ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.4978C>G (p.Arg1660Gly) (rs1131691406)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000493739 SCV000582063 uncertain significance not provided 2017-05-09 criteria provided, single submitter clinical testing The R1660G variant in the RYR1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R1660G variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R1660G 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 where amino acids with similar properties to Arginine are tolerated across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R1660G as a variant of uncertain significance.
Invitae RCV000655573 SCV000777504 uncertain significance RYR1-Related Disorders 2017-10-31 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 1660 of the RYR1 protein (p.Arg1660Gly). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RYR1-related disease. ClinVar contains an entry for this variant (Variation ID: 429482). 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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