Submissions for variant NM_000540.3(RYR1):c.7361G>A (p.Arg2454His)

gnomAD frequency: 0.00001  dbSNP: rs118192122

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PharmGKB	RCV001787854	SCV000925254	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	RCV001787855	SCV000925255	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	RCV001787856	SCV000925256	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	RCV001787857	SCV000925371	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	RCV001787858	SCV000925372	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	RCV001787859	SCV000925373	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	RCV001787860	SCV000925374	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	RCV000709760	SCV002570133	pathogenic	Malignant hyperthermia, susceptibility to, 1	2021-03-19	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 arginine with histidine at codon 2454 of the RYR1 protein, p.(Arg2454His). The maximum allele frequency for this variant among the six major gnomAD populations is AFR: 0.000062, a frequency consistent with pathogenicity for MHS. This variant has been reported in 34 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all 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, 12059893, 16163667, 24433488, 11575529, 10051009, 10823104, 17081152, 20618998, 21455645, 23460944, 23558838, 25960145). This variant has been identified in an individual with a negative IVCT/CHCT result, BS2_Moderate (PMID: 30236257). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID: 27586648). An ex vivo assay in patient derived immortalized lymphoblastoid cells also shows an increased sensitivity to RYR1 agonists (PMID: 19191333). 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 11 individuals/families PP1_Strong (PMID: 12059893, 10051009). A REVEL score >0.85 (0.923) 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_Moderate, PS4, PM1, PP1_Strong, PP3_Moderate, BS2_Moderate.
Invitae	RCV000699835	SCV000828564	pathogenic	RYR1-Related Disorders	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2454 of the RYR1 protein (p.Arg2454His). This variant is present in population databases (rs118192122, gnomAD 0.007%). This missense change has been observed in individuals with malignant hyperthermia susceptibility (MHS) (PMID: 10051009, 12059893, 19191333, 19648156). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 65980). 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: 19191333, 19648156). This variant disrupts the p.Arg2454 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10612851, 12411788, 16163667). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000709760	SCV000840062	pathogenic	Malignant hyperthermia, susceptibility to, 1	2018-01-15	criteria provided, single submitter	clinical testing	This c.7361G>A (p.Arg2454His) variant in exon 46 of the RYR1 gene has been reported in multiple individuals with susceptibility to malignant hyperthermia that was diagnosed either by a well-defined laboratory diagnostic test or patients developed malignant hyperthermia crisis during anesthesia (PMID: 16163667, 19648156, 10051009, 20301565). Independently performed functional assays also support the pathogenicity of this variant (PMID, 19191333, 16163667, 27586648). Moreover, European Malignant Hyperthermia Group (EMHG) has categorized this variant as diagnostic for susceptibility to malignant hyperthermia https://emhg.org/genetics/mutations-in-ryr1/. The c.7361G>A (p.Arg2454His) variant in the RYR1 gene is classified as pathogenic .
PreventionGenetics, part of Exact Sciences	RCV000119710	SCV000852768	pathogenic	not provided	2016-03-11	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000119710	SCV001249991	pathogenic	not provided	2022-06-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000119710	SCV001823275	pathogenic	not provided	2020-05-20	criteria provided, single submitter	clinical testing	Reported previously, in the heterozygous state, as a pathogenic variant associated with malignant hyperthermia (Barone et al., 1999; Rueffert et al. 2002; Carpenter et al., 2009); B-lymphocytes from individuals with the R2454H variant displayed an increased extracellular acidification rate compared with wild-type cells, suggesting that the R2454H variant causes increased calcium channel activity (Zullo et al., 2009); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31447099, 32174957, 30788618, 30499100, 30236257, 19648156, 12059893, 10051009, 28687594, 28682948, 26951757, 28325813, 27586648, 19191333, 31206373)
Institute of Human Genetics, University of Leipzig Medical Center	RCV000709760	SCV001934353	pathogenic	Malignant hyperthermia, susceptibility to, 1	2021-07-28	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000119710	SCV002019929	pathogenic	not provided	2021-10-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000709760	SCV003834827	pathogenic	Malignant hyperthermia, susceptibility to, 1	2022-12-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000709760	SCV004358128	pathogenic	Malignant hyperthermia, susceptibility to, 1	2023-06-21	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 2454 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 functional study has shown that this variant causes increased cellular sensitivity to caffeine compared to wild-type RYR1 (PMID: 16163667). This variant occurs in a region of the RYR1 protein that is considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). This variant has been reported in over 25 families and/or individuals affected with malignant hyperthermia susceptibility (PMID: 12709367, 15448513, 16163667, 17081152, 19648156, 20681998, 21455645, 24433488, 25960145, 26951757) and has been reported to segregate with disease in over ten families (PMID: 30236257). This variant has been identified in 2/251210 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
GeneReviews	RCV000056227	SCV000087316	pathologic	Central core myopathy	2010-05-11	no assertion criteria provided	curation	Converted during submission to Pathogenic.
Leiden Muscular Dystrophy (RYR1)	RCV000119710	SCV000154617	not provided	not provided		no assertion provided	not provided
deCODE genetics, Amgen	RCV000709760	SCV004022262	pathogenic	Malignant hyperthermia, susceptibility to, 1	2023-07-21	no assertion criteria provided	research	The variant NM_000540.3:c.7361G>A (chr19:38500643) in RYR1 was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar previously as pathogenic and is one of the diagnostic MH variants (https://www.emhg.org/diagnostic-mutations). Based on ACMG criteria (PS3, PM2, PP3, PP4, PP5_Strong) this variant classifies as pathogenic.