ClinVar Miner

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

dbSNP: rs386833675
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 24
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000284330 SCV000232541 pathogenic not provided 2017-09-21 criteria provided, single submitter clinical testing
GeneDx RCV000284330 SCV000329056 pathogenic not provided 2021-11-29 criteria provided, single submitter clinical testing Considered to be a founder variant in the Anglo-American population (Pearce et al., 1998; Heino et al., 2001); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies indicate the variant may have a minor dominant negative effect, which in heterozygotes could lead to atypical phenotypes with later onset and reduced penetrance (Oftedal et al., 2015); This variant is associated with the following publications: (PMID: 24948345, 19265170, 10677297, 27588307, 28769929, 28911151, 27219120, 11916620, 11207636, 19807739, 23620608, 9921903, 10720083, 17118990, 14557425, 26912174, 25707324, 9398840, 27253668, 28323927, 11298085, 31589614, 9837820, 26084028, 11524731)
Invitae RCV000049635 SCV000629960 pathogenic Polyglandular autoimmune syndrome, type 1 2024-01-31 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. Loss-of-function variants in AIRE are known to be pathogenic (PMID: 11524731, 26141571). This variant is present in population databases (rs779937061, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) and is the most common variant found in affected individuals of British or Anglo-American ancestry (PMID: 9837820, 11524731, 27588307). It has also been observed to segregate with disease in related individuals. This variant is also known as c.964del13, c.967_979del13, p.C322del13, or c.1094_1106del. ClinVar contains an entry for this variant (Variation ID: 3309). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000049635 SCV000696656 pathogenic Polyglandular autoimmune syndrome, type 1 2020-12-24 criteria provided, single submitter clinical testing Variant summary: AIRE c.967_979del13 (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. c.967_979del13 has been widely reported in the literature as a frequent mutation in multiple individuals affected with Autoimmune Polyglandular Syndrome Type 1 (example, Wang_1998, Dominguez_2006). These data indicate that the variant is very likely to be associated with disease. A mice model of this 13-bp deletion displaying a mild autoimmune phenotype characterized by a disturbance of medullary epithelial compartment, increased levels of activated T cells and autoantibodies against multiple organs has been reported (Hubert_2009). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Athena Diagnostics 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
Myriad Genetics, Inc. RCV000049635 SCV001193892 pathogenic Polyglandular autoimmune syndrome, type 1 2019-12-17 criteria provided, single submitter clinical testing NM_000383.3(AIRE):c.967_979del13(L323Sfs*51) is classified as pathogenic in the context of autoimmune polyglandular syndrome type 1. Sources cited for classification include the following: PMID 17220063, 12050215, 17118990, 9921903, 9837820, 21295522, 17118990 and 12050215. Classification of NM_000383.3(AIRE):c.967_979del13(L323Sfs*51) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000049635 SCV001365629 pathogenic Polyglandular autoimmune syndrome, type 1 2022-12-22 criteria provided, single submitter clinical testing The p.Leu323SerfsX51 variant in AIRE is a well-established pathogenic variant, which represents the most common variant identified in Anglo-American autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) patients (Heino 2001 PMID: 11524731, Ferre 2016 PMID: 27588307). It has also been identified in 0.096% (121/125552) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 323 and leads to a premature termination codon 51 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the AIRE gene is an established disease mechanism in autosomal recessive APECED. Finally, the p.Leu323SerfsX51 has been reported as Pathogenic by multiple clinical labs in ClinVar (Variation ID 3309). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive APECED. ACMG/AMP Criteria applied: ACMG/AMP criteria applied: PVS1, PM3_VeryStrong.
Genomics England Pilot Project, Genomics England RCV000049635 SCV001760477 likely pathogenic Polyglandular autoimmune syndrome, type 1 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000049635 SCV002024173 pathogenic Polyglandular autoimmune syndrome, type 1 2023-11-02 criteria provided, single submitter clinical testing
DASA RCV000049635 SCV002097301 pathogenic Polyglandular autoimmune syndrome, type 1 2022-02-14 criteria provided, single submitter clinical testing The c.967_979del;p.(Leu323Serfs*51) is a null frameshift variant in the AIRE gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript -PVS1_strong. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 3309; PMID: 11524731; 9837820; 27588307) - PS4. The variant is present at low allele frequencies population databases (rs386833675 - gnomAD 0.0005850%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Leu323Serfs*51) was detected in trans with a pathogenic variant (PMID: 11524731; 9837820; 27588307) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic.
3billion RCV000049635 SCV002520966 pathogenic Polyglandular autoimmune syndrome, type 1 2022-05-22 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.050%). Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000003309). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
CeGaT Center for Human Genetics Tuebingen RCV000284330 SCV002585907 pathogenic not provided 2024-03-01 criteria provided, single submitter clinical testing AIRE: PM3:Strong, PVS1:Strong, PM2:Supporting, PS3:Supporting
National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health RCV000049635 SCV004036173 pathogenic Polyglandular autoimmune syndrome, type 1 2023-09-14 criteria provided, single submitter clinical testing
Neuberg Centre For Genomic Medicine, NCGM RCV000049635 SCV004048245 pathogenic Polyglandular autoimmune syndrome, type 1 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu323Serfs*51) in the AIRE gene. This variant causes a frameshift starting with codon Leucine 323, changes this amino acid to Serine residue, and creates a premature Stop codon at position 51 of the new reading frame, denoted p.Leu323SerfsTer51. It is expected to result in an absent or disrupted protein product. 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 (Heino, Maarit, et al, Pearce, Simon HS, et al). An experimental study has shown that this sequence change has a dominant negative effect on the gene regulation of tested AIRE-regulated genes (Oftedal, Bergithe E., et al). This variant has been reported to the ClinVar database as Pathogenic/ Likely pathogenic. The variant is reported with the allele frequency of 0.05032% in gnomAD Exome is novel (not in any individuals) in 1000 Genomes. For these reasons, this variant has been classified as pathogenic
PreventionGenetics, part of Exact Sciences RCV003407265 SCV004115444 pathogenic AIRE-related disorder 2023-06-15 criteria provided, single submitter clinical testing The AIRE c.967_979del13 variant is predicted to result in a frameshift and premature protein termination (p.Leu323Serfs*51). This variant has been reported in many unrelated individuals to be pathogenic for autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) (Finnish-German APECED Consortium. 1997. PubMed ID: 9398840). This variant is reported in 0.096% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/21-45711062-TGCCTGTCCCCTCC-T) and is interpreted as pathogenic or likely pathogenic by many labs in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/3309). Frameshift variants in AIRE are expected to be pathogenic. This variant is interpreted as pathogenic for autosomal recessive APECED.
Genetics and Molecular Pathology, SA Pathology RCV000049635 SCV004175444 pathogenic Polyglandular autoimmune syndrome, type 1 2020-09-29 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.
Natera, Inc. RCV000049635 SCV001457181 pathogenic Polyglandular autoimmune syndrome, type 1 2020-09-16 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000284330 SCV001742992 pathogenic not provided no assertion criteria provided clinical testing
GenomeConnect - Invitae Patient Insights Network RCV000049635 SCV001749902 not provided Polyglandular autoimmune syndrome, type 1 no assertion provided phenotyping only Variant interpreted as Pathogenic and reported on 11-09-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000284330 SCV001932897 pathogenic not provided no assertion criteria provided clinical testing

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.