MYL3: Hypertrophic Cardiomyopathy. The MYL3 gene has been associated with autosomal dominant hypertrophic cardiomyopathy (HCM) in at least 20 probands in 13 publications. More than 8 unique variants (mostly missense, 1 splice acceptor variant) have been reported in humans, and variants in this gene segregated with disease in 24 additional family members. MYL3 was first associated with HCM in humans in 1996 (Poetter et al, PMID 8673105). The MYL3 gene was significantly enriched for missense variants in Walsh et al. 2016 (PMID 27532257), with an Odds Ratio of 5.00 (3.43-7.27) for HCM. This gene-disease association is supported by expression studies (Fujimoto et al, 1993, PMD 8417110), a mouse model (Vemuri et al, 1991, PMID 9927691), and evidence of interaction with MYH7 (Petzhold et al, 2011, PMID 21262909) as well as ACTC1 (Haase et al, 2006, PMID 16675844). In summary, MYL3 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 December 22, 2017 using version 5 of the SOP and was recurated on March 15, 2021. As a result of this reevaluation, the classification did not change but one publication was added for additional experimental evidence (PMID:12186978).
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