MYL2

Inheritance Pattern: AD

Disease ID:MONDO:0009711

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0016333

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0859168

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0016587

Submitter: ClinGen

MYL2: Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) HGNC: 7583 http://purl.obolibrary.org/obo/MONDO_0016587 Mode of Inheritance: Autosomal dominant inheritance (HP:0000006) Expert Panel: Arrhythmogenic Right Ventricular Cardiomyopathy SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6 Calculated Classification (date) No reported evidence 22/03/2019 Evidence Summary: There is no evidence that MYL2 is involved in ARVC. This gene has been investigated for pathogenic variants in two populations of gene-elusive ARVC patients: a cohort of 14 Spanish unrelated patients (22421524) and a cohort of 137 ARVC patients meeting 2010 Task Force criteria for ARVC (29709087). No variants in MYL2 were reported.

Inheritance Pattern: AD

Disease ID:MONDO:0005045

Submitter: ClinGen

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. This classification was last reevaluated on January 8th, 2021 using SOP11 to update the case scoring. As a result, several cases carrying the Glu22Lys variant were downscored due to evidence of founder status (PMID 26497160). Alternatively, the Arg58Gln variant has been obvserved multiple times in unrelated probands with consistent phenotypes and no evidence of shared ancestry so cases carrying the variant have increased scores to reflect the possibility that the locus is a hot spot. As a result of this reevaluation, the definitive classification did not change.

Inheritance Pattern: AD

Disease ID:MONDO:0005021

Submitter: ClinGen

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).

Inheritance Pattern: AD

Disease ID:MONDO:0012112

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0012112

Submitter: Labcorp Genetics (formerly Invitae)