MYL2 was first reported in relation to autosomal dominant (AD) dilated cardiomyopathy (DCM) in 2015 (Huang et al., 2015, PMID 25825243). MYL2 was originally evaluated for DCM by the ClinGen DCM GCEP on September 11, 2020. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on May 16, 2025. As a result, the classification did not change. A summary of the information contributing to the classification of this gene at the time of re-evaluation is summarized herein. In addition to DCM, MYL2 has also been reported with hypertrophic cardiomyopathy and myofibrillar myopathy at the time of review. This was considered in accordance with ClinGen lumping and splitting criteria. Due to the distinct differences in phenotypic variability the curation was split and curated for AD DCM. Human genetic evidence supporting this gene-disease relationship includes case-level data. At least one missense variant has been reported in humans with DCM. Huang et al., (2015, PMID 25825243) reported p.Asp94Ala in three family members with DCM. In addition, this gene-disease assertion is supported by animal models, expression studies, and protein interaction studies. MYL2 has been shown to be expressed in cardiac tissue (Price et al., 1980, PMID 7236212, Chen et al., 1998, PMID 9422794, Rottbauer et al, 2006, PMID 16809551). It has been shown MYL2 interacts with MYH7 (Rayment et al., 1993, PMID: 8316857, Huang et al., 2015, PMID: 25825243). Yuan et al., reported an heterozygous mouse model with the p.Asp94Ala variant where the mice developed DCM (2018, PMID 29463717). Three other animal models have been reported but all were knockout models and consequently only 0.5 pts were awarded for each model (Chen et al., 1998, PMID 9422794, Rottbauer et al, 2006, PMID 16809551, Sheikh et al., 2012, PMID 22426213). In summary, there is limited evidence to support this gene-disease relationship. More evidence is needed to support the relationship of MYL2 with AD DCM. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on May 16, 2025 (SOP Version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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