ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.1186_1187inv (p.Glu396Ser)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000192565 SCV000248759 uncertain significance not specified 2013-10-23 criteria provided, single submitter clinical testing
Invitae RCV000553675 SCV000659778 uncertain significance RYR1-Related Disorders 2016-09-12 criteria provided, single submitter clinical testing This sequence change deletes 2 nucleotide and inserts 2 nucleotides in exon 12 of the RYR1 mRNA (c.1186_1187delGAinsTC), causing a missense change that replaces glutamic acid with serine at codon 396 of the RYR1 protein (p.Glu396Ser). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and serine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a RYR1-related disease. ClinVar contains an entry for this variant (Variation ID: 212091). 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 (PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This missense change is located in an N-terminal region of the RYR1 protein where many other previously reported pathogenic mutations have been found (PMID: 16084090). In summary, this variant is a rare missense change with uncertain impact on protein function. Therefore, it has been classified as a Variant of Uncertain Significance.

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