ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.7372C>T (p.Arg2458Cys) (rs28933397)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000796565 SCV000936084 pathogenic RYR1-Related Disorders 2018-11-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 2458 of the RYR1 protein (p.Arg2458Cys). 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 to segregate with autosomal dominant malignant hyperthemia in several families (PMID:9450902, 11668625). ClinVar contains an entry for this variant (Variation ID: 12971). Experimental studies have shown that this missense change alters protein function in vitro (PMID:27586648, 9334205, 9873004). This variant disrupts the p.Arg2458 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been observed in individuals with RYR1-related conditions (PMID:9450902, 22415532, 16732084, 18564801, 12700608), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000614410 SCV000731268 likely pathogenic Malignant hyperthermia susceptibility 2017-01-05 criteria provided, single submitter clinical testing The p.Arg2458Cys variant in RYR1 has been reported in 9 individuals with maligna nt hyperthermia, segregated with disease in 7 affected relatives from 2 families (Manning 1998, Girard 2001, Galli 2006, Klingler 2014) and was absent from larg e population studies. Computational prediction tools suggest that it affects pro tein function. In vitro functional studies provide conflicting evidence about th e impact of p.Arg2458Cys variant on protein function (Tong 1997, Tong 1999, Gira rd 2001, Bannister 2007). However, these types of assays may not accurately repr esent biological function. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg2458Cys variant is likely pathogenic. ACMG/AMP Criteria applied: PP1_Strong, PM2, PS4_Moderate, PP3.
Leiden Muscular Dystrophy (RYR1) RCV000119711 SCV000154618 not provided not provided no assertion provided not provided
OMIM RCV000013838 SCV000034085 risk factor Malignant hyperthermia, susceptibility to, 1 1998-01-01 no assertion criteria provided literature only
PharmGKB RCV000786680 SCV000925502 drug response desflurane response - Toxicity/ADR reviewed by expert panel curation PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.
PharmGKB RCV000786681 SCV000925503 drug response enflurane response - Toxicity/ADR reviewed by expert panel curation PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.
PharmGKB RCV000786682 SCV000925504 drug response halothane response - Toxicity/ADR reviewed by expert panel curation PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.
PharmGKB RCV000786683 SCV000925505 drug response isoflurane response - Toxicity/ADR reviewed by expert panel curation PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.
PharmGKB RCV000786684 SCV000925506 drug response methoxyflurane response - Toxicity/ADR reviewed by expert panel curation PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.
PharmGKB RCV000786726 SCV000925548 drug response sevoflurane response - Toxicity/ADR reviewed by expert panel curation PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.
PharmGKB RCV000786727 SCV000925549 drug response succinylcholine response - Toxicity/ADR reviewed by expert panel curation PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.
PreventionGenetics RCV000119711 SCV000852769 pathogenic not provided 2015-08-19 criteria provided, single submitter clinical testing

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