VCV002925614.1 - ClinVar

NM_139276.3(STAT3):c.1907C>T (p.Ser636Phe)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(1)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_139276.3(STAT3):c.1907C>T (p.Ser636Phe)

Variation ID: 2925614 Accession: VCV002925614.1

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q21.2 17: 42322476 (GRCh38) [ NCBI UCSC ] 17: 40474494 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 29, 2024	Feb 28, 2024	Jan 19, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_139276.3:c.1907C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_644805.1:p.Ser636Phe	missense
NM_001369512.1:c.1907C>T	NP_001356441.1:p.Ser636Phe	missense
NM_001369513.1:c.1907C>T	NP_001356442.1:p.Ser636Phe	missense
NM_001369514.1:c.1907C>T	NP_001356443.1:p.Ser636Phe	missense
NM_001369516.1:c.1907C>T	NP_001356445.1:p.Ser636Phe	missense
NM_001369517.1:c.1907C>T	NP_001356446.1:p.Ser636Phe	missense
NM_001369518.1:c.1907C>T	NP_001356447.1:p.Ser636Phe	missense
NM_001369519.1:c.1907C>T	NP_001356448.1:p.Ser636Phe	missense
NM_001369520.1:c.1907C>T	NP_001356449.1:p.Ser636Phe	missense
NM_001384984.1:c.1823C>T	NP_001371913.1:p.Ser608Phe	missense
NM_001384985.1:c.1829C>T	NP_001371914.1:p.Ser610Phe	missense
NM_001384986.1:c.1922C>T	NP_001371915.1:p.Ser641Phe	missense
NM_001384987.1:c.1886C>T	NP_001371916.1:p.Ser629Phe	missense
NM_001384988.1:c.1907C>T	NP_001371917.1:p.Ser636Phe	missense
NM_001384989.1:c.1811C>T	NP_001371918.1:p.Ser604Phe	missense
NM_001384990.1:c.1922C>T	NP_001371919.1:p.Ser641Phe	missense
NM_001384991.1:c.1880C>T	NP_001371920.1:p.Ser627Phe	missense
NM_001384992.1:c.1847C>T	NP_001371921.1:p.Ser616Phe	missense
NM_001384993.1:c.1907C>T	NP_001371922.1:p.Ser636Phe	missense
NM_003150.4:c.1907C>T	NP_003141.2:p.Ser636Phe	missense
NM_213662.2:c.1907C>T	NP_998827.1:p.Ser636Phe	missense
NC_000017.11:g.42322476G>A
NC_000017.10:g.40474494G>A
NG_007370.1:g.71020C>T
LRG_112:g.71020C>T
LRG_112t1:c.1907C>T	LRG_112p1:p.Ser636Phe

... more HGVS ... less HGVS

Protein change

S610F, S627F, S636F, S604F, S608F, S629F, S616F, S641F

Other names

Canonical SPDI

NC_000017.11:42322475:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
STAT3		-	-	GRCh38 GRCh37	721	774

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hyper-IgE recurrent infection syndrome 1, autosomal dominant STAT3 gain of function	Pathogenic (1)	criteria provided, single submitter	Jan 19, 2024	RCV003783708.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jan 19, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	STAT3 gain of function Hyper-IgE recurrent infection syndrome 1, autosomal dominant Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004571429.1 First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024	Publications: PubMed (4) PubMed: 18602572‚ 21300911‚ 20159255‚ 28359783 Comment: This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 636 of the STAT3 protein (p.Ser636Phe). … (more) This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 636 of the STAT3 protein (p.Ser636Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hyper IgE syndrome (PMID: 18602572, 21300911; Invitae). 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 not expected to disrupt STAT3 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects STAT3 function (PMID: 18602572). This variant disrupts the p.Ser636 amino acid residue in STAT3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20159255, 28359783; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)

Comment:

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 636 of the STAT3 protein (p.Ser636Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hyper IgE syndrome (PMID: 18602572, 21300911; Invitae). 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 not expected to disrupt STAT3 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects STAT3 function (PMID: 18602572). This variant disrupts the p.Ser636 amino acid residue in STAT3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20159255, 28359783; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Systematic analysis of splicing defects in selected primary immunodeficiencies-related genes.	Grodecká L	Clinical immunology (Orlando, Fla.)	2017	PMID: 28359783
Defective IL-10 signaling in hyper-IgE syndrome results in impaired generation of tolerogenic dendritic cells and induced regulatory T cells.	Saito M	The Journal of experimental medicine	2011	PMID: 21300911
Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome.	Woellner C	The Journal of allergy and clinical immunology	2010	PMID: 20159255
Novel signal transducer and activator of transcription 3 (STAT3) mutations, reduced T(H)17 cell numbers, and variably defective STAT3 phosphorylation in hyper-IgE syndrome.	Renner ED	The Journal of allergy and clinical immunology	2008	PMID: 18602572

Text-mined citations for this variant ...

Record last updated Jan 13, 2025

ClinVar Genomic variation as it relates to human health

NM_139276.3(STAT3):c.1907C>T (p.Ser636Phe)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...