NM_139276.3(STAT3):c.1145G>A (p.Arg382Gln) AND Hyper-IgE recurrent infection syndrome 1, autosomal dominant

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Oct 9, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000019967.34

Allele description [Variation Report for NM_139276.3(STAT3):c.1145G>A (p.Arg382Gln)]

NM_139276.3(STAT3):c.1145G>A (p.Arg382Gln)

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.1145G>A (p.Arg382Gln)

HGVS:

NC_000017.11:g.42329642C>T
NG_007370.1:g.63854G>A
NM_001369512.1:c.1145G>A
NM_001369513.1:c.1145G>A
NM_001369514.1:c.1145G>A
NM_001369516.1:c.1145G>A
NM_001369517.1:c.1145G>A
NM_001369518.1:c.1145G>A
NM_001369519.1:c.1145G>A
NM_001369520.1:c.1145G>A
NM_001384984.1:c.1145G>A
NM_001384985.1:c.1067G>A
NM_001384986.1:c.1160G>A
NM_001384987.1:c.1145G>A
NM_001384988.1:c.1145G>A
NM_001384989.1:c.1049G>A
NM_001384990.1:c.1160G>A
NM_001384991.1:c.1145G>A
NM_001384992.1:c.1085G>A
NM_001384993.1:c.1145G>A
NM_003150.4:c.1145G>A
NM_139276.3:c.1145G>AMANE SELECT
NM_213662.2:c.1145G>A
NP_001356441.1:p.Arg382Gln
NP_001356442.1:p.Arg382Gln
NP_001356443.1:p.Arg382Gln
NP_001356445.1:p.Arg382Gln
NP_001356446.1:p.Arg382Gln
NP_001356447.1:p.Arg382Gln
NP_001356448.1:p.Arg382Gln
NP_001356449.1:p.Arg382Gln
NP_001371913.1:p.Arg382Gln
NP_001371914.1:p.Arg356Gln
NP_001371915.1:p.Arg387Gln
NP_001371916.1:p.Arg382Gln
NP_001371917.1:p.Arg382Gln
NP_001371918.1:p.Arg350Gln
NP_001371919.1:p.Arg387Gln
NP_001371920.1:p.Arg382Gln
NP_001371921.1:p.Arg362Gln
NP_001371922.1:p.Arg382Gln
NP_003141.2:p.Arg382Gln
NP_644805.1:p.Arg382Gln
NP_644805.1:p.Arg382Gln
NP_998827.1:p.Arg382Gln
LRG_112t1:c.1145G>A
LRG_112:g.63854G>A
LRG_112p1:p.Arg382Gln
NC_000017.10:g.40481660C>T
NM_139276.2:c.1145G>A
P40763:p.Arg382Gln

Protein change:

R350Q; ARG382GLN

Links:

UniProtKB: P40763#VAR_037366; OMIM: 102582.0003; dbSNP: rs113994136

NCBI 1000 Genomes Browser:

rs113994136

Molecular consequence:

NM_001369512.1:c.1145G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369513.1:c.1145G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369514.1:c.1145G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369516.1:c.1145G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369517.1:c.1145G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369518.1:c.1145G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369519.1:c.1145G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369520.1:c.1145G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001384984.1:c.1145G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001384985.1:c.1067G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001384986.1:c.1160G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001384987.1:c.1145G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001384988.1:c.1145G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001384989.1:c.1049G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001384990.1:c.1160G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001384991.1:c.1145G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001384992.1:c.1085G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001384993.1:c.1145G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_003150.4:c.1145G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_139276.3:c.1145G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_213662.2:c.1145G>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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000040265	OMIM	no assertion criteria provided	Pathogenic (Oct 18, 2007)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 17676033, 17881745
SCV000041587	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 17881745, 20301786
SCV001934253	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 19, 2020)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004048303	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004122657	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Oct 9, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 17881745, 18706697, 18591410, 18978467, 18602572, 18591412, 17676033, 20159255, 22581330, 21288777 Citation Link

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, literature only
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

STAT3 Hyper IgE Syndrome.

Hsu AP, Davis J, Puck JM, Holland SM, Freeman AF.

2010 Feb 23 [updated 2020 Mar 26]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

PubMed [citation]

PMID:: 20301786

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

See all PubMed Citations (12)

Details of each submission

From OMIM, SCV000040265.2

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

Description

In a Japanese patient with hyper-IgE syndrome-1 (HIES1; 147060), Minegishi et al. (2007) identified heterozygosity for a 1145G-A transition in the STAT3 gene, resulting in an arg382-to-gln (R382Q) substitution.

In affected members of 4 families segregating hyper-IgE syndrome, Holland et al. (2007) identified heterozygosity for the R382Q mutation in the STAT3 gene. One of the families was black and 3 were white.

#	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 GeneReviews, SCV000041587.3

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

#	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

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001934253.1

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

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

From Neuberg Centre For Genomic Medicine, NCGM, SCV004048303.1

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

Description

This variant has been observed to be de novo in individuals affected with hyper-IgE syndrome (Holland SM, 2007). It also segregates with hyper-IgE syndrome in a family and has been identified in several individuals affected with hyper-IgE syndrome (Minegishi Y, 2007) and an individual with selective IgG subclass deficiency (Ohnishi H, 2016). This variant has been reported to affect STAT3 protein function (Minegishi Y, 2007). This sequence change replaces arginine with glutamine at codon 382 of the STAT3 protein (p.Arg382Gln). Other variant(s) that disrupt p.Arg382 residue have been determined to be pathogenic (Renner ED, 2007). The variant has been reported to the ClinVar database as Pathogenic. The p.Arg382Gln variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The variant is predicted to be damaging by both SIFT and PolyPhen2. The amino acid change p.Arg382Gln in STAT3 is predicted as conserved by GERP++ and PhyloP across 100 vertebratesFor these reasons, this variant has been classified as Pathogenic.

#	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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004122657.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

Variant summary: STAT3 c.1145G>A (p.Arg382Gln) results in a conservative amino acid change located in the STAT transcription factor, DNA-binding (IPR013801) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251470 control chromosomes. c.1145G>A has been reported in the literature in multiple individuals affected with Hyper IgE Syndrome (e.g. Holland 2007). It has been observed as de novo and also seen to segregate with disease. These data indicate that the variant is very likely to be associated with disease. Additionally, other variants affected the same codon have been associated with Hyper-IgE syndrome in HGMD and ClinVar (e.g. R382G, R382P and R382W). At least one publication reports experimental evidence evaluating an impact on protein function by severely reducing the DNA binding ability of the homodimer (He_2012). The following publications have been ascertained in the context of this evaluation (PMID: 17881745, 20159255, 22581330).Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	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: Apr 15, 2024

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