ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.7300G>A (p.Gly2434Arg)

gnomAD frequency: 0.00006  dbSNP: rs121918593
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Total submissions: 33
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PharmGKB RCV001787719 SCV000925395 drug response desflurane response - Toxicity 2021-03-24 reviewed by expert panel curation PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.
PharmGKB RCV001787720 SCV000925396 drug response enflurane response - Toxicity 2021-03-24 reviewed by expert panel curation PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.
PharmGKB RCV001787721 SCV000925397 drug response halothane response - Toxicity 2021-03-24 reviewed by expert panel curation PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.
PharmGKB RCV001787722 SCV000925398 drug response isoflurane response - Toxicity 2021-03-24 reviewed by expert panel curation PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.
PharmGKB RCV001787723 SCV000925399 drug response methoxyflurane response - Toxicity 2021-03-24 reviewed by expert panel curation PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.
PharmGKB RCV001787724 SCV000925400 drug response sevoflurane response - Toxicity 2021-03-24 reviewed by expert panel curation PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.
PharmGKB RCV001787725 SCV000925401 drug response succinylcholine response - Toxicity 2021-03-24 reviewed by expert panel curation PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen RCV000013837 SCV002570137 pathogenic Malignant hyperthermia, susceptibility to, 1 2022-07-11 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 2434 of the RYR1 protein, p.(Gly2434Arg). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000078, a frequency consistent with pathogenicity for MHS. This variant has been reported in 178 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 174 of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted, PS4 (PMID: 30236257, 10484775, 23558838, 16163667, 21455645, 23842196, 7849712, 7881417, 11575529, 15731587, 11668625, 12059893, 12151923, 31559918, 10700782, 17081125, 18564801, 20681998, 21965348, 23460944, 25735680, 25960145, 9030597, 25268394, 17667681). This variant has been identified in six individuals with negative IVCT/CHCT results, BS2 (PMID:30236257). A functional study in HEK293 cells shows an increased sensitivity to RYR1 agonists (PMID: 27586648). p.(Gly2434Arg) knock-in mice are susceptible to malignant hyperthermia due to volatile anesthetics and ex vivo assays demonstrate increased sensitivity to RYR1 agonists for knock-in myotubes, PS3 (PMID:30236258). 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 at least 20 individuals, PP1_Strong (PMID: 7849712, 11575529, 12059893, 25960145). A REVEL score >0.85 (0.956) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). Criteria implemented: PS3, PS4, PM1, PP1_Strong, PP3_Moderate, BS2.
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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000551243 SCV000660024 pathogenic RYR1-related disorder 2024-01-24 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2434 of the RYR1 protein (p.Gly2434Arg). This variant is present in population databases (rs121918593, gnomAD 0.008%). This missense change has been observed in individuals with malignant hyperthermia (PMID: 7849712, 9030597, 10484775, 11668625, 19648156, 23842196, 24433488). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Gly2433Arg. ClinVar contains an entry for this variant (Variation ID: 12970). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RYR1 function (PMID: 9030597, 9334205). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000612258 SCV000711729 pathogenic Malignant hyperthermia of anesthesia 2020-01-15 criteria provided, single submitter clinical testing The p.Gly2434Arg variant in RYR1 is an established pathogenic variant for malignant hyperthermia (MH). It has been reported in >100 individuals with MH and segregated with disease in >100 affected relatives from several families (Keating 1994, Phillips 1994, Richter 1997, Sambuughin 2001, Carpenter 2009, Dlamini 2013). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 12970) and has been identified in 0.008% (10/129020) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of MH in the general population. 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 criteria to be classified as pathogenic for MH in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4, PP1_Strong, PS3_Moderate.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000013837 SCV000778611 pathogenic Malignant hyperthermia, susceptibility to, 1 2020-02-28 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.
PreventionGenetics, part of Exact Sciences RCV000119698 SCV000852763 pathogenic not provided 2018-02-08 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000119698 SCV001249988 pathogenic not provided 2023-03-01 criteria provided, single submitter clinical testing RYR1: PP1:Strong, PS3, PS4, PM1, PP3, BS2
Institute of Human Genetics, University of Leipzig Medical Center RCV000013837 SCV001429341 pathogenic Malignant hyperthermia, susceptibility to, 1 2019-12-10 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000119698 SCV001447354 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV000119698 SCV001468077 pathogenic not provided 2020-08-25 criteria provided, single submitter clinical testing
Athena Diagnostics RCV000119698 SCV001880064 pathogenic not provided 2020-09-24 criteria provided, single submitter clinical testing The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant is also referred to as p.Gly2433Arg and p.Gly2435Arg in some published literature. Computational tools yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. This variant segregates with disease in multiple families with susceptibility to malignant hyperthermia. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant leads to impaired calcium homeostasis (PMID: 9334205, 30236258, 27586648). Computational tools predict that this variant is damaging.
Revvity Omics, Revvity RCV000119698 SCV002019949 pathogenic not provided 2019-12-10 criteria provided, single submitter clinical testing
AiLife Diagnostics, AiLife Diagnostics RCV000119698 SCV002501735 pathogenic not provided 2022-01-03 criteria provided, single submitter clinical testing
Molecular Genetics, Royal Melbourne Hospital RCV000612258 SCV002503670 pathogenic Malignant hyperthermia of anesthesia 2024-02-05 criteria provided, single submitter clinical testing This sequence change in RYR1 is predicted to replace glycine with arginine at codon 2434, p.(Gly2434Arg). The glycine residue is highly conserved (100 vertebrates, Multiz Alignments), and is located in exon 45 in the central region, amino acids 2,101-2,458, which is defined as a mutational hotspot. There is a large physicochemical difference between glycine and arginine. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.01% (149/1,180,014 alleles) in the European (non-Finnish) population. The variant is the most common malignant hyperthermia susceptibility (MHS) variant detected in the United Kingdom (PMID: 30236257), and segregates with MHS in multiple families (PMID: 7849712). In vitro functional studies are supportive of a gain of function effect on intracellular calcium release and a knock-in mouse model recapitulates the human MHS response (PMID: 9334205, 27586648, 30236258). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.965). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM1, PP1_Strong, PP3_Moderate, PS3, PS4.
National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health RCV000612258 SCV002522194 pathogenic Malignant hyperthermia of anesthesia 2021-08-06 criteria provided, single submitter clinical testing
MGZ Medical Genetics Center RCV002288488 SCV002580012 pathogenic Central core myopathy 2022-05-30 criteria provided, single submitter clinical testing
Ambry Genetics RCV002513026 SCV003575370 pathogenic Inborn genetic diseases 2021-09-30 criteria provided, single submitter clinical testing The c.7300G>A (p.G2434R) alteration is located in exon 45 (coding exon 45) of the RYR1 gene. This alteration results from a G to A substitution at nucleotide position 7300, causing the glycine (G) at amino acid position 2434 to be replaced by an arginine (R). Based on data from gnomAD, the A allele has an overall frequency of 0.004% (11/282,648) total alleles studied. The highest observed frequency was 0.008% (10/129,020) of European (non-Finnish) alleles. This alteration has been reported heterozygous in multiple patients and their family members with features consistent with malignant hyperthermia (Keating, 1994; Riazi, 2014; Snoeck, 2015; Witting, 2018; Knuiman, 2019). This amino acid position is highly conserved in available vertebrate species. This alteration has been shown in vitro to enhance the sensitivity of RYR1 to activating concentrations of Ca2+ and to the exogenous ligands, caffeine and 4-chloro-m-cresol. The study also showed reduced sensitivity to inhibiting concentrations of Ca2+ and calmodulin, transferring the mutant Ca2+ release channel into a hyperexcitable state (Richter, 1997). Another study by Chen et al. (2017) showed that the p.G2434R alteration, when expressed in HEK293 cells, reduced the threshold for store overload-induced Ca2+ release (SOICR), allowing for spontaneous Ca2+ release from the sarcoplasmic reticulum, which has been proposed as the cause of uncontrolled muscle contraction. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Genetics and Molecular Pathology, SA Pathology RCV002288488 SCV004175675 pathogenic Central core myopathy 2023-01-04 criteria provided, single submitter clinical testing The RYR1 c.7300G>A variant is classified as Pathogenic (PS3, PS4, PP3, PP5) The RYR1 c.7300G>A variant is a single nucleotide change in exon 45/106 of the RYR1 gene, which is predicted to change the amino acid glycine at position 2434 in the protein to arginine. The variant has been frequently reported in the literature in association with a malignant hyperthermia and central core disease (PS4). This variant is present at low frequency in population databases. Lopez et al (2018) reports that RYR1 p.G2435R knock-in mice demonstrated gene dose-dependent in vitro and in vivo responses to pharmacological and environmental stressors that parallel those seen in patients with the human RYR1 variant p.G2434R (PMID: 30236258) (PS3). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs121918593) and in the HGMD database: CM941269. It has been reported as Drug response by other diagnostic laboratories (ClinVar Variation ID: 12970), including the ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel (PP5).
Color Diagnostics, LLC DBA Color Health RCV000013837 SCV004358126 pathogenic Malignant hyperthermia, susceptibility to, 1 2023-03-01 criteria provided, single submitter clinical testing This missense variant replaces glycine with arginine at codon 2434 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A study using genetically engineered mice has shown that mice carrying this variant develop malignant hyperthermia when exposed to halothane (PMID: 30236258). Further, functional studies on myotubes from the genetically engineered mice showed increased sensitivity to caffeine, halothane, and KCI in comparison to myotubes expressing wild-type RYR1 (PMID: 30236258). This variant has been reported in over 100 families and individuals affected with malignant hyperthermia susceptibility (PMID: 21455645, 23558838, 23842196, 24433488, 25268394, 25735680, 25960145, 27646467, 30236257, 30788618, 31206373). This variant has been identified in 11/282648 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
All of Us Research Program, National Institutes of Health RCV000013837 SCV004820910 pathogenic Malignant hyperthermia, susceptibility to, 1 2024-01-08 criteria provided, single submitter clinical testing The c.7300G>A (p.Gly2434Arg) variant, located on the exon 45 of the RYR1 gene, replaces glycine with arginine at codon 2434 of the RYR1 protein (p.Gly2434Arg). This missense change has been observed in >100 individuals with personal or family histories of a malignant hyperthermia reaction, positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) (PMID: 30236257, 10484775, 23558838, 16163667, 21455645, 23842196, 7849712, 7881417, 11575529, 15731587, 11668625, 12059893, 12151923, 31559918, 10700782, 17081125, 18564801, 20681998, 21965348, 23460944, 25735680, 25960145, 9030597, 25268394, 17667681). This variant segregates with malignant hyperthermia (MHS) in at least 20 individuals (PMID: 7849712, 11575529, 12059893, 25960145). This missense variant is located in a mutational hot spot region that contributes to MHS (PMID: 21118704). A functional study in HEK293 cells shows an increased sensitivity to RYR1 agonists (PMID: 27586648). Such effect was confirmed in human skeletal muscle specimens isolated from MHS individuals carrying this RYR1 variant (PMID:9030597). Additionally, p.Gly2434Arg knock-in mice are susceptible to malignant hyperthermia due to volatile anesthetics, and ex vivo assays demonstrate increased sensitivity to RYR1 agonists for knock-in myotubes (PMID:30236258). Computational prediction (REVEL >0.85) suggests that this variant may have deleterious impact on protein structure and function. For these reasons, the c.7300G>A (p.Gly2434Arg) variant of RYR1 is classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000013837 SCV005398080 pathogenic Malignant hyperthermia, susceptibility to, 1 2022-02-02 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with RYR1-related disorders. Central core disease (MIM#117000), congenital neuromuscular disease with uniform type 1 fiber (MIM#17000) and minicore myopathy with external ophthalmoplegia (MIM#255320) are associated with loss of function, while a gain of function mechanism has been described in the context of malignant hyperthermia susceptibility (MIM#145600; PMIDs: 27855725, 23919265). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (11 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has very strong previous evidence of pathogenicity in multiple unrelated individuals with susceptibility to malignant hyperthermia (ClinVar, PMID: 28326467). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM RCV000013837 SCV000034084 risk factor Malignant hyperthermia, susceptibility to, 1 1997-02-21 no assertion criteria provided literature only
Leiden Muscular Dystrophy (RYR1) RCV000119698 SCV000154605 not provided not provided no assertion provided not provided
Gharavi Laboratory, Columbia University RCV000119698 SCV000809466 pathogenic not provided 2018-09-16 no assertion criteria provided research
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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