Submissions for variant NM_000540.3(RYR1):c.6502G>A (p.Val2168Met)

dbSNP: rs118192176

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PharmGKB	RCV001787761	SCV000925285	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	RCV001787762	SCV000925286	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	RCV001787763	SCV000925287	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	RCV001787764	SCV000925288	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	RCV001787765	SCV000925387	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	RCV001787766	SCV000925388	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	RCV001787767	SCV000925389	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	RCV000013845	SCV002570125	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 Valine with Methionine at codon 2168 of the RYR1 protein, p.(Val2168Met). This variant is not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in over 25 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, over 25 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 (PMID:11668625; PMID:30236257; PMID:20681998 and others). Functional studies in human myotubes from nine individuals (5 families) showed an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:15299003). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1 (PMID: 21118704). This variant segregates with MHS eight individuals PP1_Strong (PMID:12434264, PMID:11575529). A REVEL score >0.85 (0.896)supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as Pathogenic. Criteria implemented: PS3_Moderate, PS4, PM1, PP1_Strong, PP3_Moderate.
Invitae	RCV000557804	SCV000659996	pathogenic	RYR1-related disorder	2023-12-15	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 2168 of the RYR1 protein (p.Val2168Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with malignant hyperthermia susceptibility (PMID: 9497245, 11668625, 19648156, 25466363). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12976). 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: 11668625). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000578323	SCV000680358	pathogenic	Congenital multicore myopathy with external ophthalmoplegia	2017-11-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000119656	SCV000852713	pathogenic	not provided	2017-09-27	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV001729347	SCV001976854	pathogenic	Central core myopathy	2021-10-01	criteria provided, single submitter	clinical testing	PM2, PP2, PP3, PP5
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003398498	SCV004122468	pathogenic	Malignant hyperthermia of anesthesia	2023-10-04	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.6502G>A (p.Val2168Met) results in a conservative amino acid change located in the RIH domain (IPR000699) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250298 control chromosomes. c.6502G>A has been reported in the literature in multiple individuals affected with autosomal dominant Malignant Hyperthermia Susceptibility with evidence of familial co-segregation (e.g. Manning_1998, Girard_2001). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence showing altered calcium-induced calcium release in vitro, however, without evidence to confirm variant effect in skeletal muscle (e.g. Murayama_2016). The following publications have been ascertained in the context of this evaluation (PMID: 11673462, 9497245, 27586648). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV003398498	SCV004848341	pathogenic	Malignant hyperthermia of anesthesia	2020-06-11	criteria provided, single submitter	clinical testing	The p.Val2168Met variant in RYR1 has been previously reported in >25 individuals with malignant hyperthermia susceptibility (MHS), segregated in >10 affected family members, and was absent from large population studies (PMID, 19648156, 25466363, 11668625, 9497245, 30236257, 8010475, 29635721). In vitro functional studies showed that this variant results in an increased sensitivity to caffeine, as well as additional findings that indicate that this variant would result in a MHS phenotype (27586648, 12732639). Computational prediction tools and conservation analyses also suggest that this variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant malignant hyperthermia susceptibility. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2, PP3, PS3_Supporting.
OMIM	RCV000013845	SCV000034092	risk factor	Malignant hyperthermia, susceptibility to, 1	2001-10-15	no assertion criteria provided	literature only
Leiden Muscular Dystrophy (RYR1)	RCV000119656	SCV000154563	not provided	not provided		no assertion provided	not provided
OMIM	RCV001729347	SCV005046821	pathogenic	Central core myopathy	2001-10-15	no assertion criteria provided	literature only