Submissions for variant NM_000383.4(AIRE):c.1066C>T (p.Arg356Trp)

gnomAD frequency: 0.00016  dbSNP: rs376901046

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000361358	SCV000339087	uncertain significance	not provided	2016-02-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001060623	SCV001225325	uncertain significance	Polyglandular autoimmune syndrome, type 1	2022-09-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 356 of the AIRE protein (p.Arg356Trp). This variant is present in population databases (rs376901046, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of autosomal dominant AIRE-related conditions (PMID: 26650942, 32441320). ClinVar contains an entry for this variant (Variation ID: 285876). Advanced 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 at Invitae 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001532961	SCV001748782	uncertain significance	not specified	2021-07-01	criteria provided, single submitter	clinical testing	Variant summary: AIRE c.1066C>T (p.Arg356Trp) 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 0.00014 in 162232 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in AIRE causing Autoimmune Polyglandular Syndrome Type 1 (0.00014 vs 0.0028), allowing no conclusion about variant significance. c.1066C>T has been reported in the literature in individuals affected with Autoimmune Polyglandular Syndrome Type 1 (e.g. Tsai_2016, Suspitsin_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. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV001060623	SCV002778604	uncertain significance	Polyglandular autoimmune syndrome, type 1	2022-01-11	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001060623	SCV002083887	uncertain significance	Polyglandular autoimmune syndrome, type 1	2020-03-06	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003957448	SCV004770911	uncertain significance	AIRE-related disorder	2023-11-21	no assertion criteria provided	clinical testing	The AIRE c.1066C>T variant is predicted to result in the amino acid substitution p.Arg356Trp. This variant has been reported in an individual with primary adrenal insufficiency (Table 1, Tsai et al. 2016. PubMed ID: 26650942) and in an individual with inborn error of immunity (Suspitsin et al. 2020. PubMed ID: 32441320). This variant is reported in 0.029% of alleles in individuals of European (non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.