ClinVar

Description

This MYH7 Arg143Trp variant has previously been reported in HCM cohorts (Erdmann J, et al., 2003; Van Driest SL, et al., 2004; Maron BJ, et al., 2011; Liu W, et al., 2013; Kapplinger JD, et al., 2014; Chiou KR, et al., 2014). No strong evidence of segregation with disease phenotype have been published. However, Kapplinger et al. (2014) report this variant in 6 unrelated HCM cases and describe this MYH7 Arg143Trp variant to be nominally over represented in cases compared to control samples. We have identified this variant in one isolated HCM case (no familial segregation is possible). This variant is absent in the 1000 genomes project (http://www.1000genomes.org/), and present at a low frequency (MAF=0.00004942) in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). Interestingly, a different rare variant at this position (Arg143Gln) has been reported in multiple HCM individuals, suggesting that an amino acid substitution at this site may not be tolerated. Computational tools SIFT predicts this variant to be "deleterious", but no prediction is called by PolyPhen-HCM. In summary, the identification of this variant in multiple unrelated individuals with the same phenotype and its extreme rarity/absence in controls suggest that MYH7 Arg143Trp is "likely pathogenic". Additional evidence is required to fully establish its pathogenic role.