Submissions for variant NM_000383.4(AIRE):c.274C>T (p.Arg92Trp)

gnomAD frequency: 0.00002  dbSNP: rs140630532

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000425106	SCV000516083	pathogenic	not provided	2018-05-09	criteria provided, single submitter	clinical testing	The R92W missense variant in the AIRE gene has been reported previously in two compoundheterozygous individals with APS1 (Magitta et al., 2008). R92W was not observed with any significantfrequency in the NHLBI Exome Sequencing Project. In addition, missense variants in nearby residues(L87P, Y90C, L93R, L97P) have been reported in the Human Gene Mutation Database in association with APECED (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret this variant as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000666247	SCV000696653	pathogenic	Polyglandular autoimmune syndrome, type 1	2019-02-20	criteria provided, single submitter	clinical testing	Variant summary: AIRE c.274C>T (p.Arg92Trp) results in a non-conservative amino acid change located in the HSR domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 276962 control chromosomes (gnomAD and publication). c.274C>T has been reported in the literature in multiple affected individuals with features of Autoimmune Polyglandular Syndrome Type 1 (Zaidi_2017, Al-Mousa_2016, Magitta_2008). These data indicate that the variant is very likely to be associated with disease. The variant was also identified in our laboratory as a compound heterozygote with another variant (c.967_979delCTGTCCCCTCCGC, p.Leu323fsX51) in a patient presenting with features of hyperparathyroidism, Addisons disease, hepatitis, esophagitis, asplenia, poor dental enamel, growth hormone deficiency, and retinal dystrophy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic (1x) and once as likely pathogenic. This variant was previously classified conservatively as a VUS-possibly pathogenic variant by our laboratory in 2016. At-least two other reports reporting its presence in 4 additional affected individuals have been reported since its original classification by our laboratory. Based on all the evidence outlined above, the variant is now classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000666247	SCV001405378	pathogenic	Polyglandular autoimmune syndrome, type 1	2023-05-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 379319). This missense change has been observed in individuals with autoimmune polyendocrinopathy syndrome (PMID: 18426830, 24158785, 28446514). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 92 of the AIRE protein (p.Arg92Trp).
Fulgent Genetics, Fulgent Genetics	RCV000666247	SCV002809614	pathogenic	Polyglandular autoimmune syndrome, type 1	2022-04-09	criteria provided, single submitter	clinical testing
National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	RCV000666247	SCV004036192	pathogenic	Polyglandular autoimmune syndrome, type 1	2023-09-14	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000666247	SCV004048244	likely pathogenic	Polyglandular autoimmune syndrome, type 1		criteria provided, single submitter	clinical testing	The AIRE c.274C>T (p.Arg92Trp) variant has been reported in individuals affected with Autoimmune polyendocrine syndrome type I (Ng’weina F et al). The amino acid Arg at position 92 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. This variant has been reported to the ClinVar database as pathogenic. The p.Arg92Trp variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Arg92Trp in AIRE is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
Counsyl	RCV000666247	SCV000790506	likely pathogenic	Polyglandular autoimmune syndrome, type 1	2018-04-04	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000666247	SCV002083849	pathogenic	Polyglandular autoimmune syndrome, type 1	2021-02-01	no assertion criteria provided	clinical testing