Submissions for variant NM_000540.3(RYR1):c.1209C>G (p.Ile403Met)

dbSNP: rs118192116

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PharmGKB	RCV001787712	SCV000925247	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	RCV001787713	SCV000925248	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	RCV001787714	SCV000925249	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	RCV001787715	SCV000925250	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	RCV001787716	SCV000925251	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	RCV001787717	SCV000925252	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	RCV001787718	SCV000925253	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	RCV003231102	SCV003930279	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-05-20	reviewed by expert panel	curation	The ClinGen RYR1-MHS variant curation expert panel is focused on assessing variants in RYR1 for pathogenicity as related to 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 Isoleucine with Methionine at codon 403 of the RYR1 protein, p.(Ile403Met). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0000088, a frequency consistent with pathogenicity for MHS. This variant has been reported in individuals with a personal or family history of an MH episode or central core disease but without sufficient information to consider the reports for informing PS4 in relation to MHS inherited in an autosomal dominant pattern (PMID:8220423). This variant has been identified in an individual with negative IVCT/CHCT results, BS2_Moderate (PMID:32861507). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:9334205). Additional functional studies have been published for this variant that did not show statistical differences in Ca2+ release when compared to wildtype RYR1, however, those assays were not considered standard assays for variant interpretation in regard to MHS by the ClinGen RYR1 VCEP (PMID:11524458). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). A REVEL score of 0.618 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance in relation to MHS inherited in an autosomal dominant pattern. Criteria implemented: PS3_Moderate, PM1, BS2_Moderate.
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000013835	SCV000891293	likely pathogenic	Central core myopathy	2017-11-15	criteria provided, single submitter	clinical testing
Invitae	RCV003591629	SCV004353247	uncertain significance	RYR1-related disorder	2023-03-29	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects RYR1 function (PMID: 9334205, 9873004, 11524458). 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. ClinVar contains an entry for this variant (Variation ID: 12968). This missense change has been observed in individual(s) with RYR1-related conditions (PMID: 8220423, 32861507, 35428369). This variant is present in population databases (rs118192116, gnomAD 0.0009%). This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 403 of the RYR1 protein (p.Ile403Met).
All of Us Research Program, National Institutes of Health	RCV003231102	SCV004820740	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with methionine at codon 403 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that the resting Ca2+ concentration was found to be higher and the maximum caffeine-induced Ca2+ released was lower in cells expressing this variant compared to cells expressing wild-type RYR1 (PMID: 9873004). This variant has not been reported in individuals affected with autosomal dominant malignant hyperthermia in the literature, although it is associated with other phenotype(s) (ClinVar Variation ID: 12968). This variant has been reported in an individual who tested negative for malignant hyperthermia susceptibility by CHCT (PMID: 32861507). This variant has been identified in 1/251444 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.
OMIM	RCV000013835	SCV000034082	pathogenic	Central core myopathy	1993-09-01	no assertion criteria provided	literature only
GeneReviews	RCV000013835	SCV000087290	pathologic	Central core myopathy	2010-05-11	no assertion criteria provided	curation	Converted during submission to Pathogenic.
Leiden Muscular Dystrophy (RYR1)	RCV000119453	SCV000154360	not provided	not provided		no assertion provided	not provided