ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.10616G>A (p.Arg3539His)

gnomAD frequency: 0.00171  dbSNP: rs143987857
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Total submissions: 23
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel,ClinGen RCV001802859 SCV002047661 likely benign Malignant hyperthermia of anesthesia 2021-11-10 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 3539 of the RYR1 protein, p.(Arg3539His). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.00305, this is considered to be more common than expected for a pathogenic variant causing autosomal dominantly inherited MHS, BS1. This variant has been reported in 10 unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, all 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) (PMID:30236257; PMID:23460944; PMID:23558838; PMID:24433488; PMID:25960145), however, the high MAF in the NFE population precludes the use of PS4. This variant has been identified in multiple individuals with negative IVCT/CHCT results, BS2 (PMID:18253926, PMID:22473935). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score >0.85 (0.877) supports a pathogenic status for this variant, PP3_Moderate. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID: 29300386). Criteria implemented: PP3_Moderate, BS1, BS2.
Eurofins NTD LLC (GA) RCV000119414 SCV000232393 uncertain significance not provided 2016-08-01 criteria provided, single submitter clinical testing
GeneDx RCV000119414 SCV000234974 likely benign not provided 2021-08-16 criteria provided, single submitter clinical testing See Variant Classification Assertion Criteria.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000203202 SCV000257708 uncertain significance not specified 2015-06-18 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000209955 SCV000265737 uncertain significance Malignant hyperthermia, susceptibility to, 1 2013-07-01 criteria provided, single submitter research
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000203202 SCV000540251 uncertain significance not specified 2017-01-24 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is classified in HGMD as DM relating to central core disease and is reported in 10 papers, with comments suggesting VUS/LB. This variant has a Max MAF of 0.30% in ExAC (384/126200 European chrs including 1 homozygote - high for central core disease prevalence of 6/100,000). It is classified in ClinVar as VUS by 4 submitters (Emory, GeneDx, CHOP, Biesecker), and Likely benign by U Wash.
CeGaT Center for Human Genetics Tuebingen RCV000119414 SCV000575180 uncertain significance not provided 2020-08-01 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000203202 SCV000596887 uncertain significance not specified 2017-02-02 criteria provided, single submitter clinical testing
Invitae RCV001085699 SCV000659754 likely benign RYR1-Related Disorders 2021-12-15 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000119414 SCV000852216 uncertain significance not provided 2016-05-25 criteria provided, single submitter clinical testing
Mendelics RCV000209955 SCV001141071 benign Malignant hyperthermia, susceptibility to, 1 2019-05-28 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000119414 SCV001474664 uncertain significance not provided 2020-03-24 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000203202 SCV002074555 likely benign not specified 2022-01-07 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories,Mayo Clinic RCV000119414 SCV002541636 uncertain significance not provided 2021-06-03 criteria provided, single submitter clinical testing
Leiden Muscular Dystrophy (RYR1) RCV000119414 SCV000154321 not provided not provided no assertion provided not provided
CSER _CC_NCGL, University of Washington RCV000148796 SCV000190534 likely benign Central core myopathy 2014-06-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000119414 SCV001552609 uncertain significance not provided no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000119414 SCV001744337 uncertain significance not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000119414 SCV001806817 uncertain significance not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000119414 SCV001953585 uncertain significance not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000119414 SCV001980081 uncertain significance not provided no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000119414 SCV002037066 uncertain significance not provided no assertion criteria provided clinical testing
GenomeConnect, ClinGen RCV001085699 SCV002075091 not provided RYR1-Related Disorders no assertion provided phenotyping only Variant interpreted as Uncertain significance and reported on 05-17-2017 by Lab or GTR ID 303161. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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