ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.13919T>G (p.Met4640Arg) (rs1568594068)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics,PreventionGenetics RCV000721341 SCV000852377 pathogenic not provided 2018-04-18 criteria provided, single submitter clinical testing
Invitae RCV000806085 SCV000946066 likely pathogenic RYR1-Related Disorders 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces methionine with arginine at codon 4640 of the RYR1 protein (p.Met4640Arg). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with central core disease and to be de novo in one affected individual (PMID: 23183335, 26799446). ClinVar contains an entry for this variant (Variation ID: 590442). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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