ClinVar

Description

This MYH7 Arg453Cys mutation is well described in the literature. The mutation has been identified in multiple unrelated individuals and families with HCM (see references). This mutation is not a founder mutation but rather, occurs in a well known hotspot region of the MYH7 gene and has an independent origin is each family (Watkins H, et al., 1993). Additionally, a different mutation affecting the same protein position (Arg453Ser) has been identified to also cause HCM (Frazier A, et al., 2008). Interestingly, this MYH7 Arg453Cys mutation has been identified as the cause of disease in the first HCM family described by Teare in 1958 (Watkins H, et al., 1992). This mutation is inherited as an autosomal trait with high penetrance, has been shown to cosegregate with disease, and is associated with unfavourable prognoses in multiple families (Solomon SD, et al., 1990; Watkins H, et al., 1992 & 1993; Ko YL, et al., 1996; Greber-Platzer S, et al., 2001). We have identified this mutation in one HCM family from our cohort. Based on the available literature, segregation analysis, and absence in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), we classify this variant as "pathogenic".