ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.1840C>T (p.Arg614Cys) (rs118192172)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 17
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000624176 SCV000742007 pathogenic Inborn genetic diseases 2016-03-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000013830 SCV000265688 pathogenic Malignant hyperthermia, susceptibility to, 1 2013-07-01 criteria provided, single submitter research
CSER_CC_NCGL; University of Washington Medical Center RCV000013830 SCV000190544 pathogenic Malignant hyperthermia, susceptibility to, 1 2014-06-01 no assertion criteria provided research
GeneDx RCV000119586 SCV000329611 pathogenic not provided 2018-08-15 criteria provided, single submitter clinical testing The R614C variant in the RYR1 gene has been reported previously in the heterozygous state in multiple individuals with malignant hyperthermia susceptibility (MHS) (Gillard et al., 1991; Girard et al., 2001; Carpenter et al., 2009; Kraeva et al., 2011; Riazi et al., 2014). The R614C variant is one of the most commonly identified RYR1 variants among individuals of Western European backgrounds (Rueffert et al., 2002; Kraeva et al., 2011). The R614C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R614C 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 that is conserved across species. Functional studies demonstrate that the R614C variant is sufficient to induce malignant hyperthermic episodes by causing impaired calcium and magnesium inhibition and reduced activation of the mutant protein at calcium concentrations typical of normal myotubes at rest (Tong et al., 1997; Yang et al., 2003). R614C has also been classified as pathogenic multiple times in the RYR1 Leiden Open Variation Database (LOVD) (Fokkema et al., 2011). A different missense variant at the same codon, R614L, has been reported in association with malignant hyperthermia (Quane et al., 1997), supporting the functional importance of this region of the protein. Based on the ACMG recommendations, R614C is interpreted as a known pathogenic sequence change.
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000013830 SCV000840059 pathogenic Malignant hyperthermia, susceptibility to, 1 2017-10-16 criteria provided, single submitter clinical testing This c.1840C>T (p.Arg614Cys) variant in the RYR1 gene has been reported in multiple unrelated individuals with malignant hyperthermia (PMID: 1774074, 7762556, 10051009, 10484775, 19648156, 23842196, 11668625) or myopathy (PMID: 21795085). This variant has been shown to segregate with features of malignant hyperthermia in multiple families (PMID: 7762556, 7586638, 9520251). The c.796G>A variant is rare in the general population and arginine at position 614 of the RYR1 protein is highly evolutionarily conserved. The c.1840C>T (p.Arg614Cys) variant in the RYR1 gene is classified as pathogenic.
Invitae RCV000538121 SCV000659874 pathogenic RYR1-Related Disorders 2018-08-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 614 of the RYR1 protein (p.Arg614Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs118192172, ExAC 0.01%). This variant has been reported to segregate with malignant hyperthermia (MH) in several families (PMID: 1774074, 11493496, 8602662, 12411788, 10352931). This variant has been identified in many individuals affected with malignant hyperthermia, central core disease, and in one female with severe statin myopathy. The variant is considered to be one of the most common causative variants for MH in populations primarily originating from Western Europe (PMID: 11668625, 19648156, 23842196, 21795085, 21455645). ClinVar contains an entry for this variant (Variation ID: 12964). Experimental studies have shown this missense change to be more sensitive to caffeine and halothane than the normal calcium release channel (PMID: 11668625, 12732639, 9334205) . In addition, this missense change is located in an N-terminal region of the RYR1 protein where many other previously reported MH-associated variants have been found (PMID: 16084090). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000608635 SCV000711657 pathogenic Malignant hyperthermia susceptibility 2018-04-17 criteria provided, single submitter clinical testing The p.Arg614Cys variant in RYR1 has been reported in >30 individuals with malign ant hyperthermia, and segregated with disease more than 6 affected relatives fro m more than 3 families (Gillard 1991, Hogan 1992, Serfas 1996, Fortunato 1999, R ueffert 2001, Girard 2001, Muniz 2003, Vladutiu 2011, Klingler 2014, LMM unpubli shed data). In vitro functional studies provide some evidence that the p.Arg614C ys variant may impact protein function (Tong 1999, 2003, Girard 2001). However, these types of assays may not accurately represent biological function. Animal m odels in pigs further support a contribution to malignant hyperthermia (Ostu 199 1). This variant has been identified in 0.02% (24/126704) of European chromosome s by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs118192172). Please note that for diseases with clinical variability or r educed penetrance, pathogenic variants may be present at a low frequency in the general population. In summary, this variant meets criteria to be classified as pathogenic for malignant hyperthermia in an autosomal dominant manner based upon segregation studies, functional evidence, its presence in a large number of ind ividuals with malignant hyperthermia. ACMG/AMP Criteria applied: PS3, PS4,
Leiden Muscular Dystrophy (RYR1) RCV000119586 SCV000154493 not provided not provided no assertion provided not provided
OMIM RCV000013830 SCV000034077 risk factor Malignant hyperthermia, susceptibility to, 1 1996-04-01 no assertion criteria provided literature only
PharmGKB RCV000786449 SCV000925271 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 RCV000786450 SCV000925272 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 RCV000786451 SCV000925273 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 RCV000786452 SCV000925274 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 RCV000786453 SCV000925275 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 RCV000786454 SCV000925276 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 RCV000786455 SCV000925277 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 RCV000119586 SCV000852495 pathogenic not provided 2018-03-22 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.