ClinVar Miner

Submissions for variant NM_000383.4(AIRE):c.581T>C (p.Met194Thr)

dbSNP: rs1351412367
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000705899 SCV000834917 uncertain significance Polyglandular autoimmune syndrome, type 1 2021-08-31 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 194 of the AIRE protein (p.Met194Thr). The methionine residue is weakly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with AIRE-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). 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.
Genetic Services Laboratory, University of Chicago RCV001816737 SCV002067562 uncertain significance not specified 2021-04-07 criteria provided, single submitter clinical testing DNA sequence analysis of the AIRE gene demonstrated a sequence change, c.581T>C, in exon 5 that results in an amino acid change, p.Met194Thr. This sequence change does not appear to have been previously described in patients with AIRE-related disorders and has been described in the gnomAD database with a low population frequency of 0.00040% (dbSNP rs1351412367). The p.Met194Thr change affects a poorly conserved amino acid residue located in a domain of the AIRE protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Met194Thr substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Met194Thr change remains unknown at this time.
Natera, Inc. RCV000705899 SCV002083861 uncertain significance Polyglandular autoimmune syndrome, type 1 2020-02-21 no assertion criteria provided clinical testing

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