ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.7360C>T (p.Arg2454Cys) (rs193922816)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 11
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000119709 SCV000203458 likely pathogenic not provided 2014-04-29 criteria provided, single submitter clinical testing
Invitae RCV000655594 SCV000777525 pathogenic RYR1-Related Disorders 2017-09-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 2454 of the RYR1 protein (p.Arg2454Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs193922816, ExAC 0.006%). This variant has been reported in individuals and families affected with malignant hyperthermia (MH). In one family, this variant was reported to segregate with the MH phenotype (PMID: 10612851, 12411788, 16163667, 10484775). ClinVar contains an entry for this variant (Variation ID: 133202). Experimental studies have shown that this missense change disrupts RYR1 protein function in vitro (PMID: 16958617, 27586648, 16163667). 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). A different missense substitution at this codon (p.Arg2454His) has been determined to be pathogenic (PMID: 15448513, 10484775, 16163667, 10051009, 27586648, 16163667). This suggests that the arginine residue is critical for RYR1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000601471 SCV000712562 likely pathogenic Malignant hyperthermia susceptibility 2016-10-21 criteria provided, single submitter clinical testing The p.Arg2454Cys variant in RYR1 has been reported in 4 individuals with maligna nt hyperthermia and segregated with disease in 2 affected relatives from 1 famil y (Brandt 1999, Gencik 2000, Monnier 2002, Monnier 2005). This variant has been identified in 2/30780 South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs193922816). In vitro functio nal studies provide some evidence that the p.Arg2454Cys variant may impact prote in function (Monnier 2005, Bannister 2007). However, these types of assays may n ot accurately represent biological function. Another variant at the same amino a cid position (p.Arg2454His) is likely disease causing for malignant hyperthermia , increasing the likelihood that the change to a cysteine would also be disease causing. Computational prediction tools and conservation analysis suggest that t he p.Arg2454Cys variant may impact the protein, though this information is not p redictive enough to determine pathogenicity. In summary, although additional stu dies are required to fully establish its clinical significance, the p.Arg2454Cys variant is likely pathogenic.
Leiden Muscular Dystrophy (RYR1) RCV000119709 SCV000154616 not provided not provided no assertion provided not provided
PharmGKB RCV000786669 SCV000925491 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 RCV000786670 SCV000925492 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 RCV000786671 SCV000925493 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 RCV000786672 SCV000925494 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 RCV000786673 SCV000925495 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 RCV000786674 SCV000925496 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 RCV000786675 SCV000925497 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.

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.