ClinVar Miner

Submissions for variant NM_000383.4(AIRE):c.1411C>T (p.Arg471Cys) (rs74203920)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics,PreventionGenetics RCV000116295 SCV000303914 benign not specified criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000514017 SCV000609534 likely benign not provided 2017-04-18 criteria provided, single submitter clinical testing
Invitae RCV000526170 SCV000629949 benign Polyglandular autoimmune syndrome, type 1 2020-12-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000116295 SCV001623210 likely benign not specified 2021-04-28 criteria provided, single submitter clinical testing 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.
GeneDx RCV000514017 SCV001835220 benign not provided 2015-03-03 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 28911151, 26650942, 20718774, 25402387, 24014553, 21070315, 19863576)
Genetic Services Laboratory, University of Chicago RCV000116295 SCV000150213 likely benign not specified no assertion criteria provided clinical testing Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000514017 SCV001799335 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000116295 SCV001930261 benign not specified no assertion criteria provided clinical testing

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