ClinVar Miner

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

gnomAD frequency: 0.00014  dbSNP: rs561652010
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Total submissions: 5
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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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000823710 SCV000964580 uncertain significance Polyglandular autoimmune syndrome, type 1 2022-09-19 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 493 of the AIRE protein (p.Ala493Thr). This variant is present in population databases (rs561652010, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with AIRE-related conditions. ClinVar contains an entry for this variant (Variation ID: 377459). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt AIRE protein function. 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.
Fulgent Genetics, Fulgent Genetics RCV000823710 SCV002814014 uncertain significance Polyglandular autoimmune syndrome, type 1 2021-07-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV003168621 SCV003879635 uncertain significance Inborn genetic diseases 2023-02-23 criteria provided, single submitter clinical testing The c.1477G>A (p.A493T) alteration is located in exon 12 (coding exon 12) of the AIRE gene. This alteration results from a G to A substitution at nucleotide position 1477, causing the alanine (A) at amino acid position 493 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc. RCV000823710 SCV002076137 uncertain significance Polyglandular autoimmune syndrome, type 1 2019-10-28 no assertion criteria provided clinical testing

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