ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.6488G>A (p.Arg2163His)

dbSNP: rs118192163
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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PharmGKB RCV001787747 SCV000925380 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 RCV001787748 SCV000925381 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 RCV001787749 SCV000925382 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 RCV001787750 SCV000925383 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 RCV001787751 SCV000925384 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 RCV001787752 SCV000925385 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 RCV001787753 SCV000925386 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 RCV000013841 SCV002570154 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 Histidine at codon 2163 of the RYR1 protein, p.(Arg2163His). This variant is not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in 16 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, 14 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:30236257, PMID:9497245, PMID:21455645, PMID:15731587, PMID:23558838). This variant has been identified in three individuals with negative IVCT/CHCT results, BS2 (PMID:30236257). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:9334205). Additional functional studies in dyspedic myotubes were published for this variant, this assay is not considered a standard assay by the ClinGen RYR1 VCEP for MHS (PMID:12732639, PMID:15347586). 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 in seven families, PP1_Strong (PMID:30236257, PMID:9497245). A REVEL score >0.85 (0.933) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Pathogenic, (PMID: 29300386). Criteria implemented: PS3_Moderate, PS4, PM1, PP1_Strong, PP3_Moderate, BS2.
GeneDx RCV000119654 SCV000589650 likely pathogenic not provided 2015-11-09 criteria provided, single submitter clinical testing The R2163H likely pathogenic variant in the RYR1 gene has been reported in association with malignant hyperthermia and central core disease (Manning et al., 1998; Robinson et al., 2002). Functional studies indicate that the R163H variant is more sensitive to calcium- and halothane-induced intracellular calcium release when compared to the wild type channel (Tong et al., 1997). The R2163H variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R2163H variant is a conservative amino acid substitution, which occurs within the 6 X approximate repeats region and within the cytoplasmic topo domain at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same and in nearby residues (G2160S, R2163P, R2163C, V2168M, I2182F) have been reported in the Human Gene Mutation Database in association with RYR1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. The R2163H variant is a strong candidate for a pathogenic variant. However the possibility it may be a rare benign variant cannot be excluded
PreventionGenetics, part of Exact Sciences RCV000119654 SCV000852710 pathogenic not provided 2013-11-20 criteria provided, single submitter clinical testing
Invitae RCV001204982 SCV001376216 pathogenic RYR1-related disorder 2023-07-31 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2163 of the RYR1 protein (p.Arg2163His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with malignant hyperthermia susceptibility (MHS) with or without central core disease and/or severe congenital myopathy (PMID: 9497245, 12124989, 19648156, 29169929, 30236257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12974). 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. Experimental studies have shown that this missense change affects RYR1 function (PMID: 9334205, 9873004, 11524458, 27586648, 28687594). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV000119654 SCV002019918 pathogenic not provided 2020-03-25 criteria provided, single submitter clinical testing
OMIM RCV000013841 SCV000034088 risk factor Malignant hyperthermia, susceptibility to, 1 1998-03-01 no assertion criteria provided literature only
OMIM RCV000013842 SCV000034089 pathogenic Central core myopathy 1998-03-01 no assertion criteria provided literature only
GeneReviews RCV000013842 SCV000087313 pathologic Central core myopathy 2010-05-11 no assertion criteria provided curation Converted during submission to Pathogenic.
Leiden Muscular Dystrophy (RYR1) RCV000119654 SCV000154561 not provided not provided no assertion provided not provided

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