NM_000383.4(AIRE):c.274C>T (p.Arg92Trp) AND Polyglandular autoimmune syndrome, type 1

Clinical significance:Pathogenic (Last evaluated: Jul 25, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000666247.6

Allele description [Variation Report for NM_000383.4(AIRE):c.274C>T (p.Arg92Trp)]

NM_000383.4(AIRE):c.274C>T (p.Arg92Trp)

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.274C>T (p.Arg92Trp)
HGVS:
  • NC_000021.9:g.44286698C>T
  • NG_009556.1:g.5819C>T
  • NM_000383.4:c.274C>TMANE SELECT
  • NP_000374.1:p.Arg92Trp
  • LRG_18t1:c.274C>T
  • LRG_18:g.5819C>T
  • NC_000021.8:g.45706581C>T
  • NM_000383.2:c.274C>T
  • NM_000383.3:c.274C>T
Protein change:
R92W
Links:
dbSNP: rs140630532
NCBI 1000 Genomes Browser:
rs140630532
Molecular consequence:
  • NM_000383.4:c.274C>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; PGA I; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0009411; MedGen: C0085859; Orphanet: 3453; OMIM: 240300

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000696653Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Feb 20, 2019)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV000790506Counsylno assertion criteria providedLikely pathogenic
(Apr 4, 2018)
unknownclinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV001405378Invitaecriteria provided, single submitter
Pathogenic
(Jul 25, 2019)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Autoantibodies against type I interferons as an additional diagnostic criterion for autoimmune polyendocrine syndrome type I.

Meloni A, Furcas M, Cetani F, Marcocci C, Falorni A, Perniola R, Pura M, Bøe Wolff AS, Husebye ES, Lilic D, Ryan KR, Gennery AR, Cant AJ, Abinun M, Spickett GP, Arkwright PD, Denning D, Costigan C, Dominguez M, McConnell V, Willcox N, Meager A.

J Clin Endocrinol Metab. 2008 Nov;93(11):4389-97. doi: 10.1210/jc.2008-0935. Epub 2008 Aug 26.

PubMed [citation]
PMID:
18728167

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy: insights into genotype-phenotype correlation.

Capalbo D, De Martino L, Giardino G, Di Mase R, Di Donato I, Parenti G, Vajro P, Pignata C, Salerno M.

Int J Endocrinol. 2012;2012:353250. doi: 10.1155/2012/353250. Epub 2012 Oct 22.

PubMed [citation]
PMID:
23133448
PMCID:
PMC3485503
See all PubMed Citations (8)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696653.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

Variant summary: AIRE c.274C>T (p.Arg92Trp) results in a non-conservative amino acid change located in the HSR domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 276962 control chromosomes (gnomAD and publication). c.274C>T has been reported in the literature in multiple affected individuals with features of Autoimmune Polyglandular Syndrome Type 1 (Zaidi_2017, Al-Mousa_2016, Magitta_2008). These data indicate that the variant is very likely to be associated with disease. The variant was also identified in our laboratory as a compound heterozygote with another variant (c.967_979delCTGTCCCCTCCGC, p.Leu323fsX51) in a patient presenting with features of hyperparathyroidism, Addisons disease, hepatitis, esophagitis, asplenia, poor dental enamel, growth hormone deficiency, and retinal dystrophy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic (1x) and once as likely pathogenic. This variant was previously classified conservatively as a VUS-possibly pathogenic variant by our laboratory in 2016. At-least two other reports reporting its presence in 4 additional affected individuals have been reported since its original classification by our laboratory. Based on all the evidence outlined above, the variant is now classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Counsyl, SCV000790506.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001405378.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces arginine with tryptophan at codon 92 of the AIRE protein (p.Arg92Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with autoimmune polyendocrinopathy syndrome (APS) in a family and has also been observed in several individuals with APS (PMID: 18426830, 24158785, 28446514). ClinVar contains an entry for this variant (Variation ID: 379319). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 14, 2021

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