NM_000383.4(AIRE):c.342G>T (p.Lys114Asn) AND Polyglandular autoimmune syndrome, type 1

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Dec 25, 2024
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:: RCV000029311.10

Allele description [Variation Report for NM_000383.4(AIRE):c.342G>T (p.Lys114Asn)]

NM_000383.4(AIRE):c.342G>T (p.Lys114Asn)

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.342G>T (p.Lys114Asn)

HGVS:

NC_000021.9:g.44287012G>T
NG_009556.1:g.6133G>T
NM_000383.4:c.342G>TMANE SELECT
NP_000374.1:p.Lys114Asn
LRG_18t1:c.342G>T
LRG_18:g.6133G>T
NC_000021.8:g.45706895G>T
NM_000383.2:c.342G>T
NM_000383.3:c.342G>T

Protein change:

K114N

Links:

dbSNP: rs142788946

NCBI 1000 Genomes Browser:

rs142788946

Molecular consequence:

NM_000383.4:c.342G>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000951384	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 25, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28472507, 28492532
SCV001464456	Natera, Inc.	no assertion criteria provided	Uncertain significance (Apr 20, 2020)	germline	clinical testing
SCV002777859	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 20, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005919077	Department of Pathology and Laboratory Medicine, Sinai Health System	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 1, 2022)	germline	research	PubMed (1) [See all records that cite this PMID]

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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, research
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A Case Report of Hypoglycemia and Hypogammaglobulinemia: DAVID Syndrome in a Patient With a Novel NFKB2 Mutation.

Lal RA, Bachrach LK, Hoffman AR, Inlora J, Rego S, Snyder MP, Lewis DB.

J Clin Endocrinol Metab. 2017 Jul 1;102(7):2127-2130. doi: 10.1210/jc.2017-00341.

PubMed [citation]

PMID:: 28472507
PMCID:: PMC11651530

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000951384.4

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

Description

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 114 of the AIRE protein (p.Lys114Asn). This variant is present in population databases (rs142788946, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of AIRE-related conditions (PMID: 28472507). ClinVar contains an entry for this variant (Variation ID: 35663). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on AIRE protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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., SCV001464456.1

#	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 Fulgent Genetics, Fulgent Genetics, SCV002777859.1

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

#	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 Department of Pathology and Laboratory Medicine, Sinai Health System, SCV005919077.1

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

#	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: May 16, 2025

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