ClinVar Miner

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

dbSNP: rs118192176
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Total submissions: 17
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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

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