NM_000383.4(AIRE):c.868del (p.Gln290fs) AND Polyglandular autoimmune syndrome, type 1

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Dec 21, 2021
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:: RCV001904436.6

Allele description [Variation Report for NM_000383.4(AIRE):c.868del (p.Gln290fs)]

NM_000383.4(AIRE):c.868del (p.Gln290fs)

Gene:

AIRE:autoimmune regulator [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

21q22.3

Genomic location:

Preferred name:

NM_000383.4(AIRE):c.868del (p.Gln290fs)

HGVS:

NC_000021.9:g.44290057del
NG_009556.1:g.9178del
NM_000383.4:c.868delMANE SELECT
NP_000374.1:p.Gln290fs
LRG_18:g.9178del
NC_000021.8:g.45709936del
NC_000021.8:g.45709940del

Protein change:

Q290fs

Links:

dbSNP: rs2146379725

NCBI 1000 Genomes Browser:

rs2146379725

Molecular consequence:

NM_000383.4:c.868del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV002124469	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 14, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 11524731, 26141571, 28492532
SCV002602223	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))	Likely pathogenic (Dec 21, 2021)	unknown	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002124469

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 14, 2021)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV002602223

Myriad Genetics, Inc.

criteria provided, single submitter

(Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))

Likely pathogenic
(Dec 21, 2021)

unknown

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
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	clinical testing

Citations

PubMed

APECED mutations in the autoimmune regulator (AIRE) gene.

Heino M, Peterson P, Kudoh J, Shimizu N, Antonarakis SE, Scott HS, Krohn K.

Hum Mutat. 2001 Sep;18(3):205-11. Review.

PubMed [citation]

PMID:: 11524731

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy.

Kisand K, Peterson P.

J Clin Immunol. 2015 Jul;35(5):463-78. doi: 10.1007/s10875-015-0176-y. Epub 2015 Jul 5. Review.

PubMed [citation]

PMID:: 26141571

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002124469.3

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

Description

This sequence change creates a premature translational stop signal (p.Gln290Serfs*88) 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 not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with AIRE-related conditions. 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 Myriad Genetics, Inc., SCV002602223.2

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

Description

NM_000383.3(AIRE):c.868delC(Q290Sfs*88) is expected to be pathogenic in the context of autoimmune polyglandular syndrome type 1. This variant is predicted to lead to an abnormal or absent protein product due to the creation of a premature termination codon in AIRE, a gene where loss-of-function variants are known to be pathogenic. Please note: this variant was assessed in the context of healthy population screening.

#	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

Last Updated: Sep 29, 2024

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