ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.13898T>C (p.Leu4633Pro) (rs1555801874)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000547545 SCV000659832 likely pathogenic RYR1-Related Disorders 2017-04-26 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 4633 of the RYR1 protein (p.Leu4633Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. 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. This variant has been shown to arise de novo in an individual affected with neuromuscular disease (Invitae database). 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"). This sequence change is located in the C-terminal mutational hotspot of the RYR1 protein where a significant number of previously reported RYR1 missense mutations are found (PMID: 16084090). In summary, this variant is a novel missense change that has been observed to arise de novo in a single affected individual. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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