Submission Details

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.