD2 domain, suggesting that these variants may affect interaction with the sarcomeric Z-disk. Variants associated with skeletal myopathy have been shown to induce intracellular aggregation of mutant FLNC.
Loss-of-function variants in FLNC have been associated with non-syndromic dilated and arrhythmogenic cardiomyopathy.
Sequencing of FLNC exons 46-48 is complicated by the presence of a pseudogene with >98% homology.

GLA - HCM - X-linked recessive¶

Gene symbol	GLA
Gene mim	300644
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Rare syndromic disorder with hypertrophic cardiomyopathy - isolated LVH
Disease name	GLA-related Fabry disease
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_X_hem
Inheritance	X-linked recessive
Inheritance modifiers	NA
Disease-associated variant consequence	altered gene product sequence; decreased gene product level
Mechanism	NA
Mutation consequence flag	restricted repertoire of mutations
Restricted repertoire of pathogenic variants	A recurrent intronic variant NM_000169.3(GLA):c.640-801G\>A is recognised as pathogenic and leads to aberrant mRNA splicing
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	splice_acceptor_variant; splice_donor_variant; frameshift_variant; stop_gained; missense_variant; inframe_deletion; intron_variant; inframe_insertion; stop_gained_NMD_triggering; splice_donor_variant_NMD_triggering; frameshift_variant_NMD_triggering; splice_acceptor_variant_NMD_triggering
PMIDs	34776082; 30988410; 18940466; 6023233; 27560961; 26937390; 34576250; 32640076; 2539398; 11322659
Disease accession	MONDO:0010526
Curated date	15.11.2021
Expert panel review date	24.11.2021
Expert panel	Cardiomyopathy expert panel

Narrative

Pathogenic GLA variants cause Fabry disease by decreased gene product level or altered gene product sequence. The disease mechanism is loss of function (PMID: 18940466; 26937390; 6023233; 2539398). GLA pathogenic variants result in mRNA instability and/or severely truncated a-galactosidase A (a-Gal A) enzyme or an enzyme with markedly decreased activity (NBK1292).

Fabry disease is an X-linked lysosomal storage disease caused by pathogenic variants in the GLA gene leading to a greatly reduced or absent activity of a-Gal A, responsible for metabolizing glycosphingolipids. This condition is associated with a progressive accumulation of globotriaosylceramide (Gb3) and its deacylated form, globotriaosylsphingosine (lysoGb3), potentially affecting any organ or tissue (PMID: 32640076).
Fabry disease is inherited in an X linked manner. Heterozygous females typically have milder symptoms at a later age of onset than males. Rarely, they may be relatively asymptomatic throughout a normal life span or may have symptoms as severe as those observed in males with the classic phenotype (NBK1292).

Variant classes include missense, nonsense, splice site, frameshift, in-frame deletions, and structural variants. A recurrent intronic variant (c.640-801G>A) is recognised as pathogenic and leads to aberrant mRNA splicing.
Many variants are unique however there are recognised recurrent variants also. (NBK1292; PMID 27560961; 30988410; 11322659; 34576250).
Pathogenic variants leading to complete loss of function of the gene product are usually associated with classic forms of the disease, whereas variants resulting in amino acid substitutions and residual enzyme activity can present atypically with either symptoms not specific to Fabry’s (e.g. cardiomyopathy) or a milder phenotype and later onset. Attempts to correlate genotype with clinical presentation have been largely unsuccessful. (PMID 27560961; 18940466). Experts noted that conduction disease can be the presenting or only feature of disease.

The expert consensus on the management of Fabry Disease in 2020 suggested that ‘Assessment of plasma lyso-Gb3 should be considered for assessment of disease severity in FD patients or in the diagnostic algorithm for patients with GLA genetic variants of unknown significance.’ (PMID: 32640076)

LAMP2 - HCM - X-linked dominant¶

Gene symbol	LAMP2
Gene mim	309060
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Rare syndromic disorder with hypertrophic cardiomyopathy - isolated LVH
Disease name	LAMP2-related Danon disease
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_X_het
Inheritance	X-linked dominant
Inheritance modifiers	Typified by age-related onset
Disease-associated variant consequence	altered gene product sequence; decreased gene product level
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	splice_region_variant; start_lost; missense_variant; stop_gained_NMD_triggering; splice_donor_variant_NMD_triggering; frameshift_variant_NMD_triggering; splice_acceptor_variant_NMD_triggering
PMIDs	19057086; 30681346; 19588270; 20173215; 10972294; 15673802; 30857840; 15907287; 16217705
Disease accession	MONDO:0010281
Curated date	27.03.2021
Expert panel review date	12.01.2022
Expert panel	Cardiomyopathy expert panel

Narrative

Pathogenic LAMP2 variants cause Danon disease. Danon disease follows X-linked inheritance, with high penetrance of cardiomyopathy (dilated or hypertrophic) in hemizygous males. Onset is age-related, with an older age of onset in females than in hemizygous males, and males are more likely to have syndromic involvement (including skeletal myopathy and cognitive impairment).
In the majority of cases, the mechanism is loss of function due to decreased gene product, as a result of frameshift variants, nonsense variants, splice-site variants, and copy-number variants. Individual pathogenic missense variants have been reported. Some missense variants also cause a reduction in protein level, e.g. due to aberrant splicing, but there are pathogenic missense variants which have been shown to affect protein structure rather than reducing protein expression.
A possible transcript-specific mechanism has been suggested, with variants affecting exon 9b reported as causing a primarily skeletal muscle phenotype, with limited cardiac involvement.

PRKAG2 - HCM - Autosomal dominant¶

Gene symbol	PRKAG2
Gene mim	602743
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Rare syndromic disorder with hypertrophic cardiomyopathy - isolated LVH
Disease name	PRKAG2-related cardiomyopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	NA
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant; inframe_insertion
PMIDs	28009297; 11371514; 26729852; 12015471; 32646569; 32259713; 32646570
Disease accession	MONDO:0010946
Curated date	20.11.2021
Expert panel review date	24.11.2021
Expert panel	Cardiomyopathy expert panel

Narrative

PRKAG2 pathogenic variants cause disease through altered gene product sequence.
PRKAG2 syndrome is a rare, early-onset autosomal dominant inherited disease, characterized by ventricular pre-excitation, supraventricular arrhythmias, and cardiac hypertrophy (PMID: 26729852; 32259713; 32646570).
There is a debate about penetrance but there appears to be variable expressivity of the clinical phenotype which may be variant specific (PMID: 32646569; 12015471).

PRKAG2 variants have been recognized mainly in the context of patients with non-sarcomeric familial hypertrophic cardiomyopathy associated with Wolff-Parkinson-White (WPW) syndrome (PMID: 26729852). The PRKAG2 gene encodes for the 5’ Adenosine Monophosphate-Activated Protein Kinase (AMPK), specifically for its gamma2 regulatory subunit (PRKAG2). PRKAG2 pathogenic variants are suspected to modify the tri-dimensional structure of AMPK, altering its affinity for AMP and modifying the enzyme activity (PMID: 32259713; 28009297).

Nearly all pathogenic variants are missense (PMID: 32259713; 32646569; 12015471; 28009297).
Blair et al. documented a TTA codon insertion in exon 5 in 2001 in a family affected by severe early onset cardiomyopathy and multiple sudden deaths in early adult life (PMID: 11371514). The variant is in a highly conserved region and co-segregated with disease. This has not been reported again on ClinVar.
Lopez-Sainz A et al reported one frameshift and one intronic variant (the rest missense) in their multi-centre retrospective study of 90 PRKAG2 variant carriers in 2020 (PMID: 32646569). However, the significance of truncating variants remains uncertain with insufficient evidence to support loss of function as a mechanism of disease. ClinGen found no evidence to support haploinsufficiency as a mechanism (https://search.clinicalgenome.org/kb/gene-dosage/HGNC:9386).
Two commonly reported variants are C.905G>A (p.Arg302Gln) and c.1463A>T (p.Asn488Ile). Lopez-Sainz A et al found they were present in 44% of the patients included in the cohort (PMID: 32646569).

PTPN11 - HCM - Autosomal dominant¶

Gene symbol	PTPN11
Gene mim	176876
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Rare syndromic disorder with hypertrophic cardiomyopathy - isolated LVH
Disease name	PTPN11-related Noonan syndrome
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	NA
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant; inframe_deletion
PMIDs	15521065; 21533187; 24739123; 16358218; 30681346; 25974318; 15240615; 14974085; 18348260; 21269411; 11992261; 19760651; 23312968
Disease accession	MONDO:0008104
Curated date	27.03.2021
Expert panel review date	12.01.2022
Expert panel	Cardiomyopathy expert panel

Narrative

PTPN11-related Noonan syndrome is inherited as an autosomal dominant condition with variable expressivity. Pulmonary stenosis is the most common cardiac manifestation. The penetrance of hypertrophic cardiomyopathy in PTPN11-related Noonan syndrome has been reported as 20-30%.
There is no definite evidence of PTPN11 variants causing isolated cardiac disease without other features of Noonan syndrome, but the syndromic phenotype can be subtle and may be underdiagnosed. This suggests that cardiac involvement can be the initial presentation in some cases, and PTPN11 should be considered in the differential diagnosis of HCM.
PTPN11 variants are the most common cause of Noonan syndrome, accounting for approximately 50% of cases. The mechanism is likely gain of function due to missense variants (particularly variants disrupting interaction between the N-SH2 and PTP domains), leading to activation of the RAS-MAPK pathway. There are at least two reports of Noonan syndrome due to single-residue in-frame deletions in PTPN11.
There are reports of structural duplications including PTPN11 causing Noonan syndrome, but all patients reported to date have had a relatively non-specific phenotype and large duplications encompassing other genes. It is therefore not clear whether gene duplication specifically causes Noonan syndrome.
Allelic disorders include Noonan syndrome with multiple lentigines (NSML, previously known as LEOPARD syndrome), caused by dominant-negative PTPN11 variants, and metachondromatosis, caused by loss-of-function PTPN11 variants.

PTPN11 - HCM - Autosomal dominant¶

Gene symbol	PTPN11
Gene mim	176876
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Rare syndromic disorder with hypertrophic cardiomyopathy - isolated LVH
Disease name	PTPN11-related Noonan syndrome with multiple lentigines
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	NA
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant
PMIDs	16377799; 15121796; 12161596; 16358218; 12058348; 33354767; 11992261; 17697839
Disease accession	MONDO:0100082
Curated date	27.03.2021
Expert panel review date	12.01.2022
Expert panel	Cardiomyopathy expert panel

Narrative

Noonan syndrome with multiple lentigines (NSML, previously known as LEOPARD syndrome) is inherited as an autosomal dominant condition. Missense variants in PTPN11 are responsible for the majority of cases. Rare cases have been attributed to variants in RAF1, BRAF, and MAP2K1. There is no definite evidence of PTPN11 variants causing isolated cardiac disease without other features of NSML, but the syndromic phenotype can be subtle and may be underdiagnosed. This suggests that cardiac involvement can be the initial presentation in some cases, and PTPN11 should be considered in the differential diagnosis of HCM.
PTPN11 variants associated with NSML are clustered in the phosphotyrosine phosphatase (PTP) domain and have been shown to inhibit phosphatase activity. Since null variants have not been associated with the NSML phenotype, it has been suggested that NSML is caused by a dominant-negative effect rather than simple loss of function, possibly due to altered interaction between PTPN11 and binding partners.
Allelic disorders include Noonan syndrome, caused by gain-of-function variants in PTPN11, and metachondromatosis, caused by loss-of-function PTPN11 variants.

RAF1 - HCM - Autosomal dominant¶

Gene symbol	RAF1
Gene mim	164760
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Rare syndromic disorder with hypertrophic cardiomyopathy - isolated LVH
Disease name	RAF1-related Noonan syndrome
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	NA
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant; inframe_deletion
PMIDs	29271604; 17603483; 30681346; 25974318; 17603482; 22786616; 24782337; 30762279
Disease accession	MONDO:0012690
Curated date	27.03.2021
Expert panel review date	12.01.2022
Expert panel	Cardiomyopathy expert panel

Narrative

RAF1 variants are responsible for ~5% of Noonan syndrome cases. RAF1-related Noonan syndrome is inherited as an autosomal dominant condition.
The mechanism is likely RAF1 gain of function, due to missense variants leading to activation of the Ras-MAPK pathway.
The penetrance of hypertrophic cardiomyopathy is higher in patients with RAF1 variants, compared to other forms of Noonan syndrome. There is no definite evidence of RAF1 variants causing isolated cardiac disease without other features of Noonan syndrome, but RAF1 variants have been identified in multiple patients who were being investigated for HCM, indicating that the syndromic phenotype can be subtle and may be underdiagnosed. Since cardiac involvement can be the initial presentation in some cases, RAF1 should be considered in the differential diagnosis of HCM.
There is evidence for a genotype-phenotype correlation, with variants in the CR2 domain of RAF1 more likely to be associated with HCM. There is a further mutational hotspot in the kinase domain of CR3, but pathogenic variants have also been identified outside these hotspots.
There are reports of patients with chromosomal duplications including RAF1, but their phenotype is relatively non-specific and there is no definitive evidence that whole-gene duplications cause Noonan syndrome.

RIT1 - HCM - Autosomal dominant¶

Gene symbol	RIT1
Gene mim	609591
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Rare syndromic disorder with hypertrophic cardiomyopathy - isolated LVH
Disease name	RIT1-related Noonan syndrome
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	NA
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant
PMIDs	26446362; 27101134; 30681346; 25959749; 23791108
Disease accession	MONDO:0014143
Curated date	27.03.2021
Expert panel review date	12.01.2022
Expert panel	Cardiomyopathy expert panel

Narrative

RIT1 variants are responsible for ~5% of Noonan syndrome cases. RIT1-related Noonan syndrome is inherited as an autosomal dominant condition.
The penetrance of hypertrophic cardiomyopathy is higher in patients with RIT1 variants, compared to other forms of Noonan syndrome (estimated at 70-75%). There is no definite evidence of RIT1 variants causing isolated cardiac disease without other features of Noonan syndrome, but the syndromic phenotype can be subtle and may be underdiagnosed. This suggests that cardiac involvement can be the initial presentation in some cases, and RIT1 should be considered in the differential diagnosis of HCM.
The mechanism is likely RIT1 gain of function, due to missense variants leading to activation of the Ras-MAPK pathway. The precise mechanism by which missense variants lead to gain of function remains unclear. There is clustering of variants, particularly in the switch II region.

TTR - HCM - Autosomal dominant¶

Gene symbol	TTR
Gene mim	176300
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Rare syndromic disorder with hypertrophic cardiomyopathy - isolated LVH
Disease name	TTR-related hereditary ATTR amyloidosis
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	Typified by incomplete penetrance
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant; inframe_deletion; inframe_insertion
PMIDs	32969287; 25604431; 9191784; 28213611; 15185500; 29941560; 30328212; 15930086
Disease accession	MONDO:0019441
Curated date	11.11.2021
Expert panel review date	12.01.2022
Expert panel	Cardiomyopathy expert panel

Narrative

The mechanism in TTR-related hereditary ATTR amyloidosis is due to altered gene product sequence.
The mechanism appears to be gain-of-function; pathogenic variants cause either tetramer dissociation or monomer denaturation, which both contribute to the formation of amyloid fibrils in tissue (PMID 25604431; NBK1194).
Of note, wildtype TTR can also cause an age-related late onset form of amyloidosis where patients almost exclusively present with cardiac involvement.

TTR-related hereditary ATTR amyloidosis is characterised by autosomal dominant inheritance with incomplete penetrance. There are reports of homozygous and compound heterozygous variants. Biallelic variants appear to cause a more severe phenotype (PMID: 28213611; 15185500; 30328212), however one study reported no difference in phenotype between homozygous and heterozygous carriers (PMID: 15930086).

TTR-related hereditary ATTR amyloidosis includes the phenotypes ATTR amyloid neuropathy, ATTR cardiac amyloidosis, ATTR leptomeningeal/CNS amyloidosis. Phenotype varies considerably; individuals can present with multi-systemic phenotypes including, polyneuropathy, carpal tunnel syndrome, cardiomyopathy, gastrointestinal features, autonomic insufficiency, and renal insufficiency. ‘The prevalence of HCM and/or RCM in Hereditary ATTR amyloidosis is high but exact percentages have not been accurately defined due the high prevalence of HCM and RCM (~25%) development in senile cardiac amyloidosis, which occurs due to accumulation of wildtype TTR accumulation in the heart with age.’ (ClinGen summary)

More than 100 different variants have been reported in the Hereditary Amyloidosis Registry (http://www.amyloidosismutations.com).
Variants are all missense apart from one inframe deletion of a valine residue in exon 4 (Plasma transthyretin levels in the mutant gene carriers measured by nephelometry were very low) and one 6 nucleotide duplication in exon 3. The duplication was reported to be associated with a particularly aggressive phenotype and although it did not alter the protein secondary or tertiary structure, it decreased the stability of the TTR monomer and tetramer (PMID: 9191784; 29941560).
Several variants including TTR-V30M, TTR-T60A, and TTR-V122L are commonly associated with cardiac amyloidosis (PMID: 28739313). There are other genotype phenotype correlations (PMID: 25604431; NBK1194).

The ATTR Val122Ile variant (also reported as pVal142Ile) is a risk allele in patient subpopulations of African American descent. The variant in this population has a high prevalence (estimated 3-4%) and patients are at particular risk for developing cardiac-related ATTR. (PMID: 28213611).

A systematic review in 2020 evaluating specific therapies for transthyretin cardiac amyloidosis supported the use of tafamidis (a tetramer stabiliser) and noted that other novel therapeutic targets including transthyretin gene silencers are currently under investigation (PMID: 32969287).

Syndrome with hypertrophic cardiomyopathy - no isolated LVH¶

ABCC9 - HCM - Autosomal dominant¶

Gene symbol	ABCC9
Gene mim	601439
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Syndrome with hypertrophic cardiomyopathy - no isolated LVH
Disease name	ABCC9-related Cantu Syndrome
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	NA
Disease-associated variant consequence	altered gene product sequence
Mechanism	gain of function
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant
PMIDs	31828977; 22608503; 34453476; 33529173; 31175705; 22610116; 30089727
Disease accession	MONDO:0009406
Curated date	11.11.2021
Expert panel review date	13.01.2025
Expert panel	DDG2P team

Narrative

ABCC9 pathogenic variants cause Cantu Syndrome (CS) through altered gene product sequence. The mechanism is likely gain of function (NBK246980; PMIDs: 22610116; 31175705; 30089727).
Harakalova et al showed that variants in ABCC9 reduce the ATP-mediated potassium channel inhibition, resulting in channel opening (PMID: 22610116). Pathophysiologic mechanisms resulting in the clinical manifestations remain poorly understood.

Cantu syndrome is characterized by congenital hypertrichosis, distinctive facial features, osteochondrodysplasia and cardiac defects. The cardiac manifestations include patent ductus arteriosus, cardiomegaly, hypertrophy and pericardial effusion. Our literature review has not found patients who have presented with isolated left ventricular hypertrophy (LVH). All participants with LVH in the Cantu registry who harboured a pathogenic missense variant have at least some additional features in keeping with Cantu syndrome, even if mild. There is however significant variability in phenotype even amongst family members with the same variant (PMID 33529173) and no clear genotype phenotype correlation (PMID 31828977).

Inheritance is autosomal dominant characterized by variable expressivity.

De novo variants are common, Grange et al found only 16/74 (22%) patients had inherited the ABCC9 variant from an affected parent (PMID: 31828977). It is caused by heterozygous missense mutations in ABCC9 (or less commonly variants in KCNJ8). A review of 74 patients in the International Registry for Cantu syndrome in 2019 found 28 distinct variants (97% were in ABCC9). All were simple missense apart from one insertion deletion involving 2 nucleotides (c.3055_3056 del ins GA). Missense variants were located throughout the protein, however a majority (68%) clustered around transmembrane domain 2 (TMD2). Variants at NM_020297.3(ABCC9): p.Arg1154 (identified in 24 subjects, 33%) and NM_020297.3(ABCC9):p.Arg1116 (identified in 11 subjects, 15%), were most commonly observed (PMID: 31828977). Zhang et al 2021 showed that p.Arg1154Gln variants in genetically modified mice might result in an effective mixed loss/gain of function phenotype, potentially explaining the diverse disease features in patients with CS. The mechanisms resulting in the clinical manifestations of CS remain to be fully elucidated (PMIDs 33529173; 34453476).

BAG3 - HCM - Autosomal dominant¶

Gene symbol	BAG3
Gene mim	603883
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Syndrome with hypertrophic cardiomyopathy - no isolated LVH
Disease name	BAG3-related Myofibrillar myopathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	Typically de novo
Disease-associated variant consequence	altered gene product sequence
Mechanism	NA
Mutation consequence flag	restricted repertoire of mutations
Restricted repertoire of pathogenic variants	NM_004281.4(BAG3):c.626C\>T (p.Pro209Leu)
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant
PMIDs	23995273; 20605452; 32453099; 22734908; 25728519; 19085932; 21361913
Disease accession	MONDO:0018943
Curated date	11.11.2021
Expert panel review date	12.01.2022
Expert panel	Cardiomyopathy expert panel

Narrative

BAG3 pathogenic variants cause a rare subtype of myofibrillar myopathy through altered gene product sequence.

Of note, loss of function of BAG3 is an established cause of dilated cardiomyopathy. Multiple missense, nonsense, frameshift variants have been described in association with DCM and there is sufficient evidence for haploinsufficiency as a mechanism (https://search.clinicalgenome.org/kb/genes/HGNC:939).

In contrast, a specific (missense) variant has been associated with myofibrillar myopathy (MFM). Typical presentation is toe walking and clumsiness with progression to cardiomyopathy and restrictive lung disease. The majority of evidence comes from one recurrent missense variant which causes MFM with prominent cardiac involvement. To our knowledge isolated hypertrophic or restrictive cardiomyopathy without skeletal muscle pathology has not been reported for BAG3 related MFM. In 2013, Olive et al (PMID: 23995273) summarised that only 12 patients with BAG3 related MFM, all carrying the same p.P209L recurrent de-novo mutation transmitted from a mosaic parent, have been reported to date (PMID: 19085932; 22734908; 21361913; 20605452).

A missense variant, p.Ala558Val, was reported in an infant with myofibrillar myopathy in 2011 (https://doi.org/10.1016/j.nmd.2011.06.1083) and the variant Pro209Gln is described in a patient with adult onset disease in 2014 (PMID 25208129). Malatesta L et al 2020 found that most patients who carry the p.Pro209Leu variant have cardiomyopathy (restrictive or hypertrophic) (14 of 18 patients) (PMID: 32453099). BAG3 is a cytoprotective protein that plays a role in the breakdown of misfolded proteins. It is produced in response to stress and is thought to be essential for the survival of mature skeletal and heart muscle cells by inhibiting the activation of apoptosis (PMID 25728519).

CRYAB - HCM - Autosomal dominant¶

Gene symbol	CRYAB
Gene mim	123590
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Syndrome with hypertrophic cardiomyopathy - no isolated LVH
Disease name	CRYAB-related Alpha-related B crystallinpathy
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	Typified by age-related onset
Disease-associated variant consequence	altered gene product sequence
Mechanism	undetermined non-loss-of-function
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	missense_variant; stop_gained_NMD_escaping; frameshift_variant_NMD_escaping; stop_lost
PMIDs	14681890; 21130652; 21337604; 570292; 28493373; 9731540; 30681346; 32420686; 21920752; 38212463; 33272090
Disease accession	MONDO:0013472
Curated date	27.03.2021
Expert panel review date	13.01.2025
Expert panel	DDG2P team

Narrative

CRYAB-related alpha-crystallinopathy is typically inherited as an autosomal dominant condition with age-related penetrance.

The mechanism is likely altered gene sequence of CRYAB due to either (1) missense variants or (2) truncating variants in the 3’ region which are predicted to escape nonsense mediated decay (NMD). A dominant-negative mechanism has been suggested (Selcen et al 2003 , Wang et al 2001 ). In addition two stop lost variants have been reported (PMIDs:38212463, 33272090).

Variants in CRYAB have been associated with systemic features of crystallinopathy (cataract, skeletal myopathy) with and without cardiac involvement. The cardiomyopathy phenotype includes various subtypes. Our literature search did not identify cases presenting with isolated left ventricular hypertrophy (LVH).

Evidence for dosage sensitivity is limited. Homozygous truncating variants predicted to cause NMD have been associated with autosomal recessive congenital/early-onset cataracts and myopathy with respiratory involvement in early childhood, and the heterozygous parents of probands are reported as being healthy.

FXN - HCM - Autosomal recessive¶

Gene symbol	FXN
Gene mim	606829
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Syndrome with hypertrophic cardiomyopathy - no isolated LVH
Disease name	FXN-related Friedreich ataxia
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	biallelic_autosomal
Inheritance	Autosomal recessive
Inheritance modifiers	Typified by age-related onset
Disease-associated variant consequence	altered gene product sequence; decreased gene product level
Mechanism	loss of function
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	splice_region_variant; start_lost; inframe_deletion; inframe_insertion; splice_donor_variant_NMD_triggering; frameshift_variant_NMD_triggering; splice_acceptor_variant_NMD_triggering; trinucleotide_repeat_expansion; exon_loss_variant; transcript_ablation
PMIDs	28405347; 25566998; 30681346; 24705334; 10633128; 22409940; 26704351; 22691228
Disease accession	MONDO:0100339
Curated date	27.03.2021
Expert panel review date	13.01.2025
Expert panel	DDG2P team

Narrative

FXN-related Friedreich ataxia is inherited as an autosomal recessive condition. It is characterised by a progressive ataxia usually manifesting as poor balance when walking before progressing to upper limb ataxia and dysarthria. Two thirds of individuals have hypertrophic cardiomyopathy (HCM); diabetes mellitus can also be associated. Our literature search did not identify cases presenting with isolated left ventricular hypertrophy (LVH). Heterozygous carriers of FXN expansions or other pathogenic variants have not been reported to develop symptoms.

Homozygous expansion of the GAA triplet repeat in exon 1 of FXN is responsible for the majority of cases (95-98%). There is an inverse correlation between the size of the expansion and age of onset (particularly the size of the shorter allele). Anticipation is not observed as the disorder follows autosomal recessive inheritance.

The remaining cases are due to compound heterozygosity for a GAA expansion and a sequence variant (truncating, splice-site, or missense) or structural variant (single/multi-exon or whole-gene deletion). There is evidence that compound heterozygosity is associated with earlier onset of symptoms than homozygosity for the GAA triplet repeat expansion, but cardiomyopathy is more common in patients with a homozygous GAA triplet repeat expansion.

The mechanism is likely loss of function of FXN due to transcriptional silencing (in the case of the GAA triplet repeat), absent/decreased gene product (truncating variants, structural variants), or missense variants causing loss of function.

GAA - HCM - Autosomal recessive¶

Gene symbol	GAA
Gene mim	606800
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Syndrome with hypertrophic cardiomyopathy - no isolated LVH
Disease name	GAA-related Pompe disease
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	biallelic_autosomal
Inheritance	Autosomal recessive
Inheritance modifiers	NA
Disease-associated variant consequence	altered gene product sequence; decreased gene product level
Mechanism	loss of function
Mutation consequence flag	restricted repertoire of mutations
Restricted repertoire of pathogenic variants	A specific 5’ UTR variant, NM_000152.5(GAA):c.-32-13T\>G, ClinVar variation ID 4027 has been reported in 40-70% of the alleles in patients affected with late onset disease (PMID 24150945; 7881425).
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	splice_region_variant; splice_acceptor_variant_NMD_triggering; splice_donor_variant_NMD_triggering; start_lost; frameshift_variant_NMD_escaping; frameshift_variant_NMD_triggering; stop_gained_NMD_triggering; missense_variant; inframe_deletion; transcript_ablation; 5_prime_UTR_variant
PMIDs	1680134; 1856189; 9668092; 14643388; 19588081; 31254424; 9535769; 8094613; 1652892; 7717400; 20882352; 30681346; 21484825; 11991748; 7981676; 10973860; 28185884; 31342611; 4286143; 17056254; 3108320
Disease accession	MONDO:0009290
Curated date	27.03.2021
Expert panel review date	13.01.2025
Expert panel	DDG2P team

Narrative

Pompe disease is inherited as an autosomal recessive condition, caused by homozygous or compound heterozygous variants in GAA. Infantile-onset Pompe disease is characterised by hypotonia, generalized muscle weakness, feeding difficulties, failure to thrive, respiratory distress, and hypertrophic cardiomyopathy; late onset Pompe disease is characterised by proximal muscle weakness and respiratory insufficiency. The mechanism of disease is loss of function of acid alpha-glucosidase, resulting in lysosomal glycogen accumulation.

There are currently over 900 variants in the Pompe variant database (N.B. this includes all known variants, regardless of pathogenicity). Multiple classes of variant have been shown to cause Pompe disease, including loss-of-function variants, missense variants, splice-site variants, 5 prime UTR variants, intronic variants, and structural variants.
A specific 5 prime UTR variant, NM_000152.5(GAA):c.-32-13T>G, (the variant is 13 bases upstream of a splice junction, which is located in the UTR 32 bases upstream of the start codon), ClinVar variation ID 4027, has been reported in 40-70% of the alleles in patients affected with late onset disease (PMID 24150945). Functional studies have shown the presence of the c.-32-13T>G variant causes aberrant splicing, resulting in exclusion of exon 2 in the processed transcript (PMID 7881425)

There is a genotype-phenotype correlation, with biallelic loss of function expected to result in a severe phenotype (infantile-onset Pompe disease), while patients with residual enzymatic activity develop late-onset Pompe disease. Cardiac involvement is a classical feature of infantile-onset Pompe disease, but has also been reported in the late-onset form. Our literature search did not identify cases presenting with isolated left ventricular hypertrophy (LVH).

MYO6 - HCM - Autosomal dominant¶

Gene symbol	MYO6
Gene mim	600970
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Syndrome with hypertrophic cardiomyopathy - no isolated LVH
Disease name	MYO6-related nonsyndromic genetic hearing loss with left ventricular hypertrophy
Gene disease validity (ClinGen)	MODERATE
Allelic requirement	monoallelic_autosomal
Inheritance	Autosomal dominant
Inheritance modifiers	Typified by age-related onset
Disease-associated variant consequence	altered gene product sequence; decreased gene product level
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	splice_acceptor_variant; splice_donor_variant; frameshift_variant; stop_gained; missense_variant
PMIDs	26265212; 15060111; 30681346; 18348273; 23485424; 12687499; 25999546; 24105371
Disease accession	MONDO:0019497
Curated date	27.03.2021
Expert panel review date	13.01.2025
Expert panel	DDG2P team

Narrative

There is evidence from multiple reports that protein truncating and missense variants in MYO6 are associated with autosomal dominant progressive hearing loss. Homozygosity or compound heterozygosity is associated with congenital hearing loss, suggesting a dose-dependent mechanism. ClinGen classified the relationship between MYO6 and hearing loss as Definitive. The relationship for hearing loss and left ventricular hypertrophy (LVH) was not classified separately as there wasn’t evidence of a distinct mechanism for the two phenotypes. Overall the evidence for cardiac involvement is limited.

Mohiddin et al. (2004, PMID: 15060111) reported a family with autosomal dominant hearing loss who were initially ascertained due to the proband presenting with hypertrophic cardiomyopathy. Linkage studies implicated the region containing MYO6, and a missense variant was identified (p.His246Arg) and segregated with disease (with the exception of one individual who was negative for the variant but described as a double phenocopy with presbycusis and cardiac abnormalities consistent with valvar and ischaemic disease). QT prolongation was observed in 5 out of 12 carriers of the variant. Evidence of LVH was observed in 4 out of 11 carriers who underwent echocardiogram. No specific mechanism of disease causation was suggested.
Studies in transgenic mouse models have suggested a link with cardiac hypertrophy, but only in biallelic knockout mice.

In summary, there is a single report linking the p.His246Arg variant in MYO6 with a hypertrophic cardiomyopathy phenotype exhibiting incomplete penetrance (Mohiddin et al. 2004, PMID: 15060111). The authors note that they were unable to definitively rule out an alternative cause for the cardiac phenotype in the family. This phenotype has not been observed in other families presenting with MYO6-related hearing loss (e.g., Sanggaard et al. 2008, PMID: 18348273; Miyagawa et al. 2015, PMID: 25999546), including patients with homozygous loss-of-function or missense variants (Ahmed et al. 2003, PMID: 12687499).

The G2P team have assigned the relationship between MYO6 and hearing loss and LVH as moderate to ensure that variants in this gene are at least considered in a patient presenting with hearing loss and LVH. Our literature search did not identify cases presenting with isolated LVH.

MYO6 - HCM - Autosomal recessive¶

Gene symbol	MYO6
Gene mim	600970
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Syndrome with hypertrophic cardiomyopathy - no isolated LVH
Disease name	MYO6-related nonsyndromic genetic hearing loss with left ventricular hypertrophy
Gene disease validity (ClinGen)	MODERATE
Allelic requirement	biallelic_autosomal
Inheritance	Autosomal recessive
Inheritance modifiers	Typified by age-related onset
Disease-associated variant consequence	altered gene product sequence; decreased gene product level
Mechanism	NA
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	splice_acceptor_variant; splice_donor_variant; frameshift_variant; stop_gained; missense_variant
PMIDs	26265212; 15060111; 30681346; 18348273; 23485424; 12687499; 25999546; 24105371
Disease accession	MONDO:0019497
Curated date	27.03.2021
Expert panel review date	13.01.2025
Expert panel	DDG2P team

Narrative

There is evidence from multiple reports that protein truncating and missense variants in MYO6 are associated with autosomal dominant progressive hearing loss. Homozygosity or compound heterozygosity is associated with congenital hearing loss, suggesting a dose-dependent mechanism. ClinGen classified the relationship between MYO6 and hearing loss as Definitive. The relationship for hearing loss and left ventricular hypertrophy (LVH) was not classified separately as there wasn’t evidence of a distinct mechanism for the two phenotypes. Overall the evidence for cardiac involvement is limited.

Mohiddin et al. (2004, PMID: 15060111) reported a family with autosomal dominant hearing loss who were initially ascertained due to the proband presenting with hypertrophic cardiomyopathy. Linkage studies implicated the region containing MYO6, and a missense variant was identified (p.His246Arg) and segregated with disease (with the exception of one individual who was negative for the variant but described as a double phenocopy with presbycusis and cardiac abnormalities consistent with valvar and ischaemic disease). QT prolongation was observed in 5 out of 12 carriers of the variant. Evidence of LVH was observed in 4 out of 11 carriers who underwent echocardiogram. No specific mechanism of disease causation was suggested.
Studies in transgenic mouse models have suggested a link with cardiac hypertrophy, but only in biallelic knockout mice.

In summary, there is a single report linking the p.His246Arg variant in MYO6 with a hypertrophic cardiomyopathy phenotype exhibiting incomplete penetrance (Mohiddin et al. 2004, PMID: 15060111). The authors note that they were unable to definitively rule out an alternative cause for the cardiac phenotype in the family. This phenotype has not been observed in other families presenting with MYO6-related hearing loss (e.g., Sanggaard et al. 2008, PMID: 18348273; Miyagawa et al. 2015, PMID: 25999546), including patients with homozygous loss-of-function or missense variants (Ahmed et al. 2003, PMID: 12687499).

The G2P team have assigned the relationship between MYO6 and hearing loss and LVH as moderate to ensure that variants in this gene are at least considered in a patient presenting with hearing loss and LVH. Our literature search did not identify cases presenting with isolated LVH.

SLC25A4 - HCM - Autosomal recessive¶

Gene symbol	SLC25A4
Gene mim	103220
Indication	HCM
Referral indication	Hypertrophic Cardiomyopathy (HCM)
Disease grouping	Syndrome with hypertrophic cardiomyopathy - no isolated LVH
Disease name	SLC25A4-related Mitochondrial disease
Gene disease validity (ClinGen)	DEFINITIVE
Allelic requirement	biallelic_autosomal
Inheritance	Autosomal recessive
Inheritance modifiers	NA
Disease-associated variant consequence	absent gene product; altered gene product sequence
Mechanism	loss of function
Mutation consequence flag	NA
Restricted repertoire of pathogenic variants	NA
Variant classes reported with evidence of pathogenicity (Other potentially relevant variant classes)	splice_donor_variant; missense_variant; frameshift_variant_NMD_triggering
PMIDs	22187496; 30013777; 16155110; 23401503; 25732997; 27693233
Disease accession	MONDO:0044970
Curated date	11.11.2021
Expert panel review date	13.01.2025
Expert panel	DDG2P team

Narrative

Pathogenic variants in SLC25A4 cause mitochondrial disease through altered gene product sequence or absent gene product level. SLC25A4 encodes AAC1 (also known as ANT1), an ADP/ATP carrier isoform expressed at high levels in the skeletal muscle, heart and brain.

Loss of function recessive mutations cause a mitochondrial myopathy and cardiomyopathy phenotype that presents in childhood or early adulthood (also known as mitochondrial DNA depletion syndrome 12). These comments refer to this phenotype category. There are two other distinct phenotype groups: inherited heterozygous missense variants have been associated with an adult-onset autosomal-dominant progressive external ophthalmoplegia; and 2 recurrent de novo missense variants have been reported in seven individuals with a characteristic and severe early onset mitochondrial disease (PMIDs: 27693233; 30013777). As far as we are aware SCL25A4 variants do not present with isolated left ventricular hypertrophy (LVH).

It is suggested that variants in SLC25A4 leading to transporter dysfunction causes insufficient adenine nucleotide availability for dATP synthesis and consequent imbalanced dNTP pools, leading to mtDNA depletion (PMID 27693233; 30013777). A small number of homozygous and compound heterozygous variants have been described including missense, frameshift and splice variants. There are 4 pathogenic submissions on ClinVar. All are predicted to cause loss of function (; ; ). Thompson et al found that 3 previously reported recessive variants resulted in \<1% transport activity compared to wild-type (PMID 27693233).

Other potentially relevant variant classes¶

Which variant classes should I filter for? The main table shows variant classes that have been reported to cause disease. We would expect other variant classes with similar consequences to cause disease (e.g. if NMD_triggering frameshift cause disease, then NMD_triggering nonsense probably do too). This table below shows the full list of variant classes mapped to each variant consequence.

Disease-associated variant consequence
Decreased_gene_product_level	Absent_gene_product_level	Altered_gene_product_sequence
splice_region_variant	splice_acceptor_variant	splice_acceptor_variant
splice_acceptor_variant	splice_acceptor_variant_NMD_triggering	splice_acceptor_variant_NMD_escaping
splice_acceptor_variant_NMD_triggering	splice_donor_variant	splice_donor_variant
splice_donor_variant	splice_donor_variant_NMD_triggering	splice_donor_variant_NMD_escaping
splice_donor_variant_NMD_triggering	start_lost	frameshift_variant_NMD_escaping
start_lost	frameshift_variant	stop_gained_NMD_escaping
frameshift_variant	frameshift_variant_NMD_triggering	stop_lost
frameshift_variant_NMD_triggering	stop_gained	missense_variant
stop_gained	stop_gained_NMD_triggering	inframe_insertion
stop_gained_NMD_triggering		inframe_deletion
Note:
Variant classes with a likelihood score of ‘3:possible’, ‘4:probable’ and ‘5:almost always’ For the different disease associated variant consequences, see Tables 2 and 3 from Roberts et al.

Roberts AM, DiStefano MT, Riggs ER, Josephs KS, Alkuraya FS, Amberger J, Amin M, Berg JS, Cunningham F, Eilbeck K, Firth HV, Foreman J, Hamosh A, Hay E, Leigh S, Martin CL, McDonagh EM, Perrett D, Ramos EM, Robinson PN, Rath A, Sant DW, Stark Z, Whiffin N, Rehm HL, Ware JS. Toward robust clinical genome interpretation: Developing a consistent terminology to characterize Mendelian disease-gene relationships-allelic requirement, inheritance modes, and disease mechanisms. Genet Med. 2024 Feb;26(2):101029. https://doi.org/10.1016/j.gim.2023.101029