ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.7063C>T (p.Arg2355Trp) (rs193922803)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000763425 SCV000894190 pathogenic Myopathy, Central Core; Malignant hyperthermia, susceptibility to, 1; Minicore myopathy; Congenital myopathy with fiber type disproportion 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000119682 SCV000329916 pathogenic not provided 2016-08-08 criteria provided, single submitter clinical testing The R2355W pathogenic variant in the RYR1 gene has been reported previously as a heterozygous variant in multiple individuals with malignant hyperthermia (McWilliams et al., 2002 and Carpernter et al., 2009). Functional characterization of the R2355W variant indicate the mutant protein results in altered receptor function as compared to wild-type (Wehner et al., 2004; Schiemann et al., 2014). The R2355W variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R2355W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. We interpret R2355W as a known pathogenic variant.
Institute of Human Genetics,Klinikum rechts der Isar RCV000578408 SCV000680359 pathogenic Minicore myopathy 2017-11-15 criteria provided, single submitter clinical testing
Invitae RCV000803469 SCV000943341 pathogenic RYR1-Related Disorders 2018-08-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 2355 of the RYR1 protein (p.Arg2355Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs193922803, ExAC 0.005%). This variant has been observed in many individuals affected with malignant hyperthemia and has been observed to segregate with malignant hyperthermia in several families (PMID: 19648156, 23558838, 15210166, 24361844). ClinVar contains an entry for this variant (Variation ID: 133183). Experimental studies have shown that this missense change results in increased sensitivity to RYR1 agonists (PMID: 28403410, 24361844, 15210166). For these reasons, this variant has been classified as Pathogenic.
Leiden Muscular Dystrophy (RYR1) RCV000119682 SCV000154589 not provided not provided no assertion provided not provided
PharmGKB RCV000786499 SCV000925321 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 RCV000786500 SCV000925322 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.
PharmGKB RCV000786761 SCV000925583 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 RCV000786762 SCV000925584 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 RCV000786763 SCV000925585 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 RCV000786764 SCV000925586 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 RCV000786765 SCV000925587 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.

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