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

gnomAD frequency: 0.01176  dbSNP: rs74203920

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000116295	SCV000150213	benign	not specified	2021-04-08	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000526170	SCV000629949	benign	Polyglandular autoimmune syndrome, type 1	2024-01-31	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)
Fulgent Genetics, Fulgent Genetics	RCV000526170	SCV002795923	likely benign	Polyglandular autoimmune syndrome, type 1	2021-07-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000514017	SCV002821093	benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	AIRE: BS1, BS2
Breakthrough Genomics, Breakthrough Genomics	RCV000514017	SCV005207505	likely benign	not provided		criteria provided, single submitter	not provided
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
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000514017	SCV001979594	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000526170	SCV002076132	benign	Polyglandular autoimmune syndrome, type 1	2019-11-14	no assertion criteria provided	clinical testing