Submission Details

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.