NM_139276.3(STAT3):c.1976T>A (p.Ile659Asn) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 27, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001860114.6

Allele description [Variation Report for NM_139276.3(STAT3):c.1976T>A (p.Ile659Asn)]

NM_139276.3(STAT3):c.1976T>A (p.Ile659Asn)

Gene:

STAT3:signal transducer and activator of transcription 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q21.2

Genomic location:

Preferred name:

NM_139276.3(STAT3):c.1976T>A (p.Ile659Asn)

HGVS:

NC_000017.11:g.42322407A>T
NG_007370.1:g.71089T>A
NM_001369512.1:c.1976T>A
NM_001369513.1:c.1976T>A
NM_001369514.1:c.1976T>A
NM_001369516.1:c.1976T>A
NM_001369517.1:c.1976T>A
NM_001369518.1:c.1976T>A
NM_001369519.1:c.1976T>A
NM_001369520.1:c.1976T>A
NM_001384984.1:c.1892T>A
NM_001384985.1:c.1898T>A
NM_001384986.1:c.1991T>A
NM_001384987.1:c.1955T>A
NM_001384988.1:c.1976T>A
NM_001384989.1:c.1880T>A
NM_001384990.1:c.1991T>A
NM_001384991.1:c.1949T>A
NM_001384992.1:c.1916T>A
NM_001384993.1:c.1976T>A
NM_003150.4:c.1976T>A
NM_139276.3:c.1976T>AMANE SELECT
NM_213662.2:c.1976T>A
NP_001356441.1:p.Ile659Asn
NP_001356442.1:p.Ile659Asn
NP_001356443.1:p.Ile659Asn
NP_001356445.1:p.Ile659Asn
NP_001356446.1:p.Ile659Asn
NP_001356447.1:p.Ile659Asn
NP_001356448.1:p.Ile659Asn
NP_001356449.1:p.Ile659Asn
NP_001371913.1:p.Ile631Asn
NP_001371914.1:p.Ile633Asn
NP_001371915.1:p.Ile664Asn
NP_001371916.1:p.Ile652Asn
NP_001371917.1:p.Ile659Asn
NP_001371918.1:p.Ile627Asn
NP_001371919.1:p.Ile664Asn
NP_001371920.1:p.Ile650Asn
NP_001371921.1:p.Ile639Asn
NP_001371922.1:p.Ile659Asn
NP_003141.2:p.Ile659Asn
NP_644805.1:p.Ile659Asn
NP_998827.1:p.Ile659Asn
LRG_112:g.71089T>A
NC_000017.10:g.40474425A>T
NM_003150.3:c.1976T>A
p.(Ile659Asn)

Protein change:

I627N

Links:

dbSNP: rs1555563717

NCBI 1000 Genomes Browser:

rs1555563717

Molecular consequence:

NM_001369512.1:c.1976T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369513.1:c.1976T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369514.1:c.1976T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369516.1:c.1976T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369517.1:c.1976T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369518.1:c.1976T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369519.1:c.1976T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369520.1:c.1976T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001384984.1:c.1892T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001384985.1:c.1898T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001384986.1:c.1991T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001384987.1:c.1955T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001384988.1:c.1976T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001384989.1:c.1880T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001384990.1:c.1991T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001384991.1:c.1949T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001384992.1:c.1916T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001384993.1:c.1976T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_003150.4:c.1976T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_139276.3:c.1976T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_213662.2:c.1976T>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hyper-IgE recurrent infection syndrome 1, autosomal dominant
Synonyms:: Hyperimmunoglobulin E recurrent infection syndrome, autosomal dominant; HIES autosomal dominant; AD hyperimmunoglobulin E syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007818; MedGen: C4721531; Orphanet: 2314; OMIM: 147060

Name:: STAT3 gain of function
Identifiers:: MedGen: C4288261

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002218879	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 27, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002218879

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 27, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

Citations

PubMed

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV002218879.3

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

Description

For these reasons, this variant has been classified as Pathogenic. 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 STAT3 protein function. ClinVar contains an entry for this variant (Variation ID: 495061). This missense change has been observed in individual(s) with clinical features of hyper IgE syndrome (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 659 of the STAT3 protein (p.Ile659Asn).

#	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: Feb 28, 2024

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