ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.7354C>T (p.Arg2452Trp) (rs118192124)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 13
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000119706 SCV000614914 pathogenic not provided 2016-11-03 criteria provided, single submitter clinical testing
GeneDx RCV000119706 SCV000567693 pathogenic not provided 2015-09-02 criteria provided, single submitter clinical testing The R2452W missense variant in the RYR1 gene has been reported previously in association with autosomal dominant malignant hyperthermia and central core myopathy (Chamley et al., 2000; Taylor et al., 2012; RYR1 LOVD). Functional studies indicate that R2452W hypersensitizes the receptor leading to significantly higher calcium release in response to agonist (Roesl et al., 2014). R2452W is a nonconservative amino acid substitution that occurs at a position that is conserved across species. Additionally, missense variants at the same position (R2452P, R2452Q) and in nearby residues (I2453T, R2454C/H, R2458L/H) have been reported in the Human Gene Mutation Database in association with RYR1-related disorders (Stenson et al., 2014). Therefore, R2452W is considered a pathogenic variant.
GeneReviews RCV000056226 SCV000087315 pathologic Myopathy, Central Core 2010-05-11 no assertion criteria provided curation Converted during submission to Pathogenic.
Invitae RCV000527240 SCV000660025 pathogenic RYR1-Related Disorders 2018-10-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 2452 of the RYR1 protein (p.Arg2452Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with malignant hyperthermia and congenital myopathies, and was shown to segregate with disease in multiple families (PMID: 10823104, 22473935, 23394784, 25086907, 24433488, 22030266, 14985404). ClinVar contains an entry for this variant (Variation ID: 65979). 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). Experimental studies have shown that cells expressing this variant release Ca2+ significantly higher than the cells expressing wild-type in response to RYR1-specific agonist, which causes hypersensitive receptor (PMID: 25086907, 27857962). For these reasons, this variant has been classified as Pathogenic.
Leiden Muscular Dystrophy (RYR1) RCV000119706 SCV000154613 not provided not provided no assertion provided not provided
PharmGKB RCV000786553 SCV000925375 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 RCV000786554 SCV000925376 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 RCV000786555 SCV000925377 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 RCV000786556 SCV000925378 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 RCV000786629 SCV000925451 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 RCV000786630 SCV000925452 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 RCV000786631 SCV000925453 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 RCV000119706 SCV000852767 pathogenic not provided 2016-03-28 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.