Submissions for variant NM_000540.3(RYR1):c.7372C>T (p.Arg2458Cys)

gnomAD frequency: 0.00001  dbSNP: rs28933397

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PharmGKB	RCV001787726	SCV000925502	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	RCV001787727	SCV000925503	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	RCV001787728	SCV000925504	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	RCV001787729	SCV000925505	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	RCV001787730	SCV000925506	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	RCV001787731	SCV000925548	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	RCV001787732	SCV000925549	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	RCV000013838	SCV002318980	likely pathogenic	Malignant hyperthermia, susceptibility to, 1	2023-04-07	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 cysteine at codon 2458 of the RYR1 protein, p.(Arg2458Cys). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000008, a frequency consistent with pathogenicity for MHS. This variant has been reported in six unrelated individuals with 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_Moderate (PMID: 24433488, 9450902, 10051009, 15731587). Functional study in HEK293 cells showed an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID: 9334205, 27586648). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, use PM1_Supporting to avoid overweighting with PM5 (PMID: 21118704). Another variant has been assessed as pathogenic occurs at this codon, p.(Arg2458His) PM5. A REVEL score >0.85 (0.922) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Likely Pathogenic, (PMID: 29300386). Criteria implemented: PS3_Moderate, PS4_Moderate, PM1_Supporting, PM5, PP3_Moderate.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000614410	SCV000731268	likely pathogenic	Malignant hyperthermia of anesthesia	2017-01-05	criteria provided, single submitter	clinical testing	The p.Arg2458Cys variant in RYR1 has been reported in 9 individuals with maligna nt hyperthermia, segregated with disease in 7 affected relatives from 2 families (Manning 1998, Girard 2001, Galli 2006, Klingler 2014) and was absent from larg e population studies. Computational prediction tools suggest that it affects pro tein function. In vitro functional studies provide conflicting evidence about th e impact of p.Arg2458Cys variant on protein function (Tong 1997, Tong 1999, Gira rd 2001, Bannister 2007). However, these types of assays may not accurately repr esent biological function. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg2458Cys variant is likely pathogenic. ACMG/AMP Criteria applied: PP1_Strong, PM2, PS4_Moderate, PP3.
PreventionGenetics, part of Exact Sciences	RCV000119711	SCV000852769	pathogenic	not provided	2015-08-19	criteria provided, single submitter	clinical testing
Invitae	RCV000796565	SCV000936084	pathogenic	RYR1-Related Disorders	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2458 of the RYR1 protein (p.Arg2458Cys). This variant is present in population databases (rs28933397, gnomAD 0.004%). This missense change has been observed in individual(s) with autosomal dominant malignant hyperthemia (PMID: 9450902, 11668625). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12971). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR1 protein function. Experimental studies have shown that this missense change affects RYR1 function (PMID: 9334205, 9873004, 27586648). This variant disrupts the p.Arg2458 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9450902, 12700608, 16732084, 18564801, 22415532). 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.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000013838	SCV000993581	likely pathogenic	Malignant hyperthermia, susceptibility to, 1	2019-03-27	criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV002490361	SCV002801261	likely pathogenic	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome	2021-09-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000614410	SCV003934632	pathogenic	Malignant hyperthermia of anesthesia	2023-05-02	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.7372C>T (p.Arg2458Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251256 control chromosomes (gnomAD). c.7372C>T has been reported in the literature in multiple individuals affected with Malignant Hyperthermia Susceptibility (example: Manning_1998 and Girard_2001). Functional studies in HEK293 cells have shown this variant increases sensitivity to RYR1 agonists (examples: Murayama_2016 and Tong_1997). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 9450902, 11668625, 9334205, 27586648). Seven submitters (including an expert panel- ClinGen) have evaluated this variant after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV000119711	SCV004021763	pathogenic	not provided	2023-07-21	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect, indicating that R2458C destabilizes the channel, resulting in increased excitability in response to caffeine or halothane and altered channel dynamics (Tong et al., 1997; Bannister et al., 2007; Murayama et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); Identified with a second variant in a patient with RYR1-recessive myopathy classified as Dusty core disease in published literature (Garibaldi et al., 2019); This variant is associated with the following publications: (PMID: 15677376, 9873004, 11668625, 22415532, 18564801, 16958617, 16732084, 16163667, 12208234, 21575570, 15611117, 27586648, 9334205, 20681998, 10051009, 31447099, 35428369, 24433488, 16835904, 12700608, 9450902, 30611313)
OMIM	RCV000013838	SCV000034085	risk factor	Malignant hyperthermia, susceptibility to, 1	1998-01-01	no assertion criteria provided	literature only
Leiden Muscular Dystrophy (RYR1)	RCV000119711	SCV000154618	not provided	not provided		no assertion provided	not provided