ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2572C>G (p.Arg858Gly) (rs2754158)

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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 RCV000698652 SCV000199180 likely pathogenic Hypertrophic cardiomyopathy 2018-03-01 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Integrated Genetics/Laboratory Corporation of America RCV000588789 SCV000696343 uncertain significance not provided 2016-03-09 criteria provided, single submitter clinical testing Variant summary: Variant affects a non-conserved nucleotide and results in a replacement of a large size and basic Arginine (R) with a small size and hydrophobic Glycine (G). 3/5 in silico tools predict the variant to be neutral. It is absent from the large and broad cohorts of the ExAC project. Studies assessing the effect of the variant on protein function were not published at the time of scoring. Variants affecting the same codon, c.2572C>T p.R858C (DM); c.2572C>G p.R858C, c.2572C>A p.R858S (DM); c.2573G>A p.R858H (DM), c.2573G>A p.R858H (DM) are listed in HGMD as Disease Mutation indicating the variant to be located in a mutational hotspot and and suggesting a particular functional importance of residue 858. A clinical diagnostic laboratory classified variant as Uncertain via ClinVar. Considering all, because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance until more information becomes available.
Invitae RCV000698652 SCV000827332 uncertain significance Hypertrophic cardiomyopathy 2018-08-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 858 of the MYH7 protein (p.Arg858Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 27247418, 27532257, 23549607). ClinVar contains an entry for this variant (Variation ID: 164325). 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: "Benign"; Align-GVGD: "Class C25"). A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). A different missense substitution at this codon (p.Arg858Cys) has been determined to be pathogenic (PMID:  15358028, 24111713, 24093860). This suggests that the arginine residue is critical for MYH7 protein function and that other missense substitutions at this position may also be pathogenic. 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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