ClinVar Miner

Submissions for variant NM_000383.4(AIRE):c.132+1_132+3delinsCT

dbSNP: rs886041293
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000361975 SCV000329648 pathogenic not provided 2024-09-05 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16965330, 25554620, 28458664, 18248641)
Labcorp Genetics (formerly Invitae), Labcorp RCV000702028 SCV000830855 pathogenic Polyglandular autoimmune syndrome, type 1 2023-09-04 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 1 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 (no rsID available, gnomAD 0.002%). Disruption of this splice site has been observed in individuals with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) (PMID: 16965330, 18248641, 25554620, 28458664). This variant is also known as 132+1_132+3delGTGinsCT and IVS1 + 1G > C; IVS1 + 5delG. 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000702028 SCV001365628 pathogenic Polyglandular autoimmune syndrome, type 1 2019-07-03 criteria provided, single submitter clinical testing The c.132+1_132+3delinsCT variant in AIRE has been reported in the homozygous or compound heterozygous state in at least 3 individuals with features of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED; Stolarski 2006, Capalbo 2008, Gutierrez 2017). It has also been identified in 0.002% (1/50686) of European chromosomes in gnomAD (http://gnomad.broadinstitute.org) and has been reported as Pathogenic in ClinVar (Variation ID 279973). This variant is a deletion of 3 nucleotides and insertion of 2 nucleotides at position c.132+1. This occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the AIRE gene is an established disease mechanism in autosomal recessive APECED. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive APECED. ACMG/AMP criteria applied: PVS1, PM3_Strong, PM2.

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