Submissions for variant NM_000383.4(AIRE):c.798+1G>A

gnomAD frequency: 0.00006  dbSNP: rs138489664

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000576629	SCV000678072	likely pathogenic	Polyglandular autoimmune syndrome, type 1	2014-07-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000576629	SCV000964791	pathogenic	Polyglandular autoimmune syndrome, type 1	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 6 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 (rs138489664, gnomAD 0.006%). Disruption of this splice site has been observed in individual(s) with clinical features of autoimmune polyendocrinopathy syndrome (Invitae). 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: 487443). 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	RCV000576629	SCV003928956	likely pathogenic	Polyglandular autoimmune syndrome, type 1	2023-04-04	criteria provided, single submitter	clinical testing	Variant summary: AIRE c.798+1G>A 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 a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.8e-05 in 247044 control chromosomes (gnomAD). To our knowledge, no occurrence of c.798+1G>A in individuals affected with Autoimmune Polyglandular Syndrome Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters have assessed the variant since 2014: both classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Natera, Inc.	RCV000576629	SCV001452114	likely pathogenic	Polyglandular autoimmune syndrome, type 1	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003905497	SCV004720187	likely pathogenic	AIRE-related disorder	2023-12-05	no assertion criteria provided	clinical testing	The AIRE c.798+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature. It reported in 0.0042% of alleles in individuals of African descent in gnomAD. Variants that disrupt the consensus splice donor site in AIRE are expected to be pathogenic. This variant is interpreted as likely pathogenic.