ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.5065C>T (p.Arg1689Cys) (rs730880915)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158870 SCV000208805 uncertain significance not specified 2017-02-01 criteria provided, single submitter clinical testing The R1689C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1689C 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. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, only one missense variant in a nearby residue (V1691M) has been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014). Furthermore, to our knowledge no studies have been performed to determine the functional effect of the R1689C variant. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae RCV000693933 SCV000822356 uncertain significance Hypertrophic cardiomyopathy 2018-05-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1689 of the MYH7 protein (p.Arg1689Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs730880915, ExAC 0.004%). This variant has not been reported in the literature in individuals with MYH7-related disease. ClinVar contains an entry for this variant (Variation ID: 181394). An algorithm developed specifically for the MYH7 gene suggests that this missense change is likely to be deleterious (PMID: 21310275). However, this prediction has not been confirmed by published functional studies and its clinical significance is uncertain. 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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