Submissions for variant NM_000540.3(RYR1):c.1201C>T (p.Arg401Cys)

gnomAD frequency: 0.00002  dbSNP: rs193922764

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001822999	SCV002570147	pathogenic	Malignant hyperthermia, susceptibility to, 1	2022-03-29	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 401 of the RYR1 protein p.(Arg401Cys). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.00005, a frequency consistent with pathogenicity for MHS. This variant has been reported in five unrelated individuals who have a personal or family history of a malignant hyperthermia reaction and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (when the proband was unavailable for testing a positive diagnostic test result in a mutation positive relative was counted), PS4_Moderate ( PMID:30236257, PMID:12434264, PMID:24433488, PMID:25735680). This variant segregates with MHS in three individuals, PP1 (PMID:12066726, PMID:18564801). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists PS3_Moderate, (PMID:23459219). Another variant has been assessed as pathogenic occurs at this codon, p.(Arg401His), PM5 (PMID:16917943). 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). A REVEL score > 0.85 (0.886) supports pathogenicity, PP3_Moderate. Criteria implemented: PS4_Moderate, PS3_Moderate, PM1_Supporting, PM5, PP1, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386).
PharmGKB	RCV003227642	SCV003925496	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	RCV003227643	SCV003925497	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	RCV003227644	SCV003925498	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	RCV003227645	SCV003925499	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	RCV003227646	SCV003925500	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	RCV003227647	SCV003925501	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	RCV003227648	SCV003925502	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000610923	SCV000712043	pathogenic	Malignant hyperthermia of anesthesia	2024-03-22	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Labcorp Genetics (formerly Invitae), Labcorp	RCV000802489	SCV000942323	pathogenic	RYR1-related disorder	2024-01-04	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 401 of the RYR1 protein (p.Arg401Cys). This variant is present in population databases (rs193922764, gnomAD 0.005%). This missense change has been observed in individual(s) with autosomal dominant malignant hyperthermia susceptibility and/or autosomal recessive RYR1-related myopathy (PMID: 12066726, 23919265, 24433488, 25735680, 28818389, 30236257). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 133029). 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: 23459219). This variant disrupts the p.Arg401 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12059893, 24433488; Invitae). 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.
Ambry Genetics	RCV001266973	SCV001445154	uncertain significance	Inborn genetic diseases	2018-02-19	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000119449	SCV002019917	pathogenic	not provided	2023-07-03	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001822999	SCV002072555	pathogenic	Malignant hyperthermia, susceptibility to, 1	2022-01-19	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PS3, PS4_MOD, PM1, PM5_STR, PM2_SUP, PP1, PP3
AiLife Diagnostics, AiLife Diagnostics	RCV000119449	SCV002501143	likely pathogenic	not provided	2021-05-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000119449	SCV002512915	pathogenic	not provided	2020-11-10	criteria provided, single submitter	clinical testing	In addition to malignant hyperthermia susceptibility, some individuals who harbored the R401C variant presented with additional neuromuscular features including muscle cramps, multicore/minicore myopathy, and elevated CK levels (Davis et al., 2002; Galli et al., 2002); Functional analysis of R401C shows that it leads to higher sensitivity to agonist compared to wildtype controls (Sato et al., 2013); Not observed at a significant frequency in large population cohorts (gnomAD); 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: 30236257, 28326467, 14999498, 32381029, 25735680, 23459219, 23919265, 29635721, 24433488, 16917943, 28818389, 12208234, 18564801, 12434264, 23553484, 12066726, 31589614)
CeGaT Center for Human Genetics Tuebingen	RCV000119449	SCV002822555	pathogenic	not provided	2022-12-01	criteria provided, single submitter	clinical testing	RYR1: PM1, PM2, PM5, PS3:Moderate, PS4:Moderate, PP1
Color Diagnostics, LLC DBA Color Health	RCV001822999	SCV004357275	pathogenic	Malignant hyperthermia, susceptibility to, 1	2023-03-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 401 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 increases sensitivity to 4-CmC and caffeine compare to wild-type RYR1 in HEK293 cells (PMID: 23459219, 26115329, 31841587). This variant has been reported in at least 4 individuals affected with malignant hyperthermia clinical crises and in at least 4 families affected with malignant hyperthermia susceptibility (PMID: 12066726, 12066726, 12434264, 18564801, 24433488, 25735680, 30236257). It has been shown that this variant segregates with disease in two families (PMID: 12066726). This variant has been identified in 2/282746 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	RCV001822999	SCV004820739	pathogenic	Malignant hyperthermia, susceptibility to, 1	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 401 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 increases sensitivity to 4-CmC and caffeine compare to wild-type RYR1 in HEK293 cells (PMID: 23459219, 26115329, 31841587). This variant has been reported in at least 4 individuals affected with malignant hyperthermia clinical crises and in at least 4 families affected with malignant hyperthermia susceptibility (PMID: 12066726, 12066726, 12434264, 18564801, 24433488, 25735680, 30236257). It has been shown that this variant segregates with disease in two families (PMID: 12066726). This variant has been identified in 2/282746 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Leiden Muscular Dystrophy (RYR1)	RCV000119449	SCV000154356	not provided	not provided		no assertion provided	not provided
PreventionGenetics, part of Exact Sciences	RCV000802489	SCV000852278	pathogenic	RYR1-related disorder	2024-08-12	no assertion criteria provided	clinical testing	The RYR1 c.1201C>T variant is predicted to result in the amino acid substitution p.Arg401Cys. This variant has been reported to be causative for Malignant Hyperthermia (MH) in multiple families (Davis et al. 2002. PubMed ID: 12066726; Robinson et al. 2006. PubMed ID: 16917943; Gillies et al. 2015. PubMed ID: 25735680; Miller et al. 2018. PubMed ID: 30236257). Functional studies in transfected cell cultures indicate that the p.Arg401Cys variant results in Ca++ channels that are more sensitive to triggering agents than wild type channels (Sato K. et al. 2013. PubMed ID: 23459219). Several other substitutions at the same amino acid (p.Arg401Gly, p.Arg401His, p.Arg401Leu and p.Arg401Ser) have also been reported to be causative for MH. In addition, this variant has been reported to be causative for recessive myopathy (Amburgey et al. 2013. PubMed ID: 23919265). This variant is reported in 0.0050% of alleles in individuals of East Asian descent in gnomAD. In summary, we conclude that the c.1201C>T variant is pathogenic for dominant inheritance of MH susceptibility and also recessive inheritance of RYR1-related myopathy.