ClinVar Genomic variation as it relates to human health

Variant summary: AIRE c.342G>T (p.Lys114Asn) results in a non-conservative amino acid change in 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 0.00019 in 246278 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in AIRE causing Autoimmune Polyglandular Syndrome Type 1 (0.00019 vs 0.0028), allowing no conclusion about variant significance. c.342G>T has been reported in the literature in one individual affected with common variable immunodeficiency (Lai_2017). The report does 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 (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 114 of the AIRE protein (p.Lys114Asn). This variant is present in population databases (rs142788946, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of AIRE-related conditions (PMID: 28472507). ClinVar contains an entry for this variant (Variation ID: 35663). Invitae Evidence 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 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.

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 28472507)