ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.7089C>G (p.Cys2363Trp) (rs2228071)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000557457 SCV000660016 uncertain significance RYR1-Related Disorders 2017-05-24 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tryptophan at codon 2363 of the RYR1 protein (p.Cys2363Trp). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tryptophan. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a RYR1-related disease. This missense change is located in a region of the RYR1 protein (the central mutation hotspot) where a significant number of pathogenic RYR1 missense mutations are found (PMID: 16917943, 12565913, 23919265). These observations suggest that a previously unreported missense substitution within this region may affect protein function, but experiments have not been done to test this possibility. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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