ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.7522C>T (p.Arg2508Cys) (rs118192178)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000624571 SCV000741781 pathogenic Inborn genetic diseases 2016-09-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000119718 SCV000230733 likely pathogenic not provided 2015-04-30 criteria provided, single submitter clinical testing
GeneReviews RCV000056228 SCV000087317 pathologic Myopathy, Central Core 2010-05-11 no assertion criteria provided curation Converted during submission to Pathogenic.
Invitae RCV000552166 SCV000660027 pathogenic RYR1-Related Disorders 2018-05-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 2508 of the RYR1 protein (p.Arg2508Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with malignant hyperthermia and central core disease (PMID: 16621918, 16732084, 25747005, 19685112, 21157159). ClinVar contains an entry for this variant (Variation ID: 65981). Different missense substitutions at this codon (p.Arg2508His and p.Arg2508Gly) have been determined to be pathogenic (PMID: 16621918, 16732084 , 26381711, 20142353). This suggests that the arginine residue is critical for RYR1 protein function and that other missense substitutions at this position may also be pathogenic. Experimental studies have shown that this missense change leads to altered calcium homeostasis after exposure to caffeine (PMID: 26381711, 19685112). For these reasons, this variant has been classified as Pathogenic.
Leiden Muscular Dystrophy (RYR1) RCV000119718 SCV000154625 not provided not provided no assertion provided not provided
PreventionGenetics RCV000119718 SCV000852780 pathogenic not provided 2013-11-21 criteria provided, single submitter clinical testing

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