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

dbSNP: rs386833675

Total submissions: 24

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)
Labcorp Genetics (formerly Invitae), Labcorp	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
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
PreventionGenetics, part of Exact Sciences	RCV003407265	SCV004115444	pathogenic	AIRE-related disorder	2024-07-17	no assertion criteria provided	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 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.