ClinVar Miner

Submissions for variant NM_002471.3(MYH6):c.2575G>A (p.Gly859Arg) (rs369274077)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000499003 SCV000590089 uncertain significance not specified 2017-05-26 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYH6 gene. The G859R variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G859R 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. However, this substitution occurs at a position that is not conserved across species and in silico analysis suggests that this variant likely does not alter the protein structure/function.
Invitae RCV000647060 SCV000768847 uncertain significance Familial hypertrophic cardiomyopathy 14 2017-12-12 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 859 of the MYH6 protein (p.Gly859Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs369274077, ExAC 0.004%). This variant has not been reported in the literature in individuals with MYH6-related disease. ClinVar contains an entry for this variant (Variation ID: 432371). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their 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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