ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.10154C>T (p.Ala3385Val) (rs772566556)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520919 SCV000621836 uncertain significance not provided 2017-10-26 criteria provided, single submitter clinical testing The A3385V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A3385V variant is observed in 6/33,940 (0.02%) alleles from individuals of Latino background, including 1 homozygous individual in large population cohorts (Lek et al., 2016). This variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000553468 SCV000659741 uncertain significance RYR1-Related Disorders 2017-05-02 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 3385 of the RYR1 protein (p.Ala3385Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs772566556, ExAC 0.02%) but has not been reported in the literature in individuals with an RYR1-related disease. 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: "Benign"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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