ClinVar

Description

Variant summary: AIRE c.1322C>T (p.Thr441Met) results in a non-conservative amino acid change located in the Zinc finger, PHD-type domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 269480 control chromosomes, including one homozygote, predominantly at a frequency of 0.0035 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 1.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in AIRE causing Autoimmune Polyglandular Syndrome Type 1 phenotype (0.0028), while, the frequency within South Asian control individuals is equal to the estimated maximal expected allele frequency for a pathogenic variant; these data suggesting that the variant is a benign polymorphism. c.1322C>T has been reported in the literature in individuals affected with Addison disease, primary immunodeficiency disease and autoimmune thyroiditis, Sjogren syndrome and mendelian susceptibility to mycobacterial diseases (Chi_2018, Ferrera_2007, Mazza_unpublished abstract_2006. Suratannon_2020). 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. The following publications have been ascertained in the context of this evaluation (PMID: 17101293, No_PMID, 30290665, 32373116). Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=4) and benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.