ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.6670C>T (p.Arg2224Cys) (rs199870223)

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Total submissions: 3
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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 RCV000210006 SCV000265716 uncertain significance Malignant hyperthermia, susceptibility to, 1 2013-07-01 criteria provided, single submitter research
GeneDx RCV000521116 SCV000618842 uncertain significance not provided 2017-07-07 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR1 gene. The R2224C variant was reported as a variant of uncertain significance in an individual with coronary artery disease who did not have any reported history of myopathy or malignant hyperthermia (Gonsalves et al., 2013). The R2224C variant is observed in 17/16508 (0.1%) alleles from individuals of South Asian background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R2224C 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, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with RYR1-related disorders (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000697616 SCV000826237 uncertain significance RYR1-Related Disorders 2018-10-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 2224 of the RYR1 protein (p.Arg2224Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs199870223, ExAC 0.1%). This variant has not been reported in the literature in individuals with RYR1-related disease. ClinVar contains an entry for this variant (Variation ID: 224387). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). This missense change is located in a region of the RYR1 protein where a significant number of previously reported RYR1 missense mutations are found (PMID: 16917943, 12565913, 23919265). These observations suggest that a previously unreported missense substitution within this region may affect protein function, but experiments have not been done to test this possibility. 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.

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