Submissions for variant NM_000383.4(AIRE):c.1249dup (p.Leu417fs)

dbSNP: rs786204567

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169307	SCV000220628	likely pathogenic	Polyglandular autoimmune syndrome, type 1	2014-08-22	criteria provided, single submitter	literature only
GeneDx	RCV000320611	SCV000329057	pathogenic	not provided	2016-12-16	criteria provided, single submitter	clinical testing	The c.1249dupC variant in the AIRE gene has been reported previously in association with APECED (Björses et al., 2000). The c.1249dupC variant causes a frameshift starting with codon Leucine 417, changes this amino acid to a Proline residue, and creates a premature Stop codon at position 7 of the new reading frame, denoted p.Leu417ProfsX7. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1249dupC variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we consider c.1249dupC to be a pathogenic variant.
Invitae	RCV000169307	SCV000944429	pathogenic	Polyglandular autoimmune syndrome, type 1	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu417Profs*7) in the AIRE gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AIRE are known to be pathogenic (PMID: 11524731, 26141571). This variant is present in population databases (rs776437891, gnomAD 0.005%). This premature translational stop signal has been observed in individuals with autosomal recessive autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy or autoimmune polyendocrine syndrome (PMID: 10677297, 17118990, 28919897). This variant is also known as C ins 1364-1365. ClinVar contains an entry for this variant (Variation ID: 188935). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169307	SCV002572318	pathogenic	Polyglandular autoimmune syndrome, type 1	2024-01-11	criteria provided, single submitter	clinical testing	Variant summary: AIRE c.1249dupC (p.Leu417ProfsX7) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2e-05 in 197512 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1249dupC has been reported in the literature as a biallelic genotype in multiple individuals affected with Autoimmune Polyglandular Syndrome Type 1 (e.g. Bjorses_2000, Halonen_2002, Wolff_2007). 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: 10677297, 12050215, 17118990). ClinVar contains an entry for this variant (Variation ID: 188935). Based on the evidence outlined above, the variant was classified as pathogenic.
National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	RCV000169307	SCV004036176	pathogenic	Polyglandular autoimmune syndrome, type 1	2023-09-14	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000169307	SCV002076115	pathogenic	Polyglandular autoimmune syndrome, type 1	2020-12-16	no assertion criteria provided	clinical testing