ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.12250C>T (p.Arg4084Cys)

gnomAD frequency: 0.00001  dbSNP: rs755879946
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498614 SCV000589439 uncertain significance not provided 2015-07-17 criteria provided, single submitter clinical testing The R4084C variant in the RYR1 gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R4084C variant was not observed in approximately 6,500 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 R4084C 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 where amino acids with similar properties to Arginine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in a nearby residue (T4081M) has been reported in the Human Gene Mutation Database in association with malignant hyperthermia (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret R4084C as a variant of uncertain significance.
Invitae RCV001368022 SCV001564398 uncertain significance RYR1-related disorder 2021-08-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 4084 of the RYR1 protein (p.Arg4084Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs755879946, ExAC 0.03%). This missense change has been observed in individual(s) with clinical features of RYR1-related congenital myopathy (PMID: 27363342, 29629541). ClinVar contains an entry for this variant (Variation ID: 431880). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or 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.
Fulgent Genetics, Fulgent Genetics RCV002506200 SCV002815752 uncertain significance Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome 2022-02-11 criteria provided, single submitter clinical testing

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