NM_000383.4(AIRE):c.205_208dup (p.Asp70fs) AND Polyglandular autoimmune syndrome, type 1

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Mar 7, 2016
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000586684.5

Allele description [Variation Report for NM_000383.4(AIRE):c.205_208dup (p.Asp70fs)]

NM_000383.4(AIRE):c.205_208dup (p.Asp70fs)

Gene:

AIRE:autoimmune regulator [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

21q22.3

Genomic location:

Preferred name:

NM_000383.4(AIRE):c.205_208dup (p.Asp70fs)

HGVS:

NC_000021.9:g.44286629_44286632dup
NG_009556.1:g.5750_5753dup
NM_000383.4:c.205_208dupMANE SELECT
NP_000374.1:p.Asp70fs
LRG_18t1:c.205_208dup
LRG_18:g.5750_5753dup
NC_000021.8:g.45706512_45706515dup
NM_000383.2:c.205_208dupCAGG
NM_000383.3:c.205_208dup

Protein change:

D70fs

Links:

OMIM: 607358.0010; dbSNP: rs886041124

NCBI 1000 Genomes Browser:

rs886041124

Molecular consequence:

NM_000383.4:c.205_208dup - 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; HYPOADRENOCORTICISM WITH HYPOPARATHYROIDISM AND SUPERFICIAL MONILIASIS; 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
SCV000023638	OMIM	no assertion criteria provided	Pathogenic (Nov 1, 2009)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 9888391, 19758376
SCV000696651	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Mar 7, 2016)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 9888391, 19758376 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV001469156	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	no assertion criteria provided	Pathogenic (Nov 12, 2020)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000023638

OMIM

no assertion criteria provided

Pathogenic
(Nov 1, 2009)

germline

literature only

PubMed (2)
[See all records that cite these PMIDs]

SCV000696651

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Mar 7, 2016)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV001469156

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

no assertion criteria provided

Pathogenic
(Nov 12, 2020)

germline

clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	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

Citations

PubMed

Mutation analyses of North American APS-1 patients.

Heino M, Scott HS, Chen Q, Peterson P, Mäebpää U, Papasavvas MP, Mittaz L, Barras C, Rossier C, Chrousos GP, Stratakis CA, Nagamine K, Kudoh J, Shimizu N, Maclaren N, Antonarakis SE, Krohn K.

Hum Mutat. 1999;13(1):69-74.

PubMed [citation]

PMID:: 9888391

Novel and recurrent mutations in the AIRE gene of autoimmune polyendocrinopathy syndrome type 1 (APS1) patients.

Faiyaz-Ul-Haque M, Bin-Abbas B, Al-Abdullatif A, Abdullah Abalkhail H, Toulimat M, Al-Gazlan S, Almutawa AM, Al-Sagheir A, Peltekova I, Al-Dayel F, Zaidi SH.

Clin Genet. 2009 Nov;76(5):431-40. doi: 10.1111/j.1399-0004.2009.01278.x. Epub 2009 Sep 15.

PubMed [citation]

PMID:: 19758376

Details of each submission

From OMIM, SCV000023638.3

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

Description

In a patient of Arab origin with autoimmune polyendocrinopathy syndrome (APS1; 240300), Heino et al. (1999) identified homozygosity for a 4-bp duplication (336dupCAGG) in exon 2 of the AIRE gene, predicted to cause a frameshift at residue 69 with the addition of 148 C-terminal amino acids unrelated to the normal AIRE protein.

In a 6-year-old girl and a 35-year-old man with APS1 from 2 unrelated consanguineous Arab families, Faiyaz-Ul-Haque et al. (2009) identified homozygosity for the 4-bp duplication in exon 2 of the AIRE gene, which they designated 205dupCAGG based on numbering from the translation initiation codon.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	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, SCV000696651.1

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

Description

Variant summary: This c.205_208dupCAGG variant causes a frameshift, which alters the proteins amino acid sequence beginning at position 70 and leads to a premature termination codon 148 amino acids downstream. It is predicted to cause a truncated or absent AIRE protein. Loss-of-function due to mutations in this gene is an established disease mechanism in APS1. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Arg257X, p.Cys311fs). This variant has been reported in multiple APS1 families in homozygous state. However, it was absent in approximately 120132 chromosomes from ExAC. One reputable database has classified this variant as pathogenic. Taken together, this variant has been classified as a Disease Variant/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 Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City, SCV001469156.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jan 13, 2025

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