ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.5029C>T (p.Arg1677Cys) (rs377461670)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158681 SCV000208616 uncertain significance not provided 2018-12-13 criteria provided, single submitter clinical testing The R1677C variant of uncertain significance in the MYH7 gene has been reported in an individual with left ventricular non-compaction cardiomyopathy who also had a novel MYH7 Q44X variant (Gerull et al., 2013). This variant has also been reported in a patient referred for HCM genetic testing (Walsh et al., 2017); however, no additional clinical information was provided. Nevertheless, the R1677C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R1677C 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 RCV000687792 SCV000815378 uncertain significance Hypertrophic cardiomyopathy 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1677 of the MYH7 protein (p.Arg1677Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs377461670, ExAC 0.001%). This variant has been observed in an individual affected with hypertrophic cardiomyopathy and an individual with clinical features of dilated cardiomyopathy (PMID: 27532257, Invitae). ClinVar contains an entry for this variant (Variation ID: 181270). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or 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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