ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.4900C>T (p.Arg1634Cys) (rs397516232)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035937 SCV000059588 uncertain significance not specified 2019-03-05 criteria provided, single submitter clinical testing The p.Arg1634Cys variant in MYH7 has been identified 1 individual with DCM (Vill ard 2005) but has also been identified in 3/251440 chromosomes by gnomAD (https: //gnomad.broadinstitute.org). Computational prediction tools and conservation an alysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical s ignificance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3.
GeneDx RCV000767017 SCV000577095 uncertain significance not provided 2017-04-11 criteria provided, single submitter clinical testing The R1634C variant in the MYH7 gene has been reported previously in an individual with sporadic dilated cardiomyopathy, however in vitro functional studies and additional clinical information were not included (Villard et al., 2005). The R1634C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R1634C 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 other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R1634C as a variant of uncertain significance.
Invitae RCV000628891 SCV000749799 uncertain significance Hypertrophic cardiomyopathy 2017-08-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1634 of the MYH7 protein (p.Arg1634Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 15769782). ClinVar contains an entry for this variant (Variation ID: 43043). 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"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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