ClinVar Miner

Submissions for variant NM_000383.4(AIRE):c.748A>T (p.Ser250Cys)

gnomAD frequency: 0.00016  dbSNP: rs141480813
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001242405 SCV001415491 uncertain significance Polyglandular autoimmune syndrome, type 1 2024-12-04 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 250 of the AIRE protein (p.Ser250Cys). This variant is present in population databases (rs141480813, gnomAD 0.05%). This missense change has been observed in individual(s) with APECED-like disease and/or autoimmunity and immunodeficiency (PMID: 25068407, 35683627). ClinVar contains an entry for this variant (Variation ID: 967483). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt AIRE protein function with a negative predictive value of 95%. 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 RCV001242405 SCV002782400 uncertain significance Polyglandular autoimmune syndrome, type 1 2021-08-03 criteria provided, single submitter clinical testing
Natera, Inc. RCV001242405 SCV002083872 uncertain significance Polyglandular autoimmune syndrome, type 1 2020-03-17 no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV004754713 SCV005354014 uncertain significance AIRE-related disorder 2024-08-08 no assertion criteria provided clinical testing The AIRE c.748A>T variant is predicted to result in the amino acid substitution p.Ser250Cys. This variant was reported in an individual with autoimmunity and immunodeficiency (Bellacchio et al. 2014. PubMed ID: 25068407; Fierabracci et al. 2022. PubMed ID: 35683627). This variant is reported in 0.041% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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