ClinVar Miner

Submissions for variant NM_000383.4(AIRE):c.226G>A (p.Asp76Asn) (rs146810389)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000525346 SCV000629952 uncertain significance Polyglandular autoimmune syndrome, type 1 2018-01-31 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 76 of the AIRE protein (p.Asp76Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs146810389, ExAC 0.09%). This variant has not been reported in the literature in individuals with AIRE-related disease. ClinVar contains an entry for this variant (Variation ID: 458617). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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