ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.13898T>A (p.Leu4633Gln) (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 RCV000694993 SCV000823467 uncertain significance RYR1-Related Disorders 2018-03-29 criteria provided, single submitter clinical testing This sequence change replaces leucine with glutamine at codon 4633 of the RYR1 protein (p.Leu4633Gln). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and glutamine. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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). A different missense substitution at this codon (p.Leu4633Pro) has been determined to be likely pathogenic (Invitae). This suggests that the leucine residue is critical for RYR1 protein function and that other missense substitutions at this position may also be pathogenic. 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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