ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.11321C>T (p.Ala3774Val) (rs146361173)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000239317 SCV000296940 uncertain significance Malignant hypothermia 2015-09-24 criteria provided, single submitter clinical testing
GeneDx RCV000520252 SCV000618501 uncertain significance not provided 2018-04-20 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR1 gene. The A3774V variant has notbeen published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is observed in 35/23846 (0.15%) alleles from individuals of African background in large population cohorts (Lek et al., 2016). The A3774V 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 a deleterious effect. Missense variants in nearby residues have been reported in the Human Gene Mutation Database in individuals with RYR1-related disorders (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000706929 SCV000836004 uncertain significance RYR1-Related Disorders 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 3774 of the RYR1 protein (p.Ala3774Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs146361173, ExAC 0.2%). This variant has not been reported in the literature in individuals with RYR1-related disease. ClinVar contains an entry for this variant (Variation ID: 252488). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
PreventionGenetics RCV000520252 SCV000852247 uncertain significance not provided 2017-03-24 criteria provided, single submitter clinical testing

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