ClinVar Miner

Submissions for variant NM_000383.4(AIRE):c.226G>A (p.Asp76Asn)

gnomAD frequency: 0.00023  dbSNP: rs146810389
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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 RCV000525346 SCV000629952 uncertain significance Polyglandular autoimmune syndrome, type 1 2024-01-06 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 76 of the AIRE protein (p.Asp76Asn). This variant is present in population databases (rs146810389, gnomAD 0.09%). 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: 458617). 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 RCV000780825 SCV000918408 uncertain significance not specified 2018-08-31 criteria provided, single submitter clinical testing Variant summary: AIRE c.226G>A (p.Asp76Asn) results in a conservative amino acid change located in the HSR domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.9e-05 in 276948 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in AIRE causing Autoimmune Polyglandular Syndrome Type 1 (7.9e-05 vs 0.0028), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.226G>A in individuals affected with Autoimmune Polyglandular Syndrome Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from another clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics RCV004619321 SCV005118722 uncertain significance Inborn genetic diseases 2024-06-11 criteria provided, single submitter clinical testing The c.226G>A (p.D76N) alteration is located in exon 2 (coding exon 2) of the AIRE gene. This alteration results from a G to A substitution at nucleotide position 226, causing the aspartic acid (D) at amino acid position 76 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc. RCV000525346 SCV001460094 uncertain significance Polyglandular autoimmune syndrome, type 1 2020-01-24 no assertion criteria provided clinical testing

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