NM_139276.3(STAT3):c.2147C>T (p.Thr716Met) AND STAT3-related early-onset multisystem autoimmune disease

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

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Oct 30, 2014
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:: RCV000210415.7

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:: STAT3-related early-onset multisystem autoimmune disease
Synonyms:: Autoimmune disease, multisystem, infantile-onset, 1
Identifiers:: MONDO: MONDO:0014414; MedGen: C4014795; OMIM: 615952

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000188612	OMIM	no assertion criteria provided	Pathogenic (Aug 1, 2014)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 25038750, 25359994
SCV000266408	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	criteria provided, single submitter (Milner et al. (Blood 2015))	Pathogenic (Oct 30, 2014)	unknown, inherited	research	PubMed (1) [See all records that cite this PMID]
SCV001427091	Clinical Genomics Program, Stanford Medicine	no assertion criteria provided	Pathogenic (Oct 22, 2019)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000188612

OMIM

no assertion criteria provided

Pathogenic
(Aug 1, 2014)

germline

literature only

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

SCV000266408

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

criteria provided, single submitter

(Milner et al. (Blood 2015))

Pathogenic
(Oct 30, 2014)

unknown, inherited

research

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

SCV001427091

Clinical Genomics Program, Stanford Medicine

no assertion criteria provided

Pathogenic
(Oct 22, 2019)

germline

clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	1	2	not provided	not provided	yes	research
not provided	inherited	yes	2	not provided	not provided	not provided	yes	research

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

Details of each submission

From OMIM, SCV000188612.4

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

Description

In a 6-year-old girl with infantile-onset multisystem autoimmune disease-1 (ADMIO1; 615952), Flanagan et al. (2014) identified a de novo heterozygous c.2147C-T transition in the STAT3 gene, resulting in a thr716-to-met (T716M) substitution at a highly conserved residue in the transactivation domain. The mutation, which was found by exome sequencing, was not present in the dbSNP (build 131), 1000 Genomes Project, or Exome Variant server databases, or in the unaffected parents.

Milner et al. (2015) identified a heterozygous T716M mutation (c.2147C-T, NM_139276)in the STAT3 gene in 3 patients from 2 unrelated families with ADMIO1. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing.

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

From Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine, SCV000266408.1

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

Description

segregates with the phenotype in an affected family

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	discovery		1	not provided	2	not provided
2	inherited	yes	not provided	not provided	discovery		2	not provided	not provided	not provided

From Clinical Genomics Program, Stanford Medicine, SCV001427091.1

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

Description

The p.Thr716Met variant has been previously reported in 5 unrelated individuals with clinical features of infantile-onset multisystem autoimmune disease 1 (ADMIO1) and co-segregated with disease in 1 affected relative (Flanagan et al., 2014; Slowik et al., 2014; Milner at al., 2015; Takagi et al., 2018; Besnard et al., 2018). This variant was identified de novo in this individual and has also been previously reported de novo in 1 additional individual (Flanagan et al., 2014). The p.Thr716Met was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Functional studies suggest the p.Thr716Met variant causes increased transptional activity (Flanagan et al., 2014; Milner et al., 2015). Additionally, the STAT3 gene has fewer missense variants in the general population than expected. A low rate of missense variation may suggest that this gene is intolerant to missense variation. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Thr716Met variant as pathogenic for ADMIO1 in an autosomal dominant manner based on the information above. [ACMG evidence codes used: PS2, PM2, PS3_moderate, PP2, PS4_supporting]

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

Last Updated: Jun 23, 2024

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