ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.11798A>G (p.Tyr3933Cys) (rs147136339)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000148797 SCV000265744 uncertain significance Malignant hyperthermia, susceptibility to, 1 2013-07-01 criteria provided, single submitter research
CSER_CC_NCGL; University of Washington Medical Center RCV000148797 SCV000190535 likely benign Malignant hyperthermia, susceptibility to, 1 2014-06-01 no assertion criteria provided research
CeGaT Praxis fuer Humangenetik Tuebingen RCV000119441 SCV000575182 uncertain significance not provided 2016-09-30 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000119441 SCV000203471 uncertain significance not provided 2018-03-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764196 SCV000895199 uncertain significance Myopathy, Central Core; Malignant hyperthermia, susceptibility to, 1; Minicore myopathy; Congenital myopathy with fiber type disproportion 2018-10-31 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000119441 SCV000194792 uncertain significance not provided 2014-04-29 criteria provided, single submitter clinical testing
Invitae RCV000655533 SCV000777464 uncertain significance RYR1-Related Disorders 2018-11-27 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 3933 of the RYR1 protein (p.Tyr3933Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs147136339, ExAC 0.1%). Three missense variants, p.Ile1571Val, p.Arg3366His, and p.Tyr3933Cys, which includes this variant (p.Tyr3933Cys), have been reported together in multiple individuals and families affected with RYR1-related disorders including malignant hyperthermia (MH) syndrome, congenital myopathy, central core disease (CCD), and multi minicore disease (MmD). In some cases, the phase of the three variants along with additional RYR1 variants was established, while in other cases it could not be determined. It is therefore unclear if one of the three variants or the additive effect of some or all of these mutations are causative for the RYR1-associated diseases in reported individuals (PMID: 25958340, 25735680, 25214167, 24950660, 25960145, 25658027, 21674524, 18564801, 20681998, 23558838). ClinVar contains an entry for this variant (Variation ID: 133021). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Leiden Muscular Dystrophy (RYR1) RCV000119441 SCV000154348 not provided not provided no assertion provided not provided
PreventionGenetics RCV000119441 SCV000852270 uncertain significance not provided 2016-08-15 criteria provided, single submitter clinical testing

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