Submissions for variant NM_000383.4(AIRE):c.232T>C (p.Trp78Arg)

gnomAD frequency: 0.00002  dbSNP: rs179363880

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169457	SCV000696652	pathogenic	Polyglandular autoimmune syndrome, type 1	2023-10-11	criteria provided, single submitter	clinical testing	Variant summary: AIRE c.232T>C (p.Trp78Arg) results in a non-conservative amino acid change located in the HSR domain (IPR004865) 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 8e-06 in 250942 control chromosomes. c.232T>C has been reported in the literature in multiple individuals affected with Autoimmune Polyglandular Syndrome Type 1, either in the homozygous or compound heterozygous state (examples, Meloni_2002, Cervato_2008). At least one publication reports experimental evidence evaluating an impact on protein function (Sparks_2016). The most pronounced variant effect results in very little transcriptional activity in transfected cells. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11836330, 18616706, 27048654). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000169457	SCV000819231	pathogenic	Polyglandular autoimmune syndrome, type 1	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 78 of the AIRE protein (p.Trp78Arg). This variant is present in population databases (rs179363880, gnomAD 0.002%). This missense change has been observed in individuals with clinical features of autosomal recessive autoimmune polyendocrinopathy candidiasis-ectodermal dystrophy (APECED) (PMID: 11524733, 11836330, 15712268, 18616706, 20407228, 20718774). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 189060). 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) performed at Invitae indicates that this missense variant is expected to disrupt AIRE protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects AIRE function (PMID: 15712268). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001575328	SCV001802296	pathogenic	not provided	2019-08-22	criteria provided, single submitter	clinical testing	Functional studies using a yeast 2-hybrid system demonstrate that W78R mutants do not interact with DAXX protein most likely due to impaired AIRE homodimerization (Meloni et al., 2010); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 11524733, 31589614, 11836330, 11524731, 21295522, 23365130, 21508664, 27048654, 22104652, 14974083, 18616706, 20185822, 30018023)
National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	RCV000169457	SCV004036190	pathogenic	Polyglandular autoimmune syndrome, type 1	2023-09-14	criteria provided, single submitter	clinical testing
Counsyl	RCV000169457	SCV000220882	pathogenic	Polyglandular autoimmune syndrome, type 1	2019-06-12	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000169457	SCV001452105	pathogenic	Polyglandular autoimmune syndrome, type 1	2020-09-16	no assertion criteria provided	clinical testing