ClinVar Genomic variation as it relates to human health

Variant summary: AIRE c.1411C>T (p.Arg471Cys) results in a non-conservative amino acid change located in the PHD-type Zinc finger domain (IPR001965) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.01 in 333270 control chromosomes, predominantly at a frequency of 0.014 within the European subpopulation in the gnomAD database (v2.1, v3, and publication data), including 19 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 5-fold higher than the estimated maximal expected allele frequency for a pathogenic variant in AIRE causing Autoimmune Polyglandular Syndrome Type 1 (APS-1) phenotype (0.0028), strongly suggesting that the variant is a benign polymorphism. The variant, c.1411C>T, has been reported in homozygosity in 3 patients affected with isolated primary adrenal insufficiency (Betterle_2013, Tsai_2016), and in compound heterozygous state with a loss of function AIRE variant in an individual affected with isolated primary hypoparathyroidism (Orlova_2017), however, the three major components of APS-1 were not present in these patients, and the lack of characteristic autoantibodies present in APS-1 was also noted in several cases. On the other hand, the variant has also been reported in the literature in heterozygous state in patients with isolated adrenal insufficiency (Boe Wolff_2008, Orlova_2010), isolated hypoparathyroidism (Cervato_2010), and adrenal insufficiency with type 1 diabetes and/or autoimmune thyroid disease, i.e. with autoimmune polyglandular syndrome type 2 (APS-2) (Toth_2010, Resende_2014). Recent large scale genome-wide association studies (GWAS) demonstrated that the p.R471C (rs74203920) variant was enriched in patients affected with isolated autoimmune Addison's disease (AAD) and APS-2 (OR = 3.4) (Eriksson_2021), and also in patients affected with (isolated) type 1 diabetes (Chiou_2021), although the effect of linkage disequilibrium with nearby genes/variants cannot be excluded. Two publications reported experimental evidence evaluating an impact on protein function, and demonstrated that the R471C variant had no significant effect on the expression of AIRE-dependent genes, neither in co-transfection experiments with the wild-type gene, nor when the variant was transfected alone (Oftedal_2015, Eriksson_2021). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as benign/likely benign. In conclusion, current evidence does not support the variant as a cause of APS-1, but instead points to an increased risk of isolated- or multi-organ autoimmune endocrine diseases at the population level. Therefore, based on the evidence outlined above, the variant was classified as likely benign.

This variant is associated with the following publications: (PMID: 28911151, 26650942, 20718774, 25402387, 24014553, 21070315, 19863576)

AIRE: BS1, BS2