NM_000383.4(AIRE):c.916G>A (p.Gly306Arg) AND Polyglandular autoimmune syndrome, type 1

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Dec 31, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV001729959.3

Allele description [Variation Report for NM_000383.4(AIRE):c.916G>A (p.Gly306Arg)]

NM_000383.4(AIRE):c.916G>A (p.Gly306Arg)

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.916G>A (p.Gly306Arg)

HGVS:

NC_000021.9:g.44291131G>A
NG_009556.1:g.10252G>A
NM_000383.4:c.916G>AMANE SELECT
NP_000374.1:p.Gly306Arg
LRG_18t1:c.916G>A
LRG_18:g.10252G>A
NC_000021.8:g.45711014G>A
NM_000383.2:c.916G>A

Protein change:

G306R

Links:

dbSNP: rs754932526

NCBI 1000 Genomes Browser:

rs754932526

Molecular consequence:

NM_000383.4:c.916G>A - 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; 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
SCV001976935	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 1, 2021)	maternal	clinical testing	PubMed (2) [See all records that cite these PMIDs] 34008892, 25741868
SCV004523016	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 31, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 34008892, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001976935

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Oct 1, 2021)

maternal

clinical testing

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

SCV004523016

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 31, 2023)

germline

clinical testing

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

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	maternal	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Phenotype-driven variant filtration strategy in exome sequencing toward a high diagnostic yield and identification of 85 novel variants in 400 patients with rare Mendelian disorders.

Marinakis NM, Svingou M, Veltra D, Kekou K, Sofocleous C, Tilemis FN, Kosma K, Tsoutsou E, Fryssira H, Traeger-Synodinos J.

Am J Med Genet A. 2021 Aug;185(8):2561-2571. doi: 10.1002/ajmg.a.62338. Epub 2021 May 19.

PubMed [citation]

PMID:: 34008892

See all PubMed Citations (3)

Details of each submission

From Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV001976935.1

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

Description

PM1, PM2, PP3, PP4

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004523016.1

#	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 glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 306 of the AIRE protein (p.Gly306Arg). This variant is present in population databases (rs754932526, gnomAD 0.007%). This missense change has been observed in individual(s) with AIRE-related conditions (PMID: 34008892). ClinVar contains an entry for this variant (Variation ID: 1217643). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt AIRE protein function with a positive predictive value of 95%. 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

Last Updated: Sep 29, 2024

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