Submissions for variant NM_000383.4(AIRE):c.83T>C (p.Leu28Pro)

gnomAD frequency: 0.00001  dbSNP: rs179363878

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000059063	SCV000322389	pathogenic	not provided	2016-03-07	criteria provided, single submitter	clinical testing	The L28P pathogenic variant has been reported previously in association with APECED (Heino et al., 1999). The variant was not observed in approximately 5,600 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. L28P is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position within the HSR domain that is conserved across species, and the HSR domain is critical for the transcriptional and homodimerization properties of the AIRE protein (Pitkänen et al., 2000). In silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, functional studies have demonstrated that cells transfected with the L28P allele lack expression of mRNA from AIRE-dependent genes, and show incorrect or partial localization of the AIRE protein (Oftedal et al., 2015).
Invitae	RCV000810303	SCV000950497	pathogenic	Polyglandular autoimmune syndrome, type 1	2023-09-29	criteria provided, single submitter	clinical testing	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. This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 28 of the AIRE protein (p.Leu28Pro). This variant is present in population databases (rs179363878, gnomAD 0.006%). This missense change has been observed in individual(s) with autoimmune polyendocrinopathy type 1 (APS-1) or autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) (PMID: 9837820, 9888391, 10946904). 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: 68229). Experimental studies have shown that this missense change affects AIRE function (PMID: 14974083, 16114041, 26084028, 29335648). For these reasons, this variant has been classified as Pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV000059063	SCV002503321	pathogenic	not provided	2021-06-23	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000810303	SCV002810520	likely pathogenic	Polyglandular autoimmune syndrome, type 1	2021-10-04	criteria provided, single submitter	clinical testing
National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	RCV000810303	SCV004036187	pathogenic	Polyglandular autoimmune syndrome, type 1	2023-09-14	criteria provided, single submitter	clinical testing
UniProtKB/Swiss-Prot	RCV000059063	SCV000090584	not provided	not provided		no assertion provided	not provided