ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.14582G>A (p.Arg4861His)

dbSNP: rs63749869
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Total submissions: 21
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PharmGKB RCV001787782 SCV000925352 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 RCV001787783 SCV000925443 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 RCV001787784 SCV000925444 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 RCV001787785 SCV000925445 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 RCV001787786 SCV000925446 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 RCV001787787 SCV000925447 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 RCV001787788 SCV000925448 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 RCV000851296 SCV003930281 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-05-20 reviewed by expert panel curation This variant has strong evidence towards pathogenicity as a myopathy variant and 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 4861 of the RYR1 protein, p.(Arg4861His). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and 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_Supporting (PMID: 23558838). This variant has also been identified in two individuals with negative IVCT/CHCT results, BS2 (The UK (Leeds) MH Unit). Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID: 30236257). Additionally, a functional study in patient myotubes showed increased resting calcium and increased ECCE compared to controls (PMID: 21088110). This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Sup (PMID: 21118704). A REVEL score >0.85 (0.912) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Unknown Significance in relation to MHS. Criteria implemented: PS3_Moderate, PS4_Supporting, PM1_Supporting, PP3_Moderate, BS2.
GeneDx RCV000119533 SCV000329656 pathogenic not provided 2022-05-31 criteria provided, single submitter clinical testing Reported multiple times in association with autosomal dominant central core disease (Monnier et al., 2001; Davis et al., 2003; Kossugue et al., 2007; RYR1 LOVD); Published functional studies demonstrate that R4861H significantly alters intracellular calcium homeostasis (Tilgen et al., 2001); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27708273, 33458582, 11709545, 17483490, 17538032, 12565913, 16621918, 17226826, 25521991, 11741831, 23394784, 29629541, 27363342, 32403337, 33333461, 33726816, 31785789, 33087929, 29576327, 20681998)
Genetic Services Laboratory, University of Chicago RCV000119533 SCV000596914 pathogenic not provided 2017-03-10 criteria provided, single submitter clinical testing
Invitae RCV000534187 SCV000659854 pathogenic RYR1-related disorder 2023-11-04 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 4861 of the RYR1 protein (p.Arg4861His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant central core disease (PMID: 11709545, 12565913, 14670767, 23394784, 25521991). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12982). 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: 11741831). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences RCV000119533 SCV000852433 pathogenic not provided 2017-11-15 criteria provided, single submitter clinical testing
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes RCV000119533 SCV000920473 pathogenic not provided 2018-01-22 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000851296 SCV000993580 pathogenic Malignant hyperthermia, susceptibility to, 1 2018-09-11 criteria provided, single submitter research
CeGaT Center for Human Genetics Tuebingen RCV000119533 SCV001501718 pathogenic not provided 2021-01-01 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000119533 SCV002019938 pathogenic not provided 2019-10-17 criteria provided, single submitter clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV000013852 SCV004810081 pathogenic Central core myopathy 2024-04-04 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV004017241 SCV004848372 pathogenic Malignant hyperthermia of anesthesia 2020-06-11 criteria provided, single submitter clinical testing The p.Arg4861His variant in RYR1 has been reported in many heterozygous individuals with central core disease, segregated in many affected heterozygous relatives, and has been reported as a de novo variant in several cases (Brandom 2013 PMID 23558838, Broman 2007 PMID 17081152, Broman 2015 PMID 25989378, Davis 2003 PMID 12565913, Jeong 2018 PMID 29629541, Kossugue 2007 PMID 17226826, Lee 2014 PMID 25521991, Maggi 2013 PMID 23394784, Marks 2018 PMID 29576327, Monnier 2001 PMID 11709545, Park 2017 PMID 27363342, Reddy 2017 PMID 27708273, Sato 2008 PMID 17538032, Shepherd 2004 PMID 14985404, Tilgen 2001 PMID 11741831, Treves 2005 PMID 16084090, Wu 2006 PMID 16621918, Zhou 2007 PMID 17483490). It has also been reported in at least one individual with malignant hyperthermia susceptibility (Brandom 2013 PMID 23558838) and in ClinVar by the PharmGKB expert panel with evidence level 1A for susceptibility to malignant hyperthermia, the annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline (Variation ID 12982). It is absent from large population studies. Computational prediction tools and conservation analysis suggest that this variant may impact the protein. Furthermore, in vitro functional studies provide some evidence that this variant impacts protein function (Tilgen 2001 PMID 11741831). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant central core disease but has also been reported in MH susceptibility. ACMG/AMP criteria applied: PS4, PM6_Strong, PP1_Strong, PM2, PP3, PS3_Supporting.
OMIM RCV000013852 SCV000034099 pathogenic Central core myopathy 2008-01-08 no assertion criteria provided literature only
OMIM RCV000013853 SCV000034100 pathogenic Neuromuscular disease, congenital, with uniform type 1 fiber 2008-01-08 no assertion criteria provided literature only
Leiden Muscular Dystrophy (RYR1) RCV000119533 SCV000154440 not provided not provided no assertion provided not provided

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