NM_000383.4(AIRE):c.463+2T>C AND Polyglandular autoimmune syndrome, type 1

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Oct 13, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000169131.13

Allele description [Variation Report for NM_000383.4(AIRE):c.463+2T>C]

NM_000383.4(AIRE):c.463+2T>C

Gene:

AIRE:autoimmune regulator [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

21q22.3

Genomic location:

Preferred name:

NM_000383.4(AIRE):c.463+2T>C

HGVS:

NC_000021.9:g.44287135T>C
NG_009556.1:g.6256T>C
NM_000383.4:c.463+2T>CMANE SELECT
LRG_18t1:c.463+2T>C
LRG_18:g.6256T>C
NC_000021.8:g.45707018T>C
NM_000383.2:c.463+2T>C
NM_000383.3:c.463+2T>C

Links:

dbSNP: rs786204478

NCBI 1000 Genomes Browser:

rs786204478

Molecular consequence:

NM_000383.4:c.463+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Polyglandular autoimmune syndrome, type 1 (APS1)
Synonyms:: AUTOIMMUNE POLYENDOCRINE SYNDROME, TYPE I, WITH OR WITHOUT REVERSIBLE METAPHYSEAL DYSPLASIA; APS I; PGA I; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009411; MedGen: C0085859; Orphanet: 3453; OMIM: 240300

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000220341	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (May 21, 2014)	unknown	literature only	PubMed (4) [See all records that cite these PMIDs] 9921903, 17220063, 17189144, 11524731 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV001408348	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 13, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 16199547, 11524731, 26141571, 9921903, 17220063, 28492532
SCV002083854	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 9, 2020)	germline	clinical testing
SCV004020595	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jun 26, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 9921903, 17220063 Citation Link,
SCV004036179	National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 14, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9921903, 35753512, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Ocular complications of autoimmune polyendocrinopathy syndrome type 1.

Chang B, Brosnahan D, McCreery K, Dominguez M, Costigan C.

J AAPOS. 2006 Dec;10(6):515-20. Epub 2006 Nov 2.

PubMed [citation]

PMID:: 17189144

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

See all PubMed Citations (9)

Details of each submission

From Counsyl, SCV000220341.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (4)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001408348.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change affects a donor splice site in intron 3 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 (rs786204478, gnomAD 0.002%). Disruption of this splice site has been observed in individuals with polyendocrinopathy with candidiasis and ectodermal dysplasia (APECED) (PMID: 9921903, 17220063). This variant is also known as 5835T>C and IVS3+2T>C. ClinVar contains an entry for this variant (Variation ID: 188800). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV002083854.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004020595.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: AIRE c.463+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. The variant allele was found at a frequency of 1.2e-05 in 242240 control chromosomes (gnomAD). c.463+2T>C has been reported in the literature in multiple individuals affected with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) (examples: Wang_1998, and Dominguez_2006). This variant is also known as 5835T>C. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 9921903, 17220063). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health, SCV004036179.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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