ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.12886C>T (p.Arg4296Trp) (rs995399684)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000622930 SCV000741931 uncertain significance Inborn genetic diseases 2016-11-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
Invitae RCV000655522 SCV000777453 uncertain significance RYR1-Related Disorders 2018-07-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 4296 of the RYR1 protein (p.Arg4296Trp). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and tryptophan. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with RYR1-related disease. ClinVar contains an entry for this variant (Variation ID: 521376). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; 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 and their clinical significance is uncertain. This missense change is located in a region 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, 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.
PreventionGenetics RCV000721298 SCV000852325 uncertain significance not provided 2016-08-18 criteria provided, single submitter clinical testing

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