Submissions for variant NM_000383.4(AIRE):c.769C>T (p.Arg257Ter)

gnomAD frequency: 0.00105  dbSNP: rs121434254

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000378770	SCV000231520	pathogenic	not provided	2014-10-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000378770	SCV000329055	pathogenic	not provided	2022-02-17	criteria provided, single submitter	clinical testing	Nonsense 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 demonstrate lack of expression of mRNA from AIRE-dependent genes (Oftedal et al., 2015); R257X variant is the most common Finnish pathogenic variant, present in 82% of Finnish APECED alleles, and is also common in the Northern Italian and Eastern European APECED patient populations (Finnish-German APECED Consortium 1997; Heino et al., 2001); This variant is associated with the following publications: (PMID: 22162465, 20718774, 24948345, 16965330, 11524733, 15886230, 11524731, 11298085, 22024611, 18616706, 9921903, 19807739, 12050215, 19863576, 25707324, 27065010, 27048654, 26891119, 14582926, 24158785, 18274776, 28458664, 30018023, 12951636, 11207636, 31588815, 30863741, 31956453, 33225392, 34078422, 34426522, 24493573, 32441320, 34235359, 26084028, 9398840)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000179294	SCV000832482	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.Arg257*) 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 (rs121434254, gnomAD 0.5%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individual(s) with autoimmune polyendocrinopathy with candidiasis and ectodermal dysplasia (APECED) (PMID: 9398840, 20718774, 22024611). It is commonly reported in individuals of Finnish ancestry (PMID: 9398840). ClinVar contains an entry for this variant (Variation ID: 3307). 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.
Athena Diagnostics	RCV000378770	SCV000840731	pathogenic	not provided	2018-05-23	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000179294	SCV001194176	pathogenic	Polyglandular autoimmune syndrome, type 1	2019-12-19	criteria provided, single submitter	clinical testing	NM_000383.3(AIRE):c.769C>T(R257*) is classified as pathogenic in the context of type 1 autoimmune polyglandular syndrome. Sources cited for classification include the following: PMID 12050215, 20407228, 14974083, 9398839, 9398840, 18708298 and 10677297. Classification of NM_000383.3(AIRE):c.769C>T(R257*) 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.
CeGaT Center for Human Genetics Tuebingen	RCV000378770	SCV001247536	pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	AIRE: PVS1, PM3:Strong, PM2:Supporting, PS3:Supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000179294	SCV001361217	pathogenic	Polyglandular autoimmune syndrome, type 1	2019-10-14	criteria provided, single submitter	clinical testing	Variant summary: AIRE c.769C>T (p.Arg257X), also known as the "Finnish major mutation", 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 0.00075 in 248166 control chromosomes in the gnomAD database, including 1 homozygote. c.769C>T has been reported in the literature in multiple individuals affected with Autoimmune Polyglandular Syndrome Type 1 (example, Aaltonen_1997, Giordano_2012, Cervato_2010). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in lack of transcriptional regulation by mutant AIRE of KRT14, an AIRE-dependant gene as observed by a lack of mRNA expression in-vitro (example, Oftedal_2015). Four 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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000179294	SCV001366339	pathogenic	Polyglandular autoimmune syndrome, type 1	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PP3,PP4,PVS1,PS3,PM2. This variant was detected in homozygous state.
Johns Hopkins Genomics, Johns Hopkins University	RCV000179294	SCV001431521	pathogenic	Polyglandular autoimmune syndrome, type 1	2020-08-24	criteria provided, single submitter	clinical testing	This AIRE variant (rs121434254) is rare (<0.1%) in a large population dataset (gnomAD: 218/279538 total alleles; 0.08%; 1 homozygote) and has an entry in ClinVar. This variant has been reported previously in a homozygous or compound heterozygous state in multiple unrelated individuals affected with APS1. This nonsense variant results in a premature stop codon in exon 6 of 14 likely leading to nonsense mediated decay and lack of protein production. This variant alone is not expected to cause APS1. We consider c.769C>T to be pathogenic.
New York Genome Center	RCV000179294	SCV001480457	pathogenic	Polyglandular autoimmune syndrome, type 1	2020-06-05	criteria provided, single submitter	clinical testing	The c.769C>T, p.Arg257Ter nonsense variant identified in the AIRE gene has been reported previously in both the homozygous and compound heterozygous state in multiple unrelated individuals with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) [PMID: 9398840; PMID: 25707324; PMID: 30863741; PMID: 31588815]. This variant is the most common Finnish pathogenic variant, present in 82% of Finnish APECED alleles, and is also common in the Northern Italian and Eastern European APECED patient populations [PMID: 9398840]. Functional studies have demonstrated that cells transfected with the p.Arg257Ter allele lack expression of mRNA from AIRE-dependent genes [PMID: 26084028]. This variant has 0.06%frequency (84 heterozygous) in gnomAD database indicating this is a rare allele. The detected nonsense substitution truncates the protein at codon 257, which is 289 amino acids from the end of the protein and expected to result in an absent protein product through nonsense-mediated mRNA decay [PMID: 24681721.] Based on the available evidence, the c.769C>T, p.Arg257Ter variant in the AIRE gene is classified as pathogenic.
Revvity Omics, Revvity	RCV000179294	SCV002024184	pathogenic	Polyglandular autoimmune syndrome, type 1	2019-08-14	criteria provided, single submitter	clinical testing
DASA	RCV000179294	SCV002097300	pathogenic	Polyglandular autoimmune syndrome, type 1	2022-02-14	criteria provided, single submitter	clinical testing	The c.769C>T;p.(Arg257*) variant creates a premature translational stop signal in the AIRE gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 3307; PMID: 9398840; 20718774; 22024611; 9398840) - PS4. The variant is present at low allele frequencies population databases (rs121434254 - gnomAD 0.005649%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg257*) was detected in trans with a pathogenic variant (PMID: 9398840; 20718774; 22024611) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000179294	SCV002805919	pathogenic	Polyglandular autoimmune syndrome, type 1	2022-03-29	criteria provided, single submitter	clinical testing
National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	RCV000179294	SCV004036182	pathogenic	Polyglandular autoimmune syndrome, type 1	2023-09-14	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000179294	SCV004175443	pathogenic	Polyglandular autoimmune syndrome, type 1	2020-09-29	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000179294	SCV005051833	pathogenic	Polyglandular autoimmune syndrome, type 1	2024-02-01	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000378770	SCV005089747	pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing
OMIM	RCV000179294	SCV000023628	pathogenic	Polyglandular autoimmune syndrome, type 1	2009-11-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000179294	SCV001452113	pathogenic	Polyglandular autoimmune syndrome, type 1	2020-09-16	no assertion criteria provided	clinical testing
Genomics England Pilot Project, Genomics England	RCV000179294	SCV001760476	likely pathogenic	Polyglandular autoimmune syndrome, type 1		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000378770	SCV001978034	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000378770	SCV001980556	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003421900	SCV004117021	pathogenic	AIRE-related disorder	2024-04-02	no assertion criteria provided	clinical testing	The AIRE c.769C>T variant is predicted to result in premature protein termination (p.Arg257*). This variant has been reported with a second AIRE variant in many unrelated individuals with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) (Nagamine et al. 1997. PubMed ID: 9398839; Finnish-German APECED Consortium. 1997. PubMed ID: 9398840; Björses et al. 2000. PubMed ID: 10677297; Stolarski et al. 2006. PubMed ID: 16965330; Podkrajsek et al. 2008. PubMed ID: 18682433; Orlova et al. 2010. PubMed ID: 20407228). In vitro experimental studies have demonstrated that this variant disrupts protein function (Björses et al. 2000. PubMed ID: 10677297; Halonen et al. 2004. PubMed ID: 14974083; Oftedal et al. 2015. PubMed ID: 26084028). This variant has also been observed in the heterozygous state without a second AIRE variant in some individuals with classic and atypical APECED with a proposed incomplete penetrance (Sedivá et al. 2002. PubMed ID: 12503856; Buzi et al. 2003. PubMed ID: 12843157; Orlova et al. 2010. PubMed ID: 20407228). However, there are many heterozygous individuals with no symptoms of APECED and an autosomal dominant mode of inheritance is not established. This variant is reported at a relatively high frequency (0.50% of alleles) in individuals of Finnish descent in gnomAD, but has been shown to be a founder mutation in this population (Finnish-German APECED Consortium. 1997. PubMed ID: 9398840). This variant is also interpreted as pathogenic or likely pathogenic by many labs in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/3309). Nonsense variants in AIRE are expected to be pathogenic. This variant is interpreted as pathogenic for autosomal recessive AIRE-related disorders.