ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.4300C>T (p.Arg1434Cys) (rs730880800)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158653 SCV000208588 uncertain significance not provided 2018-05-24 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYH7 gene. The R1434C variant has been reported inassociation with DCM (Waldmuller et al., 2011; Merlo et al., 2013; Dal Ferro et al., 2017; Walsh et al., 2017);however, specific clinical information and functional studies were not included. The R1434C variant is not observedin large population cohorts (Lek et al., 2016). The R1434C variant is a non-conservative amino acid substitution,which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or otherproperties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000466942 SCV000546182 pathogenic Hypertrophic cardiomyopathy 2019-01-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1434 of the MYH7 protein (p.Arg1434Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with hypertrophic cardiomyopathy and dilated cardiomyopathy (PMID: 21750094, 24119082, 27532257, Invitae). ClinVar contains an entry for this variant (Variation ID: 181254). A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be pathogenic. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). However algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.

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