NM_000383.4(AIRE):c.1638A>T (p.Ter546Cys) AND Polyglandular autoimmune syndrome, type 1

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Sep 4, 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:: RCV000049633.5

Allele description [Variation Report for NM_000383.4(AIRE):c.1638A>T (p.Ter546Cys)]

NM_000383.4(AIRE):c.1638A>T (p.Ter546Cys)

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.1638A>T (p.Ter546Cys)

Other names:

*546C

HGVS:

NC_000021.9:g.44297727A>T
NG_009556.1:g.16848A>T
NG_034033.1:g.2694A>T
NM_000383.4:c.1638A>TMANE SELECT
NP_000374.1:p.Ter546Cys
LRG_18t1:c.1638A>T
LRG_18:g.16848A>T
NC_000021.8:g.45717610A>T
NM_000383.2:c.1638A>T
NM_000383.3:c.1638A>T

Links:

dbSNP: rs386833673

NCBI 1000 Genomes Browser:

rs386833673

Molecular consequence:

NM_000383.4:c.1638A>T - stop lost - [Sequence Ontology: SO:0001578]

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000082040	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	no assertion criteria provided	probable-pathogenic	not provided	not provided	PubMed (2) [See all records that cite these PMIDs] 9717837, 10677297
SCV000220844	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Oct 28, 2014)	unknown	literature only	PubMed (4) [See all records that cite these PMIDs] 12050215, 9717837, 10677297, 18728167 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV004298123	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Sep 4, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 28446514, 9717837, 18728167, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000082040

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

no assertion criteria provided

probable-pathogenic

not provided

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

SCV000220844

Counsyl

criteria provided, single submitter

(Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))

Likely pathogenic
(Oct 28, 2014)

unknown

literature only

PubMed (4)
[See all records that cite these PMIDs]

Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015),

Citation Link,

SCV004298123

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Sep 4, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Description

FinDis database variant: This variant was not found or characterized by our laboratory, data were collected from public sources: see reference: SCV000082040

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	literature only
not provided	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only

Citations

PubMed

AIRE mutations and human leukocyte antigen genotypes as determinants of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy phenotype.

Halonen M, Eskelin P, Myhre AG, Perheentupa J, Husebye ES, Kämpe O, Rorsman F, Peltonen L, Ulmanen I, Partanen J.

J Clin Endocrinol Metab. 2002 Jun;87(6):2568-74.

PubMed [citation]

PMID:: 12050215

Mutations in the AIRE gene: effects on subcellular location and transactivation function of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy protein.

Björses P, Halonen M, Palvimo JJ, Kolmer M, Aaltonen J, Ellonen P, Perheentupa J, Ulmanen I, Peltonen L.

Am J Hum Genet. 2000 Feb;66(2):378-92.

PubMed [citation]

PMID:: 10677297
PMCID:: PMC1288090

See all PubMed Citations (6)

Details of each submission

From Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM), SCV000082040.1

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

Description

Converted during submission to Likely pathogenic.

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

From Counsyl, SCV000220844.2

#	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, SCV004298123.1

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

Description

This variant results in an extension of the AIRE protein. Other variant(s) that result in a similarly extended protein product (p.*546Leuext*60) have been observed in individuals with AIRE-related disease (PMID: 28446514). This suggests that these extensions may be clinically significant. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. ClinVar contains an entry for this variant (Variation ID: 56222). This variant is also known as X546C. This protein extension has been observed in individuals with APECED (PMID: 9717837, 18728167). This variant is present in population databases (rs386833673, gnomAD 0.009%). This sequence change disrupts the translational stop signal of the AIRE mRNA. It is expected to extend the length of the AIRE protein by 60 additional amino acid residues.

#	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

Last Updated: Jan 13, 2025

ClinVar

Relating variation to medicine