MYH7

Inheritance Pattern: AD

Disease ID:MONDO:0013262

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0013262

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0008050

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0008050

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0013262

Submitter: ClinGen

MYH7 was originally evaluated for DCM by ClinGen DCM GCEP on November 4, 2020. Evidence of the association of this gene with DCM was re-evaluated on 04/13/2025. As a result, the classification did not change. A summary of the information contributing to the classification of the gene at the time of re-evaluation is summarized herein. MYH7 was evaluated for autosomal dominant dilated cardiomyopathy (DCM). MYH7 is composed of 1935 amino acids, including 41 exons, 38 of which are protein coding and contains a head region and a tail domain, which represent key regions for variation. The encoded beta myosin heavy chain protein, expressed in cardiac and skeletal muscle, forms part of the myosin complex which generates the mechanical force needed for contraction. Human genetic evidence supporting this gene-disease relationship includes case-level data, case-control data, and segregation data. MYH7 is not known to be haploinsufficient, and DCM has been associated with variants that produce an abnormal protein with reduced function, but not variants that introduce a premature termination codon and would be predicted to undergo nonsense mediated decay. Many variants have been reported in humans with DCM and non-truncating variants are enriched in DCM cases (Mazzarotto et al, 2020, PMID: 31983221) and truncating variants in MYH7 are unlikely to be disease causing (pLI=0; LOEUF=0.57). Of note, distinct alleles in MYH7 have been associated with hypertrophic cardiomyopathy through different molecular mechanisms than DCM-causing MYH7 variants. Accordingly, case data and segregation data with MYH7 missense variation observed in DCM was evaluated. For example, Kamisago et al (2000, PMID: 11106718) reported NM_000257.4:c.1594T>C (p.Ser532Pro) to segregate in 16 individuals in a family with DCM and NM_000157.4:c.2292C>G (p.Phe764Leu) to segregate in 3 individuals in another DCM pedigree. Additional DCM-segregating variants have also been published by other investigative groups, including the NM_000257.4:c.2773A>G (p.Arg925Gly) variant in 3 related individuals (Vasilescu et al, 2018, PMID: 30384889). In addition, the p.Asn1918Lys variant has also been reported in multiple in 7 affected individuals of Dutch ancestry, including 6 pedigrees reported by van der Linde et al (2017, PMID: 28864942), one family in whom 7 individuals with DCM were shown to segregate the variant with the phenotype. Multiple other singleton and small pedigree DCM cases have also been reported in the literature with missense variation with MYH7 that have some evidence supporting a pathogenic effect (Rampersaud et al, 2011, PMID: 21483645; Petri et al, 2019, PMID: 30874888; Millat et al, 2011, PMID: 21846512; Vasilescu et al, 2018, PMID: 30384889; Garcia-Giustiniani et al, 2015, PMID: 25935763; van Spaendonck-Zwartz et al, 2014, PMID: 24558114; Cann et al, 2017, PMID 27000522; Sausa et al, 2019, PMID: 31179125; Merlo et al, 2013, PMID: 24119082; Sajid et al, 2017, PMID: 27965028). Additional evidence is available in the literature, but the maximum score for genetic evidence has been reached. In addition, this gene-disease assertion is supported by experimental evidence, including biochemical function, functional alteration, non-human model organism, and protein interaction data. MYH7 has been shown to interact with other key proteins associated with the DCM phenotype (Dai et al, 2020, PMID: 31937807). Further, Ujfalusi et al (2018, PMID: 29666183) showed reduced force mechanics in the presence of abnormal MYH7 variation and Vikorev et al (2017, PMID: 29093449) isolated human cardiac myofibrils with the MYH7 Glu1426Lys variant and observed significantly reduced passive stiffness through kinetic studies. The DCM phenotype has also been demonstrated in heterozygous mouse models harboring the MYH7 S532P and S764L variants (Schmitt et al, 2006, PMID: 16983074). Of relevance, the investigators in the Schmitt et al murine models targeted Myh6 to mimic the DCM-associated MYH7 S532P and S764L variants, as Myh6 is the predominant myosin gene expressed in adult murine heart tissues. MYH7 has also been curated by the Hereditary Cardiovascular Disease geneHypertrophic Cardiomyopathy (HCM) expert panel for hypertrophic cardiomyopathy(Definitive, 07/12/202312/2/2017), the Congenital Myopathies gene curation expert panel for MYH7-related skeletal myopathy (Definitive, 05/13/2021), the Arrhythmogenic Right Ventricular Cardiomyopathy gene curation expert panel for ARVC (Limited, 0806/2019), and the Congenital Heart Disease gene curation expert group for congenital heart disease (Limited, 02/12/2024). . In summary, MYH7 is definitively associated with autosomal dominant DCM. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on November 4, 2020 (SOP Version 7). This written summary was updated on 04/13/2025 and approved by the DCM GCEP on 05/30/2025.

Inheritance Pattern: AD

Disease ID:MONDO:0016587

Submitter: ClinGen

MYH7: Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) HGNC: 7577 http://purl.obolibrary.org/obo/MONDO_0016587 Mode of Inheritance: Autosomal dominant inheritance (HP:0000006) Expert Panel: Arrhythmogenic Right Ventricular Cardiomyopathy SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6 Calculated Classification (date) Limited 22/03/2019 Evidence Summary: There is limited evidence that MYH7 is associated with ARVC. Screening of ARVC patient cohorts for MYH7 mutations has been performed in four studies (29709087, 27194543, 29253866 and 30385303). In these studies, a total of 245 ARVC patients were investigated and eight individuals were reported carrying MYH7 variants (a deletion and seven missense). However, the significance of these variants in the context of ARVC is unclear as they were either VUS (e.g. p.Arg1846Cys) or previously reported as causative in hypertrophic cardiomyopathy (e.g. p.Lys847del). In one ARVC pedigree the identified MYH7 p.Met877Ile variant did not segregate with ARVC in the family (28699631). In summary, there is limited evidence to support this gene-disease association. There is no clear evidence that the identified MYH7 variants contribute to the ARVC phenotype and there is no known disease mechanism that would link MYH7 with ARVC.

Inheritance Pattern: AR

Disease ID:MONDO:0009708

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0008647

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0013262

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0012018

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0009144

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: ClinGen

MYH7 was first reported in relation to autosomal dominant congenital heart disease in 2021 (Hirono et al.; PMID: 33309763). Three variants (missense, in-frame indel) that have been reported in three probands in three publications (PMID: 33309763, 35993536, 35491958) are included in this curation. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (GTEx expression data). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 2/12/2024 (SOP Version 10).

Inheritance Pattern: AD

Disease ID:MONDO:0018901

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0018889

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0008050

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0005045

Submitter: ClinGen

Variation in the MYH7 gene is associated with autosomal dominant hypertrophic cardiomyopathy (HCM). HCM was first linked to variation in MYH7 in 1990 (Geisterfer-Lowrance et al, 1990, PMID 1975517). Over 100 missense pathogenic variants have subsequently been reported in humans with HCM (Alfares et al, 2015, PMID: 25611685), and robust association and/or linkage has been demonstrated for many distinct variants (Watkins et al, 1992, PMID 1552912). Not all evidence in the literature has been curated. The mechanism for disease is gain of function. This gene-disease association is supported by functional assays (including Han et al, 2014, PMID 25209314; Lan et al, 2013, PMID 23290139; Sommese et al, 2013, PMID 23798412), expression of MYH7 in heart tissue (Perryman et al, 1992, PMID 1634614; GTEx Consortium, 2013, PMID 23715323), and an HCM mouse model that recapitulates the phenotype (Geisterfer-Lowrance et al, 1996, PMID 8614836). In summary, MYH7 is definitively associated with autosomal dominant HCM. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hypertrophic Cardiomyopathy Gene Curation Expert Panel on November 1, 2016 using SOP version 5. This gene-disease relationship was updated and recurated on January 28, 2021. On July 12, 2023, this gene was precurated to evaluate whether HCM should be curated alone or with other cardiac phenotypes. The Hereditary Cardiovascular Disease GCEP decided that HCM should be curated alone and that there was no need to recurate for this disease entity since it has a definitive relationship with MYH7. The scoring was updated to SOP version 9 at this time. As a result of these updates, the classification did not change.

Inheritance Pattern: AR

Disease ID:MONDO:0009708

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0008647

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0008050

Submitter: ClinGen

MYH7 was first reported in relation to autosomal dominant myopathy including Laing distal myopathy in 1995 (Laing et al., PMID7847377), myosin storage myopathy in 2013 (Bohlega et al.,PMID14663035) and scapuloperoneal syndrome in 2007 ( Pegoraro et al.,PMID17336526). At least 50 variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data and experimental data. Variants in this gene have been reported in at least 17​ probands in ​8​​ publications (​PMID27387980, 24664454,21211974,21279644,14520662,27519903,15322983,30794915). Variants in this gene segregated with disease in 37​​ additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is dominant negative (Sjoberg et al.,PMID10545598). Of note, this gene has also been implicated in cardiomyopathy without myopathy.These ​have been​​ assessed separately by Cardiomyopathy Expert Panel. This gene-disease association is supported by ​animal models, expression studies, ​​in vitro​​ functional assays. In summary, ​MYH7​​ is definitively associated with Autosomal dominant myopathy​​. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference for Laing distal myopathy, myosin storage myopathy and scapuloperoneal syndrome and other MYH7 related myopathies (ex. PMID23478172, PMID29624713) in molecular mechanism AND inheritance pattern AND phenotypic variability. Therefore, all of the disease entities have been lumped into one disease entity, ​MYH7-related skeletal myopathy.

Inheritance Pattern: AD

Disease ID:MONDO:0015470

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0008647

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0016587

Submitter: G2P