ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.7300G>A (p.Gly2434Arg) (rs121918593)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000119698 SCV000490785 pathogenic not provided 2016-11-23 criteria provided, single submitter clinical testing The G2434R variant in the RYR1 gene has been published previously as a pathogenic variant associated with malignant hyperthermia (Keating et al., 1994; Carpenter et al., 2009; Riazi et al., 2014). The G2434R variant was not observed in approximately 6,500 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 G2434R variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. Based on the ACMG recommendations, G2434R is interpreted as a pathogenic variant.
Gharavi Laboratory,Columbia University RCV000119698 SCV000809466 pathogenic not provided 2018-09-16 no assertion criteria provided research
HudsonAlpha Institute for Biotechnology RCV000013837 SCV000778611 pathogenic Malignant hyperthermia, susceptibility to, 1 2017-11-28 criteria provided, single submitter research
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000013837 SCV000840061 pathogenic Malignant hyperthermia, susceptibility to, 1 2017-05-25 criteria provided, single submitter clinical testing This c.7300G>A (p.Gly2434Arg) variant in the RYR1 gene has previously been reported in multiple patients with malignant hyperthermia [PMID 7849712, 23842196, 19648156, 11668625]. This variant has been functionally characterized and shown to have an increased sensitivity to activating concentrations of Ca2+ and to caffeine and 4-chloro-m-cresol in vitro. The variant is classified as pathogenic by the European malignant hyperthermia group (https://emhg.org). This variant has been observed in one 3 heterozygous individual from the ExAC database (http://exac.broadinstitute.org/variant/19-38990633-G-A). Glycine at position 2434 of the RYR1 protein is highly conserved. While not clinically validated, computer-based algorithms SIFT and Polyphen2 predict this p.Gly2434Arg change to be deleterious. It is thus interpreted as a pathogenic variant.
Invitae RCV000551243 SCV000660024 pathogenic RYR1-Related Disorders 2018-06-02 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 2434 of the RYR1 protein (p.Gly2434Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs121918593, ExAC 0.01%). This variant has been reported to segregate with malignant hyperthermia in several families (PMID: 9030597, 7849712). It has also been reported in multiple unrelated individuals affected with malignant hyperthermia (PMID: 23842196, 19648156, 11668625, 10484775, 24433488). This variant is also known as p.Gly2433Arg in the literature. ClinVar contains an entry for this variant (Variation ID: 12970). Experimental studies have shown that this missense change increases RYR1 protein sensitivity to calcium, exogenous caffeine and 4-chloro-m-cresol (PMID: 9030597, 9334205). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000612258 SCV000711729 pathogenic Malignant hyperthermia susceptibility 2016-09-19 criteria provided, single submitter clinical testing The p.Gly2434Arg variant in RYR1 is an established pathogenic variant for malignant hyperthermia. It has been reported in >100 individuals with malignant hyperthermia and segregated with disease in >100 affected relatives from several families (Keating 1994, Phillips 1994, Richter 1997, Sambuughin 2001, Carpenter 2009, Dlamini 2013). It has also been identified in 2/66466 European and 1/10366 African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs121918593). In-vitro functional studies provide evidence that the p.Gly2434Arg variant may impact protein function (Richter 1997, Tong 1999, Girard 2001, Weigl 2004). In summary, this variant meets our criteria to be classified as pathogenic for malignant hyperthermia in an autosomal dominant manner.
Leiden Muscular Dystrophy (RYR1) RCV000119698 SCV000154605 not provided not provided no assertion provided not provided
OMIM RCV000013837 SCV000034084 risk factor Malignant hyperthermia, susceptibility to, 1 1997-02-21 no assertion criteria provided literature only
PharmGKB RCV000786573 SCV000925395 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 RCV000786574 SCV000925396 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 RCV000786575 SCV000925397 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 RCV000786576 SCV000925398 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 RCV000786577 SCV000925399 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 RCV000786578 SCV000925400 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 RCV000786579 SCV000925401 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 RCV000119698 SCV000852763 pathogenic not provided 2018-02-08 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000119698 SCV000925213 pathogenic not provided 2016-09-02 no assertion criteria provided provider interpretation

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