MYH6 was first reported in association with autosomal dominant hypertrophic cardiomyopathy (HCM) in humans in 2002 (Niimura et al. 2002, PMID 11815426). MYH6 gene encodes alpha heavy chain subunit of cardiac myosin (MHC-α), which are actin-based molecular motors that convert chemical energy released from the hydrolysis of ATP. It has been associated with HCM in 3 probands in 2 publications. Four unique heterozygous missense variants have been reported in humans with limited evidence to support their pathogenicity (Niimura et al. 2002, PMID 11815426; Rubattu et al. 2016, PMID 27483260; Wang et al. 2020 PMID 33385793). Additional missense variants have been reported in humans, but were not scored because probands have variants in another HCM gene (Rubattu et al. 2016, PMID 27483260; Liu et al. 2021, PMID 34087240; Suzuki et al. 2022, PMID 35911064), or high frequency in the population (Carniel et al. 2005, PMID 15998695).
The mechanism for disease remains unknown. The gene-disease association is supported by expression studies in the human heart (Gorza, et al. 1984, PMID 6234108) and biochemical function showing MHC-α interactions with ATP, actin and the light chains (Weiss et al. 1999, PMID 10388558). Additional studies on mice models of HCM using pre-engineered heterozygous, pathogenic MYH7 variant orthologous to the human p.R403Q allele into the mouse MYH6 were reviewed, but not scored because these mice models are not analogous to human MYH6 (Geisterfer-Lowrance et al. 1996, PMID 8614836; Jiang, et al. 2013 PMID 24092743).
This classification was originally approved by the ClinGen Hypertrophic Cardiomyopathy Gene Curation Expert Panel on November 1, 2017, with a classification of “Limited”. It was reevaluated by the ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel on July 12, 2023. As a result of this reevaluation, the classification was changed from “Limited” to “Disputed” due to absence of new compelling genetic and experimental evidence.
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