ClinVar Miner

Submissions for variant NM_000383.4(AIRE):c.967_979del (p.Leu323fs) (rs386833675)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 10
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000284330 SCV000232541 pathogenic not provided 2017-09-21 criteria provided, single submitter clinical testing
GeneDx RCV000284330 SCV000329056 pathogenic not provided 2018-11-28 criteria provided, single submitter clinical testing The c.967_979del13 pathogenic variant in the AIRE gene has been reported previously in association with autoimmune polyendocrinopathy syndrome type I (Heino et al., 2001; Millar et al., 2012; Wolff et al., 2007). The c.967_979del13 variant causes a frameshift starting with codon Leucine 323, changes this amino acid to a Serine residue, and creates a premature Stop codon at position 51 of the new reading frame, denoted p.Leu323SerfsX51. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.967_979del13 variant is observed in 117/123,756 (0.09%) alleles from individuals of non-Finnish European background in large population cohorts (Lek et al., 2016). We interpret c.967_979del13 as a pathogenic variant.
Invitae RCV000049635 SCV000629960 pathogenic Polyglandular autoimmune syndrome, type 1 2019-01-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu323Serfs*51) in the AIRE gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in numerous individuals and families affected with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) and is the most common variant found in affected individuals of British or Anglo-American ancestry (PMID: 11524731, 9837820, 27588307). This variant is also known as c.964del13, c.967_979del13, p.C322del13, or c.1094_1106del in the literature. ClinVar contains an entry for this variant (Variation ID: 3309). An experimental study has shown that this sequence change has a dominant negative effect on the gene regulation of tested AIRE-regulated genes (PMID: 26084028). In addition, though Aire deficient mice with this variant demonstrate a normal T cell compartment and do not show an increased susceptibility to C. albicans infection, they do exhibit a mild autoimmune phenotype characterized by the disturbance of the medullary epithelial compartment, increased numbers of activated T cells, lymphocytic infiltration of multiple organs, and autoantibodies against multiple organs (PMID: 19265170). Loss-of-function variants in AIRE are known to be pathogenic (PMID: 11524731, 26141571). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000049635 SCV000678033 pathogenic Polyglandular autoimmune syndrome, type 1 2015-10-09 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000049635 SCV000696656 pathogenic Polyglandular autoimmune syndrome, type 1 2019-09-05 criteria provided, single submitter clinical testing Variant summary: AIRE c.967_979delCTGTCCCCTCCGC (p.Leu323SerfsX51) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.00051 in 243022 control chromosomes (gnomAD). c.967_979delCTGTCCCCTCCGC has been reported in the literature in multiple individuals affected with Autoimmune Polyglandular Syndrome Type 1 (eg . Wang_1998, Dominguez_2006). These data indicate that the variant is very likely to be associated with disease. Six ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Athena Diagnostics Inc RCV000284330 SCV000840734 pathogenic not provided 2018-03-27 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000284330 SCV000927566 pathogenic not provided 2018-03-05 criteria provided, single submitter clinical testing
OMIM RCV000049635 SCV000023630 pathogenic Polyglandular autoimmune syndrome, type 1 2009-11-01 no assertion criteria provided literature only
OMIM RCV000003473 SCV000023631 pathogenic Autoimmune polyglandular syndrome type 1, with reversible metaphyseal dysplasia 2009-11-01 no assertion criteria provided literature only
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049635 SCV000082042 probable-pathogenic Polyglandular autoimmune syndrome, type 1 no assertion criteria provided not provided Converted during submission to Likely pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.