Converted during submission to Likely pathogenic.
ClinVar Genomic variation as it relates to human health
NM_139276.3(STAT3):c.1970A>G (p.Tyr657Cys)
Germline
Classification
Help
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.
(3)
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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/Likely pathogenic
3
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_139276.3(STAT3):c.1970A>G (p.Tyr657Cys)
Variation ID: 36790 Accession: VCV000036790.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.2 17: 42322413 (GRCh38) [ NCBI UCSC ] 17: 40474431 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Apr 4, 2013 Feb 28, 2024 Feb 10, 2022 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_139276.3:c.1970A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_644805.1:p.Tyr657Cys missense NM_001369512.1:c.1970A>G NP_001356441.1:p.Tyr657Cys missense NM_001369513.1:c.1970A>G NP_001356442.1:p.Tyr657Cys missense NM_001369514.1:c.1970A>G NP_001356443.1:p.Tyr657Cys missense NM_001369516.1:c.1970A>G NP_001356445.1:p.Tyr657Cys missense NM_001369517.1:c.1970A>G NP_001356446.1:p.Tyr657Cys missense NM_001369518.1:c.1970A>G NP_001356447.1:p.Tyr657Cys missense NM_001369519.1:c.1970A>G NP_001356448.1:p.Tyr657Cys missense NM_001369520.1:c.1970A>G NP_001356449.1:p.Tyr657Cys missense NM_001384984.1:c.1886A>G NP_001371913.1:p.Tyr629Cys missense NM_001384985.1:c.1892A>G NP_001371914.1:p.Tyr631Cys missense NM_001384986.1:c.1985A>G NP_001371915.1:p.Tyr662Cys missense NM_001384987.1:c.1949A>G NP_001371916.1:p.Tyr650Cys missense NM_001384988.1:c.1970A>G NP_001371917.1:p.Tyr657Cys missense NM_001384989.1:c.1874A>G NP_001371918.1:p.Tyr625Cys missense NM_001384990.1:c.1985A>G NP_001371919.1:p.Tyr662Cys missense NM_001384991.1:c.1943A>G NP_001371920.1:p.Tyr648Cys missense NM_001384992.1:c.1910A>G NP_001371921.1:p.Tyr637Cys missense NM_001384993.1:c.1970A>G NP_001371922.1:p.Tyr657Cys missense NM_003150.4:c.1970A>G NP_003141.2:p.Tyr657Cys missense NM_213662.2:c.1970A>G NP_998827.1:p.Tyr657Cys missense NC_000017.11:g.42322413T>C NC_000017.10:g.40474431T>C NG_007370.1:g.71083A>G LRG_112:g.71083A>G LRG_112t1:c.1970A>G LRG_112p1:p.Tyr657Cys P40763:p.Tyr657Cys - Protein change
- Y657C, Y625C, Y629C, Y631C, Y637C, Y648C, Y650C, Y662C
- Other names
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- Canonical SPDI
- NC_000017.11:42322412:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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- Links
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 | ||
|---|---|---|---|---|---|---|
| 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 |
714 | 767 | |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 18, 2011 | RCV000030470.5 | |
| Pathogenic (1) |
criteria provided, single submitter
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Feb 10, 2022 | RCV000792130.8 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Hyper-IgE recurrent infection syndrome 1, autosomal dominant
Affected status: yes
Allele origin:
de novo
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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV002053765.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
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likely pathogenic
(Aug 18, 2011)
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criteria provided, single submitter
Method: curation, clinical testing
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Hyper IgE Syndrome
(autosomal dominant)
Affected status: yes, unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000053140.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 08, 2022 |
Comment:
Converted during submission to Likely pathogenic.
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
Observation 3:
Tissue: Blood
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Pathogenic
(Feb 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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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
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000931408.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
Experimental studies have shown that this missense change affects STAT3 function (PMID: 19577286). Algorithms developed to predict the effect of sequence changes on RNA splicing … (more)
Experimental studies have shown that this missense change affects STAT3 function (PMID: 19577286). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 657 of the STAT3 protein (p.Tyr657Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hyper-IgE syndrome (HIES) (PMID: 19577286, 22751495, 23584561, 30617622). ClinVar contains an entry for this variant (Variation ID: 36790). (less)
|
Comment:
Comment:
Experimental studies have shown that this missense change affects STAT3 function (PMID: 19577286). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 657 of the STAT3 protein (p.Tyr657Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hyper-IgE syndrome (HIES) (PMID: 19577286, 22751495, 23584561, 30617622). ClinVar contains an entry for this variant (Variation ID: 36790).
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:
Converted during submission to Likely pathogenic.
Comment:
Experimental studies have shown that this missense change affects STAT3 function (PMID: 19577286). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 657 of the STAT3 protein (p.Tyr657Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hyper-IgE syndrome (HIES) (PMID: 19577286, 22751495, 23584561, 30617622). ClinVar contains an entry for this variant (Variation ID: 36790).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Two Prenatal Cases of Hyper-IgE Syndrome. | Egawa M | Journal of clinical immunology | 2019 | PMID: 30617622 |
| Lung parenchyma surgery in autosomal dominant hyper-IgE syndrome. | Freeman AF | Journal of clinical immunology | 2013 | PMID: 23584561 |
| Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: molecular, cellular, and clinical features from a French national survey. | Chandesris MO | Medicine | 2012 | PMID: 22751495 |
| Destructive pulmonary staphylococcal infection in a boy with hyper-IgE syndrome: a novel mutation in the signal transducer and activator of transcription 3 (STAT3) gene (p.Y657S). | Liu JY | European journal of pediatrics | 2011 | PMID: 21107604 |
| Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome. | Woellner C | The Journal of allergy and clinical immunology | 2010 | PMID: 20159255 |
| Defects along the T(H)17 differentiation pathway underlie genetically distinct forms of the hyper IgE syndrome. | Al Khatib S | The Journal of allergy and clinical immunology | 2009 | PMID: 19577286 |
| Hyper IgE syndrome: an update on clinical aspects and the role of signal transducer and activator of transcription 3. | Paulson ML | Current opinion in allergy and clinical immunology | 2008 | PMID: 18978467 |
| Novel and recurrent STAT3 mutations in hyper-IgE syndrome patients from different ethnic groups. | Jiao H | Molecular immunology | 2008 | PMID: 18706697 |
| STAT3 mutations in the hyper-IgE syndrome. | Holland SM | The New England journal of medicine | 2007 | PMID: 17881745 |
Text-mined citations for rs193922721 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.