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In a cohort of 43 index-patients with advanced or end-stage cardiomyopathy, including 10 with arrhythmogenic right ventricular cardiomyopathy (MYL2; Arrhythmogenic right ventricular cardiomyopathy), targeted sequencing of 46 known cardiomyopathy genes identified 53 rare variants in 33 individuals, of which 27 (51%) were classified as likely pathogenic or pathogenic. Among these, one proband with ARVC harbored the MYL2 missense variant c.401A>C (p.Glu134Ala) (PMID:29253866). No further MYL2-associated probands or familial segregation data in ARVC cohorts have been reported.
To date, there are no ARVC-specific functional assays or cellular/animal models assessing the MYL2 p.Glu134Ala variant. Although MYL2 dysfunction is well characterized in hypertrophic and dilated cardiomyopathies, its role in ARVC is untested. The limited genetic evidence and absence of mechanistic studies in ARVC preclude stronger clinical validity. Key take-home: MYL2 variants identified in ARVC patients warrant cautious interpretation and should be corroborated with additional segregation or functional data.
Gene–Disease AssociationLimitedSingle likely pathogenic MYL2 missense variant in an ARVC index case; no segregation or ARVC-specific functional data Genetic EvidenceLimitedOne proband with c.401A>C (p.Glu134Ala) identified; no familial segregation in ARVC Functional EvidenceNo EvidenceNo experimental or model systems evaluating MYL2 variants in the context of ARVC have been reported |