ClinVar Miner

Submissions for variant NM_000383.4(AIRE):c.892G>A (p.Glu298Lys)

gnomAD frequency: 0.00001  dbSNP: rs763636007
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000674603 SCV000799969 uncertain significance Polyglandular autoimmune syndrome, type 1 2018-05-15 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000674603 SCV001382424 uncertain significance Polyglandular autoimmune syndrome, type 1 2021-08-27 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 298 of the AIRE protein (p.Glu298Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs763636007, ExAC 0.006%). This missense change has been observed in individual(s) with autoimmune polyendocrinopathy syndrome (PMID: 18682433, 20407228, 28911151). ClinVar contains an entry for this variant (Variation ID: 558351). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects AIRE function (PMID: 26084028). 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 RCV004782508 SCV005395326 uncertain significance not specified 2024-09-20 criteria provided, single submitter clinical testing Variant summary: AIRE c.892G>A (p.Glu298Lys) results in a conservative amino acid change located in the Zinc finger, PHD-type domain (IPR001965) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250216 control chromosomes. c.892G>A has been reported in the literature in at-least two individuals affected with autosomal recessive Autoimmune Polyglandular Syndrome (Podkrajsek_2008, Orlova_2017). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in about 15% of normal levels of AIRE-regulated IGFL1 gene in vitro (Oftedal_2015). The following publications have been ascertained in the context of this evaluation (PMID: 36732629, 26084028, 20407228, 18682433). ClinVar contains an entry for this variant (Variation ID: 558351). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
GenomeConnect - Invitae Patient Insights Network RCV001535539 SCV001749513 not provided not provided no assertion provided phenotyping only Variant interpreted as Uncertain significance and reported on 06-28-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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