ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.11599C>T (p.Arg3867Cys) (rs138593495)

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Total submissions: 5
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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 RCV000210015 SCV000265742 uncertain significance Malignant hyperthermia, susceptibility to, 1 2013-07-01 criteria provided, single submitter research
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626705 SCV000747408 uncertain significance Elevated serum creatine phosphokinase; Myalgia; Exercise-induced myalgia 2017-01-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764195 SCV000895198 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
GeneDx RCV000521020 SCV000618052 uncertain significance not provided 2017-09-18 criteria provided, single submitter clinical testing The R3867C variant in the RYR1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R3867C variant is observed in 36/66,220 (0.06%) alleles from individuals of European (non-Finnish) background in the ExAC dataset (Lek et al., 2016). The R3867C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R3867C as a variant of uncertain significance.
Invitae RCV000547789 SCV000659772 uncertain significance RYR1-Related Disorders 2018-09-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 3867 of the RYR1 protein (p.Arg3867Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs138593495, ExAC 0.06%). This variant has not been reported in the literature in individuals with a RYR1-related disease. ClinVar contains an entry for this variant (Variation ID: 224400). 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, this variant has uncertain impact on RYR1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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