Submissions for variant NM_000540.3(RYR1):c.7360C>T (p.Arg2454Cys)

gnomAD frequency: 0.00001  dbSNP: rs193922816

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PharmGKB	RCV001788014	SCV000925491	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	RCV001788015	SCV000925492	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	RCV001788016	SCV000925493	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	RCV001788017	SCV000925494	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	RCV001788018	SCV000925495	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	RCV001788019	SCV000925496	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	RCV001788020	SCV000925497	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	RCV001257496	SCV002570155	pathogenic	Malignant hyperthermia, susceptibility to, 1	2022-03-11	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 arginine with cysteine at codon 2454 of the RYR1 protein, p.(Arg2454Cys). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.000065. This variant has been reported in three 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_Moderate (PMID: 10484775, 10612851, 16163667). This variant segregates with MHS in 3 individuals, PP1 (PMI: 10484775). A functional study in HEK293 cells shows an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID: 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 that has been assessed as pathogenic occurs at this codon, p.(Arg2454His), PM5 (PMID: 26951757). A REVEL score >0.85 (0.913) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS3_Moderate, PS4_Moderate, PM1_Supporting, PM5, PP1, PP3_Moderate.
Eurofins Ntd Llc (ga)	RCV000119709	SCV000203458	likely pathogenic	not provided	2014-04-29	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000601471	SCV000712562	likely pathogenic	Malignant hyperthermia of anesthesia	2016-10-21	criteria provided, single submitter	clinical testing	The p.Arg2454Cys variant in RYR1 has been reported in 4 individuals with maligna nt hyperthermia and segregated with disease in 2 affected relatives from 1 famil y (Brandt 1999, Gencik 2000, Monnier 2002, Monnier 2005). This variant has been identified in 2/30780 South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs193922816). In vitro functio nal studies provide some evidence that the p.Arg2454Cys variant may impact prote in function (Monnier 2005, Bannister 2007). However, these types of assays may n ot accurately represent biological function. Another variant at the same amino a cid position (p.Arg2454His) is likely disease causing for malignant hyperthermia , increasing the likelihood that the change to a cysteine would also be disease causing. Computational prediction tools and conservation analysis suggest that t he p.Arg2454Cys variant may impact the protein, though this information is not p redictive enough to determine pathogenicity. In summary, although additional stu dies are required to fully establish its clinical significance, the p.Arg2454Cys variant is likely pathogenic.
Invitae	RCV000655594	SCV000777525	pathogenic	RYR1-Related Disorders	2023-12-21	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 2454 of the RYR1 protein (p.Arg2454Cys). This variant is present in population databases (rs193922816, gnomAD 0.006%). This missense change has been observed in individuals with malignant hyperthermia (MH) (PMID: 10484775, 10612851, 12411788, 16163667). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 133202). 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: 16163667, 16958617, 27586648). 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: 10051009, 10484775, 15448513, 16163667, 27586648). 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.
Division of Medical Genetics, University of Washington	RCV001257496	SCV001434313	pathogenic	Malignant hyperthermia, susceptibility to, 1	2020-04-09	criteria provided, single submitter	clinical testing	This variant is a known pathogenic variant in the RYR1 gene. This variant has been reported in multiple individuals and at least one family with malignant hyperthermia in the medical literature (Brandt 1999, Gencik 2000, Monnier 2002). This variant falls within a region known to be important for normal sarcoplasmic reticulum function (Bannister 2007, Murayama 2016). It has been observed in four individuals reported in the gnomAD database (gnomad.broadinstitute.org). Based on this evidence we interpret this as a pathogenic variant. PS4-moderate; PP3
CeGaT Center for Human Genetics Tuebingen	RCV000119709	SCV001500190	pathogenic	not provided	2021-04-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000119709	SCV002019971	pathogenic	not provided	2020-04-04	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV001257496	SCV002503616	pathogenic	Malignant hyperthermia, susceptibility to, 1	2022-04-22	criteria provided, single submitter	clinical testing	This sequence change is predicted to replace arginine with cysteine at codon 2454 of the RYR1 protein, p.(Arg2454Cys). The arginine residue is evolutionarily conserved (100 vertebrates, UCSC), and located in the RYR1 cytosolic shell. There is a large physicochemical difference between arginine and cysteine. The variant is classified as a diagnostic malignant hyperthermia (MH) mutation by the European Malignant Hyperthermia Group (EMHG). It is present in a large population cohort at a frequency of 0.002% (rs193922816, 4/251,200 alleles, 0 homozygotes in gnomAD v2.1.1). The variant has been identified in multiple MH susceptible families and segregates with the condition (PMID: 10484775, 10612851, 12411788, 29608462). Further, it has been identified in association with a clinical reaction consistent with MH under anaesthesia and confirmed by a positive in vitro contracture test (PMID: 10484775), and demonstrates gain-of-function in well-established in vitro functional studies (PMID: 16163667, 27586648). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/5 algorithms). Additionally, a different amino acid substitution at this residue (p.Arg2454His) is also an EMHG diagnostic MH mutation. Based on the classification scheme RMH Modified ACMG Guidelines v1.3.1, this variant is classified as PATHOGENIC . Following criteria are met: PS3, PM5, PP1_Moderate, PP3, PP4.
GeneDx	RCV000119709	SCV004025563	pathogenic	not provided	2023-07-26	criteria provided, single submitter	clinical testing	Reported in association with malignant hyperthermia in the published literature (Brandt et al., 1999); Published functional studies demonstrate a damaging effect as this variant results in abnormal calcium release (Bannister et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27586648, 24433488, 31447099, 16958617, 10484775)
Color Diagnostics, LLC DBA Color Health	RCV001257496	SCV004358127	likely pathogenic	Malignant hyperthermia, susceptibility to, 1	2023-07-09	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine 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). Functional studies have shown that this variant causes increased cellular sensitivity to caffeine compared to wild-type RYR1 (PMID: 16163667, 27586648). 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 6 families and/or individuals affected with malignant hyperthermia susceptibility (PMID: 10484775, 10612851, 12411788, 16163667, 24433488, 25611019, 25989378, 30864471) and has been shown to segregate with disease in a small German kindred (PMID: 10484775). This variant has been identified in 4/251200 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg2454His, is known to cause disease (ClinVar variation ID: 65980), indicating that arginine at this position is important for RYR1 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.
Leiden Muscular Dystrophy (RYR1)	RCV000119709	SCV000154616	not provided	not provided		no assertion provided	not provided