Submissions for variant NM_000383.4(AIRE):c.652+1G>T

gnomAD frequency: 0.00004  dbSNP: rs199612115

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000409920	SCV000486253	likely pathogenic	Polyglandular autoimmune syndrome, type 1	2016-04-22	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000409920	SCV000893559	likely pathogenic	Polyglandular autoimmune syndrome, type 1	2022-04-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000409920	SCV000938465	likely pathogenic	Polyglandular autoimmune syndrome, type 1	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 5 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 (rs199612115, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with AIRE-related conditions. ClinVar contains an entry for this variant (Variation ID: 370839). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Revvity Omics, Revvity	RCV000409920	SCV002024162	likely pathogenic	Polyglandular autoimmune syndrome, type 1	2022-05-13	criteria provided, single submitter	clinical testing
GeneDx	RCV004721348	SCV005328040	uncertain significance	not provided	2023-11-15	criteria provided, single submitter	clinical testing	Identified as a single heterozygous variant in patients in published literature, but additional evidence is not available (PMID: 35314707); 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: 35314707)
Natera, Inc.	RCV000409920	SCV001452112	likely pathogenic	Polyglandular autoimmune syndrome, type 1	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004754417	SCV005362413	likely pathogenic	AIRE-related disorder	2024-08-09	no assertion criteria provided	clinical testing	The AIRE c.652+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in three unaffected individuals who were part of a carrier study of autosomal recessive inherited disorders (Chau et al. 2022. PubMed ID: 35314707). This variant was reported in an individual with Autoimmune polyendocrinopathy with candidiasis and ectodermal dysplasia (Chau et al 2022. PubMed ID: 35314707; Heino M et al 2001. PubMed ID: 11524731; Placeholder for https://www.ncbi.nlm.nih.gov/pmc/?term=4544753 ; Kisand K et al 2015. PubMed ID: 26141571; Baralle D et al 2005. PubMed ID: 16199547). This variant is reported in 0.13% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/21-45708342-G-T). Variants that disrupt the consensus splice donor site in AIRE are expected to be pathogenic. This variant is interpreted as likely pathogenic.