Submissions for variant NM_000383.4(AIRE):c.62C>T (p.Ala21Val)

gnomAD frequency: 0.00001  dbSNP: rs179363886

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169178	SCV000220414	likely pathogenic	Polyglandular autoimmune syndrome, type 1	2014-06-14	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169178	SCV001386832	pathogenic	Polyglandular autoimmune syndrome, type 1	2023-07-14	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 21 of the AIRE protein (p.Ala21Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive autoimmune polyendocrinopathy syndrome (PMID: 12050215, 18708298, 21295522, 21508664). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 68228). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on AIRE function (PMID: 14974083). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169178	SCV004803676	pathogenic	Polyglandular autoimmune syndrome, type 1	2024-01-23	criteria provided, single submitter	clinical testing	Variant summary: AIRE c.62C>T (p.Ala21Val) 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 frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.62C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Autoimmune Polyglandular Syndrome Type 1 (example: Capalbo_2021). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 33247909). ClinVar contains an entry for this variant (Variation ID: 68228). Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV000059062	SCV005325505	pathogenic	not provided	2023-06-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 26114819, 21508664, 18708298, 19309509, 14974083, 27420045, 34003463, 24107778, 18682433, 26659599, 12050215, 34991662, 21295522, 25059117)
UniProtKB/Swiss-Prot	RCV000059062	SCV000090583	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000169178	SCV002083841	likely pathogenic	Polyglandular autoimmune syndrome, type 1	2021-06-12	no assertion criteria provided	clinical testing