ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.10594C>T (p.Leu3532Phe) (rs1131691407)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000494268 SCV000582064 uncertain significance not provided 2017-05-09 criteria provided, single submitter clinical testing The L3532F variant in the RYR1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The L3532F variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L3532F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret L3532F as a variant of uncertain significance.
Invitae RCV000655572 SCV000777503 uncertain significance RYR1-Related Disorders 2017-10-31 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 3532 of the RYR1 protein (p.Leu3532Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RYR1-related disease. ClinVar contains an entry for this variant (Variation ID: 429483). 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, 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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