ClinVar Miner

Submissions for variant NM_000383.4(AIRE):c.83T>C (p.Leu28Pro) (rs179363878)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
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 uncertain significance Polyglandular autoimmune syndrome, type 1 2018-08-30 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 28 of the AIRE protein (p.Leu28Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. While this variant is present in population databases (rs179363878), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in individuals affected with autoimmune polyendocrinopathy type 1 (APS-1) or autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) (PMID: 10946904, 9837820, 9888391). ClinVar contains an entry for this variant (Variation ID: 68229). Experimental studies have shown that this missense change disrupts AIRE protein function (PMID: 26084028, 29335648, 16114041, 14974083). 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.
UniProtKB/Swiss-Prot RCV000059063 SCV000090584 not provided not provided no assertion provided not provided

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.