ClinVar Miner

Submissions for variant NM_002471.3(MYH6):c.2611C>T (p.Arg871Cys) (rs376682837)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000618162 SCV000736963 uncertain significance Cardiovascular phenotype 2017-12-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770453 SCV000901896 uncertain significance Cardiomyopathy 2016-04-26 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765150 SCV000896379 uncertain significance Familial hypertrophic cardiomyopathy 1; Dilated cardiomyopathy 1EE; Familial hypertrophic cardiomyopathy 14; Atrial septal defect 3; Sick sinus syndrome 3, susceptibility to 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000656919 SCV000490649 uncertain significance not provided 2018-05-01 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYH6 gene. The R871C variant has not been published as pathogenic or been reported as benign to our knowledge. The R871C variant is observed in 12/126694 (0.009%) alleles from individuals of European (non-Finnish) ancestry and in 7/30782 (0.02%) alleles from individuals of South Asian ancestry in large population cohorts (Lek et al., 2016). Nevertheless, the R871C 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. Finally, 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 RCV000551495 SCV000648236 uncertain significance Familial hypertrophic cardiomyopathy 14 2018-01-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 871 of the MYH6 protein (p.Arg871Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs376682837, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with MYH6-related disease. ClinVar contains an entry for this variant (Variation ID: 44469). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037460 SCV000061118 uncertain significance not specified 2012-05-15 criteria provided, single submitter clinical testing The Arg871Cys variant (MYH6) has been identified in 1/7020 European American chr omosomes from a broad population by the NHLBI Exome Sequencing Project (http://e vs.gs.washington.edu/EVS/). Note this could represent a presymptomatic individua l. Computational analyses (biochemical amino acid properties, conservation, Alig nGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impa ct to the protein. Additional studies are needed to fully assess its clinical si gnificance.

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