MYL3

Inheritance Pattern: AD

Disease ID:MONDO:0005045

Submitter: ClinGen

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).

Inheritance Pattern: AD

Disease ID:MONDO:0005021

Submitter: ClinGen

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).

Inheritance Pattern: AD

Disease ID:MONDO:0012111

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0012111

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0016587

Submitter: ClinGen

There is limited evidence that MYL3 is associated with ARVC. Screening of ARVC patient cohorts for MYL3 mutations has been performed in two studies (29709087, 22421524). In first study (29709087) 137 ARVC patients were investigated for putative pathogenic variants. A missense variant causing the aminoacid substitution Arg154His was identified in one patient. This previously report variant is classified as likely pathogenic according to current ACMG criteria and has been demonstrate in vitro to disturb the binding of this protein to myosin. However, this variant has not been linked to ARVC phenotype and no segregation data were available. In the second study (22421524) 14 ARVC patients were investigated but no MYL3 variants were reported. There is no clear evidence that the identified MYL3 contribute to the ARVC phenotype and there is no known disease mechanism that would link MYL3 with ARVC.

Inheritance Pattern: AD

Disease ID:MONDO:0016333

Submitter: G2P

Inheritance Pattern: SD

Disease ID:MONDO:0012111

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0016587

Submitter: G2P