MYL3 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 29, 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.
MYL3 was first reported in relation to autosomal dominant dilated cardiomyopathy (DCM) in 2015 (Zhao et al., 2015, PMID 26458567). MYL3 has also been curated by the Hypertrophic Cardiomyopathy (HCM) Gene Curation Expert Panel for hypertrophic cardiomyopathy (Definitive, October 4, 2016) and the Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) Gene Curation Expert Panel for ARVC (Limited, September 13, 2019). Human genetic evidence supporting this gene-disease relationship includes case-level data. At least one variant (missense) has been reported in humans with DCM (Zhao et al., 2015, PMID 26458567). Next-generation sequencing and followed by variant confirmation with traditional capillary Sanger sequencing analysis was completed in 21 individuals with DCM and revealed possible causative variants in ~57% of patients, including a novel variant in MYL3 (c.377A>G, p.D126G). Experimental evidence includes expression data, but is nonspecific to dilated cardiomyopathy. In brief, Deb et al 2022 PMID: 35714796 utilized RNA-sequencing, differentially expressed gene (DEG) computational analysis and protein-protein interaction computational analysis to identify the top 15 DEGs in pig hearts affected with PCV2 compared to 5 healthy controls which identified MYL3 as one of these highly DEG genes. These findings were consistent on qRT-PCR.
In summary, the evidence presented for this gene-disease relationship does not provide convincing human genetic evidence in support of or refuting the role of MYL3 and autosomal dominant DCM. The relationship of MYL3 with DCM is unclear and therefore classified as disputed. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on May 29th, 2025 (SOP Version 10).
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