VCV000279674.8 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(5)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 279674 Accession: VCV000279674.8

Type and length

Duplication, 4 bp

Location

Cytogenetic: 21q22.3 21: 44286628-44286629 (GRCh38) [ NCBI UCSC ] 21: 45706511-45706512 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 6, 2016	Jun 17, 2024	Sep 21, 2018

HGVS

Nucleotide	Protein	Molecular consequence
NM_000383.4:c.205_208dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000374.1:p.Asp70fs	frameshift
NC_000021.9:g.44286629_44286632dup
NC_000021.8:g.45706512_45706515dup
NG_009556.1:g.5750_5753dup
LRG_18:g.5750_5753dup
LRG_18t1:c.205_208dup

... more HGVS ... less HGVS

Protein change

D70fs

Other names

Canonical SPDI

NC_000021.9:44286628:CAGG:CAGGCAGG

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA10603375 OMIM: 607358.0010 dbSNP: rs886041124 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
AIRE		-	-	GRCh38 GRCh37	1138	1282

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Sep 21, 2018	RCV000324168.5
Polyglandular autoimmune syndrome, type 1	Pathogenic (3)	criteria provided, single submitter	Mar 7, 2016	RCV000586684.5

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Mar 07, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Polyglandular autoimmune syndrome, type 1 Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000696651.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018	Publications: PubMed (2) PubMed: 9888391‚ 19758376 Comment: 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 … (more) 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. (less)
Pathogenic (Aug 22, 2016)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000329054.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Comment: The c.205_208dupCAGG variant in the AIRE gene has been reported previously in patients of Arabic ancestry in association with autoimmune polyendocrinopathy syndrome, type 1 (APS1) … (more) The c.205_208dupCAGG variant in the AIRE gene has been reported previously in patients of Arabic ancestry in association with autoimmune polyendocrinopathy syndrome, type 1 (APS1) (Heino et al., 1999; Faiyaz-Ul-Haque et al., 2009). The duplication causes a frameshift starting with codon Aspartic acid 70, changes this amino acid to an Alanine residue and creates a premature Stop codon at position 148 of the new reading frame, denoted p.Asp70AlafsX148. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. (less)
Pathogenic (Sep 21, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002069263.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022	Comment: DNA sequence analysis of the AIRE gene demonstrated a four base pair duplication in exon 2, c.205_208dup. This pathogenic sequence change results in an amino … (more) DNA sequence analysis of the AIRE gene demonstrated a four base pair duplication in exon 2, c.205_208dup. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 147 amino acids downstream of the mutation, p.Asp70Alafs*148. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated AIRE protein with potentially abnormal function. This pathogenic sequence change is not present in large population databases such as gnomAD, and has previously been described in patients with autoimmune polyendocrinopathy syndrome type 1 (PMIDs: 19758376, 9888391). (less)
Pathogenic (Nov 12, 2020)	no assertion criteria provided Method: clinical testing	Polyglandular autoimmune syndrome, type 1 Affected status: yes Allele origin: germline	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City Accession: SCV001469156.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021
Pathogenic (Nov 01, 2009)	no assertion criteria provided Method: literature only	AUTOIMMUNE POLYENDOCRINOPATHY SYNDROME, TYPE I Affected status: not provided Allele origin: germline	OMIM Accession: SCV000023638.3 First in ClinVar: Apr 04, 2013 Last updated: Jun 17, 2024	Publications: PubMed (2) PubMed: 9888391‚ 19758376 Comment on evidence: 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 … (more) 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. (less)

Comment:

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.

Comment:

The c.205_208dupCAGG variant in the AIRE gene has been reported previously in patients of Arabic ancestry in association with autoimmune polyendocrinopathy syndrome, type 1 (APS1) (Heino et al., 1999; Faiyaz-Ul-Haque et al., 2009). The duplication causes a frameshift starting with codon Aspartic acid 70, changes this amino acid to an Alanine residue and creates a premature Stop codon at position 148 of the new reading frame, denoted p.Asp70AlafsX148. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.

Comment:

DNA sequence analysis of the AIRE gene demonstrated a four base pair duplication in exon 2, c.205_208dup. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 147 amino acids downstream of the mutation, p.Asp70Alafs*148. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated AIRE protein with potentially abnormal function. This pathogenic sequence change is not present in large population databases such as gnomAD, and has previously been described in patients with autoimmune polyendocrinopathy syndrome type 1 (PMIDs: 19758376, 9888391).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Novel and recurrent mutations in the AIRE gene of autoimmune polyendocrinopathy syndrome type 1 (APS1) patients.	Faiyaz-Ul-Haque M	Clinical genetics	2009	PMID: 19758376
Mutation analyses of North American APS-1 patients.	Heino M	Human mutation	1999	PMID: 9888391

Text-mined citations for rs886041124 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jan 13, 2025

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs886041124 ...