ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.1156G>A (p.Ala386Thr) (rs532700459)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000534876 SCV000659771 uncertain significance RYR1-Related Disorders 2017-06-06 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 386 of the RYR1 protein (p.Ala386Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant has not been reported in the literature in individuals with a RYR1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This sequence change is located in a region of the RYR1 protein where a significant number of previously reported RYR1 missense mutations are found (PMID: 16084090). These observations suggest that a previously unreported missense substitution within this region may affect protein function, but experiments have not been done to test this possibility. In summary, this variant has uncertain impact on RYR1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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