Submissions for variant NM_000540.3(RYR1):c.7373G>A (p.Arg2458His)

gnomAD frequency: 0.00001  dbSNP: rs121918594

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PharmGKB	RCV001787733	SCV000925402	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	RCV001787734	SCV000925467	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	RCV001787735	SCV000925468	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	RCV001787736	SCV000925469	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	RCV001787737	SCV000925470	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	RCV001787738	SCV000925471	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	RCV001787739	SCV000925472	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.
Eurofins Ntd Llc (ga)	RCV000079164	SCV000230705	pathogenic	not provided	2013-10-18	criteria provided, single submitter	clinical testing
Invitae	RCV000793289	SCV000932637	pathogenic	RYR1-related disorder	2024-01-24	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 2458 of the RYR1 protein (p.Arg2458His). This variant is present in population databases (rs121918594, gnomAD 0.006%). This missense change has been observed in individuals with autosomal dominant malignant hyperthermia (PMID: 9450902, 12700608, 16732084, 18564801, 19648156, 22415532, 30236257). It has also been observed to segregate with disease in related individuals. This variant has been reported in individual(s) with autosomal recessive arthrogyrposis multiplex congenita (PMID: 24319099); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 12972). 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: 9334205, 9873004, 12732639, 27586648). For these reasons, this variant has been classified as Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000013839	SCV001434879	likely pathogenic	Malignant hyperthermia, susceptibility to, 1	2018-10-08	criteria provided, single submitter	clinical testing	The c.7373G>A(p.Arg2458His) variant in the RYR1 gene has been reported in multiple unrelated patients with malignant hyperthermia and segregates with disease in two unrelated families (PMID: 9450902, 22415532, 19648156). In silico analyses of this conserved variant predict damaging consequences on the RYR1 protein. The functional study also demonstrated that the variant increased the Ca2+-induced Ca2+release (CICR) activity and had enhanced sensitivity to caffeine and halothane(PMID: 12732639, 22415532, 27586648). Therefore, this c.7373G>A(p.Arg2458His) variant is classified as likely pathogenic for malignant hyperthermia.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000079164	SCV001449676	likely pathogenic	not provided	2017-02-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000793289	SCV004120070	pathogenic	RYR1-related disorder	2023-01-05	criteria provided, single submitter	clinical testing	The RYR1 c.7373G>A variant is predicted to result in the amino acid substitution p.Arg2458His. This variant has been reported in over 25 individuals and 9 families with malignant hyperthermia (MH) (Manning et al 1998. PubMed ID: 9450902; Carpenter D et al 2009. PubMed ID: 19648156; Li DW et al 2017. PubMed ID: 29355282; Miller DM et al 2018. PubMed ID: 30236257; Yeh HM et al 2020. PubMed ID: 32919876; Fusto et al. 2022. PubMed ID: 35428369). This variant is listed by the European Malignant Hyperthermia group as a clear diagnostic variant for MH (https://www.emhg.org/diagnostic-mutations). Functional studies indicate the p.Arg2458His variant results in enhanced sensitivity to caffeine and halothane (Tong et al. 1999. PubMed ID: 9873004; Murayama et al. 2016. PubMed ID: 27586648; Yang et al. 2003. PubMed ID: 12732639). The c.7373G>A variant has also been reported in the compound heterozygous state with another RYR1 variant in at least two individuals with arthrogryposis multiplex congenita, indicating this variant is also causative for autosomal recessive RYR1-related disorders (Laquérriere A et al 2013. PubMed ID: 24319099) This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-38991295-G-A). This variant is interpreted as pathogenic. THIS PATIENT IS SUSCEPTIBLE TO MALIGNANT HYPERTHERMIA! Alternative anesthetics should be used. The patient should consider wearing an ID bracelet or other alert device (see www.mhaus.org).
All of Us Research Program, National Institutes of Health	RCV000013839	SCV004820914	likely pathogenic	Malignant hyperthermia, susceptibility to, 1	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 2458 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). Functional studies in myotubes and HEK293 cells have shown this variant causes increased sensitivity to caffeine and/or 4-CmC in comparison to wild-type RYR1 (PMID: 12732639, 27586648). This variant has been reported in at least 20 families and individuals affected with malignant hyperthermia susceptibility (PMID: 14985404, 16732084, 18564801, 19648156, 22415532, 30236257, 9450902). This variant has been identified in 2/251238 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017240	SCV004848368	pathogenic	Malignant hyperthermia of anesthesia	2020-06-11	criteria provided, single submitter	clinical testing	The p.Arg2458His variant in RYR1 has been reported in >15 individuals with malignant hyperthermia and segregated in >10 affected family members (Li 2017, Shepherd 2006, Ibarra 2006, Carpenter 2009, Laquerriere 2014, Gillies 2008, Manning 1998, Rubegni 2019, Robinson 2006, Miller 2018, Kaufmann 2012). This variant has been identified in 1/18382 East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org) and in ClinVar by the PharmGKB expert panel with evidence level 1A for susceptibility to malignant hyperthermia, the annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline (Variation ID 12972). Computational prediction tools and conservation analysis suggest that this variant may impact the protein. Furthermore, in vitro functional studies indicated that this variant confers increase sensitivity to RYR1-agonists such as caffeine (Yang 2003, Tong 1997, Tong 1999). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant malignant hyperthermia. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2, PP3, PS3_Supporting.
OMIM	RCV000013839	SCV000034086	risk factor	Malignant hyperthermia, susceptibility to, 1	1998-01-01	no assertion criteria provided	literature only
Leiden Muscular Dystrophy (RYR1)	RCV000079164	SCV000154619	not provided	not provided		no assertion provided	not provided