ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.12449C>G (p.Ser4150Trp) (rs143843083)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000537564 SCV000659788 uncertain significance RYR1-Related Disorders 2018-09-14 criteria provided, single submitter clinical testing This sequence change replaces serine with tryptophan at codon 4150 of the RYR1 protein (p.Ser4150Trp). The serine residue is moderately conserved and there is a large physicochemical difference between serine and tryptophan. This variant is present in population databases (rs143843083, ExAC 0.02%) but has not been reported in the literature in individuals with a RYR1-related disease. 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: "Benign"; Align-GVGD: "Class C0"). This sequence change is located in the C-terminal mutational hotspot of the RYR1 protein where a significant number of previously reported RYR1 missense mutations are found (PMID: 16084090). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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