ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.2923C>T (p.Arg975Trp) (rs371278145)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000721478 SCV000620286 uncertain significance not provided 2017-08-23 criteria provided, single submitter clinical testing The R975W variant has been previously reported as a variant of uncertain significance in an individual with central core disease (Brandom et al., 2013). Segregation analysis and comprehensive genetic testing was not completed. The R975W variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is where amino acids with similar properties to Arginine are tolerated across species. However, this 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. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000691361 SCV000819137 uncertain significance RYR1-Related Disorders 2018-03-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 975 of the RYR1 protein (p.Arg975Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs371278145, ExAC 0.007%). This variant has been reported in an individual affected with central core disease (PMID: 23558838). ClinVar contains an entry for this variant (Variation ID: 451566. 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: "Probably Damaging"; 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.
PreventionGenetics RCV000721478 SCV000852550 uncertain significance not provided 2017-07-20 criteria provided, single submitter clinical testing

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