NM_139276.3(STAT3):c.2147C>T (p.Thr716Met) AND multiple conditions

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 31, 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:: RCV000653278.12

Allele description

NM_139276.3(STAT3):c.2147C>T (p.Thr716Met)

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.2147C>T (p.Thr716Met)

HGVS:

NC_000017.11:g.42316899G>A
NG_007370.1:g.76597C>T
NM_001369512.1:c.2147C>T
NM_001369513.1:c.2147C>T
NM_001369514.1:c.2144C>T
NM_001369516.1:c.2144C>T
NM_001369517.1:c.2145-48C>T
NM_001369518.1:c.2145-48C>T
NM_001369519.1:c.2142-48C>T
NM_001369520.1:c.2142-48C>T
NM_001384984.1:c.2063C>T
NM_001384985.1:c.2069C>T
NM_001384986.1:c.2157-48C>T
NM_001384987.1:c.2126C>T
NM_001384988.1:c.2099-48C>T
NM_001384989.1:c.2048C>T
NM_001384990.1:c.2160-48C>T
NM_001384991.1:c.2120C>T
NM_001384992.1:c.2087C>T
NM_001384993.1:c.2145-10C>T
NM_003150.4:c.2144C>T
NM_139276.3:c.2147C>TMANE SELECT
NM_213662.2:c.2145-48C>T
NP_001356441.1:p.Thr716Met
NP_001356442.1:p.Thr716Met
NP_001356443.1:p.Thr715Met
NP_001356445.1:p.Thr715Met
NP_001371913.1:p.Thr688Met
NP_001371914.1:p.Thr690Met
NP_001371916.1:p.Thr709Met
NP_001371918.1:p.Thr683Met
NP_001371920.1:p.Thr707Met
NP_001371921.1:p.Thr696Met
NP_003141.2:p.Thr715Met
NP_644805.1:p.Thr716Met
NP_644805.1:p.Thr716Met
LRG_112t1:c.2147C>T
LRG_112:g.76597C>T
LRG_112p1:p.Thr716Met
NC_000017.10:g.40468917G>A
NM_139276.2:c.2147C>T
P40763:p.Thr716Met

Protein change:

T683M; THR716MET

Links:

UniProtKB: P40763#VAR_071888; OMIM: 102582.0008; dbSNP: rs869312892

NCBI 1000 Genomes Browser:

rs869312892

Molecular consequence:

NM_001369517.1:c.2145-48C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001369518.1:c.2145-48C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001369519.1:c.2142-48C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001369520.1:c.2142-48C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001384986.1:c.2157-48C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001384988.1:c.2099-48C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001384990.1:c.2160-48C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001384993.1:c.2145-10C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_213662.2:c.2145-48C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001369512.1:c.2147C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369513.1:c.2147C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369514.1:c.2144C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369516.1:c.2144C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001384984.1:c.2063C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001384985.1:c.2069C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001384987.1:c.2126C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001384989.1:c.2048C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001384991.1:c.2120C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001384992.1:c.2087C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_003150.4:c.2144C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_139276.3:c.2147C>T - 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: CN031130; Orphanet: 2314; OMIM: 147060

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

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Bacteroides intestinalis DSM 17393 B_intestinalis-2.0.1_Cont606, whole genome shotgun sequence
gi|172072829|gnl|WGS:ABJL|B_intesti -2.0.1_Cont606|gb|ABJL02000007.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000775157	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 31, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25038750, 25359994, 29330115, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000775157

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 31, 2022)

germline

clinical testing

PubMed (4)
[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

Citations

PubMed

Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease.

Flanagan SE, Haapaniemi E, Russell MA, Caswell R, Allen HL, De Franco E, McDonald TJ, Rajala H, Ramelius A, Barton J, Heiskanen K, Heiskanen-Kosma T, Kajosaari M, Murphy NP, Milenkovic T, Seppänen M, Lernmark Å, Mustjoki S, Otonkoski T, Kere J, Morgan NG, Ellard S, et al.

Nat Genet. 2014 Aug;46(8):812-814. doi: 10.1038/ng.3040. Epub 2014 Jul 20.

PubMed [citation]

PMID:: 25038750
PMCID:: PMC4129488

Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations.

Milner JD, Vogel TP, Forbes L, Ma CA, Stray-Pedersen A, Niemela JE, Lyons JJ, Engelhardt KR, Zhang Y, Topcagic N, Roberson ED, Matthews H, Verbsky JW, Dasu T, Vargas-Hernandez A, Varghese N, McClain KL, Karam LB, Nahmod K, Makedonas G, Mace EM, Sorte HS, et al.

Blood. 2015 Jan 22;125(4):591-9. doi: 10.1182/blood-2014-09-602763. Epub 2014 Oct 30.

PubMed [citation]

PMID:: 25359994
PMCID:: PMC4304103

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000775157.8

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

Description

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects STAT3 function (PMID: 25038750, 25359994). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 224848). This missense change has been observed in individual(s) with autoimmune disease and early-onset polyautoimmunity (PMID: 25038750, 25359994, 29330115). In at least one individual the variant was observed to be de novo. This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 716 of the STAT3 protein (p.Thr716Met).

#	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: Aug 4, 2024

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