ClinVar Miner

Submissions for variant NM_000383.4(AIRE):c.1450G>A (p.Val484Met)

gnomAD frequency: 0.00010  dbSNP: rs367966318
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000665256 SCV000789347 uncertain significance Polyglandular autoimmune syndrome, type 1 2017-01-30 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000665256 SCV001417521 uncertain significance Polyglandular autoimmune syndrome, type 1 2024-08-12 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 484 of the AIRE protein (p.Val484Met). This variant is present in population databases (rs367966318, gnomAD 0.02%). This missense change has been observed in individual(s) with AIRE-related conditions (PMID: 12843157, 26084028, 34573280). ClinVar contains an entry for this variant (Variation ID: 550499). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002282297 SCV002572289 uncertain significance not specified 2022-08-24 criteria provided, single submitter clinical testing Variant summary: AIRE c.1450G>A (p.Val484Met) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 215656 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in AIRE causing Autoimmune Polyglandular Syndrome Type 1 (0.00011 vs 0.0028), allowing no conclusion about variant significance. c.1450G>A has been reported in the literature in individuals affected with Autoimmune Disorders/Immunodeficiencies (Buzi_2003, Grossi_2021). These reports do not provide unequivocal conclusions about association of the variant with Autoimmune Polyglandular Syndrome Type 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters have assessed the variant since 2014: all classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics RCV000665256 SCV002791150 uncertain significance Polyglandular autoimmune syndrome, type 1 2022-04-25 criteria provided, single submitter clinical testing
Natera, Inc. RCV000665256 SCV002076134 uncertain significance Polyglandular autoimmune syndrome, type 1 2020-01-21 no assertion criteria provided clinical testing

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