ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2011C>T (p.Arg671Cys) (rs727503263)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000461116 SCV000199213 likely pathogenic Hypertrophic cardiomyopathy 2019-02-05 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000766426 SCV000208758 likely pathogenic not provided 2018-10-19 criteria provided, single submitter clinical testing The R671C likely pathogenic variant in the MYH7 gene has been reported in association with HCM (Mohiddin et al., 2003; Richard et al., 2003; Wang et al., 2014; Walsh et al., 2017). This variant has also been identified independently and/or in conjunction with additional cardiogenetic variants in multiple individuals referred for cariomyopathy genetic testing at GeneDx. Though the variant segregated with HCM in one relative of a single proband, segregation data for the remaining probands tested at GeneDx are limited or absent. The R671C variant is not observed in large population cohorts (Lek et al., 2016). The R671C 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Finally, the R671C variant is located in the myosin motor domain, a region enriched with missense variants reported in association with cardiomyopathy (Kelly et al., 2018). In summary, R671C in the MYH7 gene is interpreted as a likely pathogenic variant.
Invitae RCV000461116 SCV000546221 pathogenic Hypertrophic cardiomyopathy 2018-12-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 671 of the MYH7 protein (p.Arg671Cys). 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 (rs727503263, ExAC no frequency). This variant has been reported in more than four individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 12820698, 25132132, 27532257, Invitae). ClinVar contains an entry for this variant (Variation ID: 164350). This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). 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). In summary, this variant is absent from population databases, is predicted to be deleterious by a well characterized prediction algorithm, and has been observed in multiple unrelated individuals with hypertrophic cardiomyopathy. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000620591 SCV000737368 likely pathogenic Cardiovascular phenotype 2018-05-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770495 SCV000901940 uncertain significance Cardiomyopathy 2015-10-06 criteria provided, single submitter clinical testing

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