ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.4816C>T (p.Arg1606Cys) (rs200530211)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000172042 SCV000051002 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154606 SCV000204279 uncertain significance not specified 2016-09-12 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000172042 SCV000208606 uncertain significance not provided 2018-02-21 criteria provided, single submitter clinical testing The R1606C variant of uncertain significance in the MYH7 gene has been previously reported in association with HCM (Helms et al., 2014; Helms et al., 2016; Homburger et al., 2016; Walsh et al., 2017). This variant has also been identified in several individuals referred for cardiomyopathy genetic testing at GeneDx; however, one of these probands harbors an additional cardiogenetic variant that likely contributes to the phenotype, and segregation analysis has been uninformative thus far. In addition, R1606C has been reported in an individual from a cohort of patients undergoing whole exome sequencing that were not selected for cardiomyopathy, arrhythmia or a family history of sudden death (Ng et al., 2013). Nevertheless, R1606C is not observed at a significant frequency in additional large population cohorts (Lek et al., 2016). The R1606C 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. Furthermore, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect.
Invitae RCV000470391 SCV000546188 uncertain significance Hypertrophic cardiomyopathy 2016-08-10 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1606 of the MYH7 protein (p.Arg1606Cys). 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 an individual affected with hypertrophic cardiomyopathy (PMID: 25031304). ClinVar contains an entry for this variant (Variation ID: 177945). 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 a rare missense change that has been reported in an affected individual and is predicted to have an impact on protein function. However, in the absence of confirmed segregation or functional studies, at this time this change has been classified as a Variant of Uncertain Significance.

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