ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.4346C>T (p.Ala1449Val) (rs775455157)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000658422 SCV000780194 uncertain significance not provided 2018-05-30 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR1 gene. The A1449V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A1449V variant is observed in 14/126,626 (0.01%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). The A1449V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000655508 SCV000777439 uncertain significance RYR1-Related Disorders 2017-11-01 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 1449 of the RYR1 protein (p.Ala1449Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs775455157, ExAC 0.02%). This variant has not been reported in the literature in individuals with RYR1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine 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. 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. 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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