Submission Details

The MYL2 gene has been associated with autosomal dominant hypertrophic cardiomyopathy (HCM) in at least 40 probands in 10 publications (Poetter et al, 1996, PMID 8673105; Flavigny et al, 1998, PMID 9535554; Kabaeva et al, 2002, PMID 12404107; Richard et al, 2003, PMID 12707239; Morner et al, 2003, PMID 12818575; Garcia-Pavia et al, 2011, PMID 21896538; Santos et al, 2012, PMID 22429680; Berge et al, 2013, PMID 24111713; Lopes et al, 2015, PMID 25351510; Claes et al, 2015, PMID 26497160). More than 8 unique variants (missense, splice site, nonsense, frameshift) have been identified in humans, and convincing segregation data has been reported (Flavigny et al, 1998, PMID 9535554). In addition, at least 8 missense VUSs in MYL2 have been reported in patients with HCM. MYL2 was first associated with HCM in humans in 1996 (Poetter et al, 1996, PMID 8673105). The MYL2 gene was significantly enriched for missense variants in Walsh et al, 2016 (PMID 27532257) with and odds ratio of 6.74 (95% CI 4.69-9.70) for non-truncating variants and 3.10 (95% CI 0.89-10.7) for truncating variants. This gene-disease association is supported by expression data (Price et al, 1980, PMID 7236212), interaction with other known HCM gene products (MYH7, MYL3) (Rayment et al, 1993, PMID 8316857), and animal models (Szczesna-Cordary et al, 2005, PMID 16076902; Wang et al, 2006, 16837010; Kerrick et al, 2009, PMID 18987303). In summary, MYL2 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 originally approved by the ClinGen Hypertrophic Cardiomyopathy Gene Curation Expert Panel on February 7th, 2017 using SOP version 4. It was reevaluated on July 7th, 2021. As a result of this reevaluation, the classification did not change.