ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.13703T>G (p.Leu4568Arg) (rs118192131)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000545985 SCV000659826 uncertain significance RYR1-Related Disorders 2016-09-09 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 4568 of the RYR1 protein (p.Leu4568Arg). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and arginine. 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. However, a different missense substitution at this codon (p.Leu4568Pro) has been reported in an individual with biopsy-confirmed central core disease (PMID: 16621918). 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 the C-terminal mutational hotspot of the RYR1 protein where a significant number of RYR1 missense mutations previously reported to cause central core disease are found (PMID: 16084090). These observations suggest that missense substitutions within this region may affect protein function. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
PreventionGenetics RCV000721329 SCV000852362 uncertain significance not provided 2013-10-29 criteria provided, single submitter clinical testing

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