ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.6374A>G (p.His2125Arg) (rs775112843)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000540120 SCV000659989 uncertain significance RYR1-Related Disorders 2016-07-03 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 2125 of the RYR1 protein (p.His2125Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs775112843, ExAC <0.01%) but has not been reported in the literature in individuals with a RYR1-related disease. Substitutions of nearby amino acids (e.g. p.Arg2118Trp, p.Asp2129Asn, p.Asp2129Glu) have been reported in patients with myopathy or malignant hyperthermia susceptibility (PMID: 25957634, 23628358, 11241852). 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 is a rare missense change with uncertain impact on protein function. There is currently no direct evidence that it causes disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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