ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.1099C>T (p.Arg367Trp) (rs140037232)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000210016 SCV000265682 uncertain significance Malignant hyperthermia, susceptibility to, 1 2013-07-01 criteria provided, single submitter research
Invitae RCV000703573 SCV000832477 uncertain significance RYR1-Related Disorders 2018-05-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 367 of the RYR1 protein (p.Arg367Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs140037232, ExAC 0.01%). This variant has not been reported in the literature in individuals with RYR1-related disease. ClinVar contains an entry for this variant (Variation ID: 224364). 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: "Probably Damaging"; Align-GVGD: "Class C0"). The observation of one or more missense substitutions at this codon (p.Arg367Gln, p.Arg367Leu) in affected individuals suggests that this may be a clinically significant residue (PMID: 16835904, 16917943). This sequence change is located in a region of the RYR1 protein where a significant number of previously reported RYR1 missense mutations are found (PMID: 16084090). 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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