ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.1021G>A (p.Gly341Arg) (rs121918592)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PharmGKB RCV000786476 SCV000925298 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 RCV000786477 SCV000925299 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 RCV000786478 SCV000925300 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 RCV000786479 SCV000925301 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 RCV000786480 SCV000925302 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 RCV000786481 SCV000925303 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 RCV000786482 SCV000925304 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.
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel,ClinGen RCV000013836 SCV001816165 pathogenic Malignant hyperthermia, susceptibility to, 1 2021-03-18 reviewed by expert panel curation This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of glycine with arginine at codon 341 of the RYR1 protein p.(Gly341Arg), c.1021G>A. This variant is not present in a large population database (gnomAD). This variant has been reported in 71 unrelated probands who have a personal or family history of a malignant hyperthermia reaction and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted), PS4 ( PMID:30236257, PMID:16163667, PMID: 8012359 and others). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:26115329). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant segregates with MHS in 66 individuals, PP1_Strong ( PMID: 8012359, PMID:9106529, PMID:17710899 and others). A REVEL score > 0.85 supports pathogenicity,PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). Criteria implemented: PS4, PS3_Moderate, PM1, PP1_Strong, PP3_Moderate, BS2_Moderate.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000119406 SCV000225241 likely pathogenic not provided 2014-09-05 criteria provided, single submitter clinical testing
Invitae RCV000655541 SCV000777472 pathogenic RYR1-Related Disorders 2020-07-09 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 341 of the RYR1 protein (p.Gly341Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with malignant hyperthermia in several families (PMID: 8012359, 24433488, 8825043), and has also been reported in numerous individuals affected with malignant hyperthermia (PMID: 19648156). ClinVar contains an entry for this variant (Variation ID: 12969). Experimental studies have shown that this missense change results in altered RYR1 channel properties (PMID: 12732639, 9334205, 9873004). This missense change is located in a region of the RYR1 protein where a significant number of previously reported RYR1 missense mutations are found (PMID: 16917943, 12565913, 23919265). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics,PreventionGenetics RCV000119406 SCV000852200 pathogenic not provided 2018-03-15 criteria provided, single submitter clinical testing
OMIM RCV000013836 SCV000034083 risk factor Malignant hyperthermia, susceptibility to, 1 1998-10-01 no assertion criteria provided literature only
Leiden Muscular Dystrophy (RYR1) RCV000119406 SCV000154313 not provided not provided no assertion provided not provided

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