ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.13933C>T (p.Arg4645Trp) (rs377667641)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000548775 SCV000659835 uncertain significance RYR1-Related Disorders 2018-10-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 4645 of the RYR1 protein (p.Arg4645Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs377667641, ExAC 0.04%) but has not been reported in the literature in individuals with an RYR1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The tryptophan amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. This sequence change is located in the C-terminal mutation hotspot of the RYR1 protein where a significant number of previously reported RYR1 missense mutations are found (PMID: 16084090). 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. In summary, this variant is a rare missense change that is not predicted to affect 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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