ClinVar Miner

Submissions for variant NM_000383.4(AIRE):c.1477G>A (p.Ala493Thr) (rs561652010)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000430079 SCV000512008 uncertain significance not provided 2015-12-20 criteria provided, single submitter clinical testing The A493T variant in the AIRE gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The 1000 Genomes Project reports that the A493T variant was not observed with any significant frequency in approximately 1000 alleles from individuals of European ancestry (McVean et al., 2012). The A493T variant is a non-conservative amino acid substitution, which occurs at a position that is not conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A missense variant in a nearby residue (V484M) has been reported in the Human Gene Mutation Database in association with APECED (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret A493T as a variant of uncertain significance.
Invitae RCV000823710 SCV000964580 uncertain significance Polyglandular autoimmune syndrome, type 1 2018-11-30 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 493 of the AIRE protein (p.Ala493Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs561652010, ExAC 0.02%). This variant has not been reported in the literature in individuals with AIRE-related conditions. ClinVar contains an entry for this variant (Variation ID: 377459). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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