Submissions for variant NM_000383.4(AIRE):c.463+2T>C

gnomAD frequency: 0.00001  dbSNP: rs786204478

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169131	SCV000220341	likely pathogenic	Polyglandular autoimmune syndrome, type 1	2014-05-21	criteria provided, single submitter	literature only
GeneDx	RCV000413548	SCV000490397	pathogenic	not provided	2023-10-12	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 11524731, 9921903, 17220063, 35753512)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169131	SCV001408348	pathogenic	Polyglandular autoimmune syndrome, type 1	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 3 of the AIRE gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in AIRE are known to be pathogenic (PMID: 11524731, 26141571). This variant is present in population databases (rs786204478, gnomAD 0.002%). Disruption of this splice site has been observed in individuals with polyendocrinopathy with candidiasis and ectodermal dysplasia (APECED) (PMID: 9921903, 17220063). This variant is also known as 5835T>C and IVS3+2T>C. ClinVar contains an entry for this variant (Variation ID: 188800). 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	RCV000169131	SCV004020595	pathogenic	Polyglandular autoimmune syndrome, type 1	2023-06-26	criteria provided, single submitter	clinical testing	Variant summary: AIRE c.463+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. The variant allele was found at a frequency of 1.2e-05 in 242240 control chromosomes (gnomAD). c.463+2T>C has been reported in the literature in multiple individuals affected with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) (examples: Wang_1998, and Dominguez_2006). This variant is also known as 5835T>C. 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: 9921903, 17220063). Three 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.
National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	RCV000169131	SCV004036179	pathogenic	Polyglandular autoimmune syndrome, type 1	2023-09-14	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000169131	SCV002083854	pathogenic	Polyglandular autoimmune syndrome, type 1	2020-09-09	no assertion criteria provided	clinical testing