segregates with the phenotype in an affected family
ClinVar Genomic variation as it relates to human health
NM_139276.3(STAT3):c.2147C>T (p.Thr716Met)
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.
(7)
Help
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
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_139276.3(STAT3):c.2147C>T (p.Thr716Met)
Variation ID: 224848 Accession: VCV000224848.39
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q21.2 17: 42316899 (GRCh38) [ NCBI UCSC ] 17: 40468917 (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 3, 2016 Oct 20, 2024 Mar 31, 2022 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_139276.3:c.2147C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_644805.1:p.Thr716Met missense NM_001369512.1:c.2147C>T NP_001356441.1:p.Thr716Met missense NM_001369513.1:c.2147C>T NP_001356442.1:p.Thr716Met missense NM_001369514.1:c.2144C>T NP_001356443.1:p.Thr715Met missense NM_001369516.1:c.2144C>T NP_001356445.1:p.Thr715Met missense NM_001369517.1:c.2145-48C>T intron variant NM_001369518.1:c.2145-48C>T intron variant NM_001369519.1:c.2142-48C>T intron variant NM_001369520.1:c.2142-48C>T intron variant NM_001384984.1:c.2063C>T NP_001371913.1:p.Thr688Met missense NM_001384985.1:c.2069C>T NP_001371914.1:p.Thr690Met missense NM_001384986.1:c.2157-48C>T intron variant NM_001384987.1:c.2126C>T NP_001371916.1:p.Thr709Met missense NM_001384988.1:c.2099-48C>T intron variant NM_001384989.1:c.2048C>T NP_001371918.1:p.Thr683Met missense NM_001384990.1:c.2160-48C>T intron variant NM_001384991.1:c.2120C>T NP_001371920.1:p.Thr707Met missense NM_001384992.1:c.2087C>T NP_001371921.1:p.Thr696Met missense NM_001384993.1:c.2145-10C>T intron variant NM_003150.4:c.2144C>T NP_003141.2:p.Thr715Met missense NM_213662.2:c.2145-48C>T intron variant NC_000017.11:g.42316899G>A NC_000017.10:g.40468917G>A NG_007370.1:g.76597C>T LRG_112:g.76597C>T LRG_112t1:c.2147C>T LRG_112p1:p.Thr716Met P40763:p.Thr716Met - Protein change
- T716M, T715M, T683M, T688M, T690M, T696M, T707M, T709M
- Other names
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- Canonical SPDI
- NC_000017.11:42316898:G:A
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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 |
716 | 769 | |
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 (3) |
criteria provided, single submitter
|
Oct 30, 2014 | RCV000210415.8 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Sep 1, 2021 | RCV000224259.25 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 31, 2022 | RCV000653278.13 |
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
(Oct 30, 2014)
|
criteria provided, single submitter
Method: research
|
STAT3-related early-onset multisystem autoimmune disease
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown,
inherited
|
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine
Accession: SCV000266408.1
First in ClinVar: Apr 03, 2016 Last updated: Apr 03, 2016 |
Comment:
segregates with the phenotype in an affected family
Observation 1:
Number of individuals with the variant: 1
Family history: yes
Observation 2:
Number of individuals with the variant: 2
Family history: yes
|
|
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Pathogenic
(Oct 03, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000281134.1
First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016 |
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Pathogenic
(Sep 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000566572.6
First in ClinVar: Jun 08, 2016 Last updated: Mar 04, 2023 |
Comment:
Observed in a patient and their parent with autoimmune enteropathy (Slowik et al., 2014); Published functional studies demonstrate variant results in a gain of function … (more)
Observed in a patient and their parent with autoimmune enteropathy (Slowik et al., 2014); Published functional studies demonstrate variant results in a gain of function effect (Flanagan SE et al., 2014; Milner JD et al., 2015); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25359994, 30942636, 25038750, 31770611, 33046446, 28960754, 29330115, 26280891) (less)
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Pathogenic
(Mar 31, 2022)
|
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
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000775157.8
First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024 |
Comment:
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 … (more)
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). (less)
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Pathogenic
(Sep 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001246592.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 2
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Pathogenic
(Aug 01, 2014)
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no assertion criteria provided
Method: literature only
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AUTOIMMUNE DISEASE, MULTISYSTEM, INFANTILE-ONSET, 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000188612.4
First in ClinVar: Aug 25, 2014 Last updated: Sep 18, 2016 |
Comment on evidence:
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 … (more)
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. (less)
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Pathogenic
(Oct 22, 2019)
|
no assertion criteria provided
Method: clinical testing
|
STAT3-related early-onset multisystem autoimmune disease
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Clinical Genomics Laboratory, Stanford Medicine
Accession: SCV001427091.1
First in ClinVar: Aug 17, 2020 Last updated: Aug 17, 2020 |
Comment:
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 … (more)
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] (less)
|
Comment:
Comment:
Observed in a patient and their parent with autoimmune enteropathy (Slowik et al., 2014); Published functional studies demonstrate variant results in a gain of function effect (Flanagan SE et al., 2014; Milner JD et al., 2015); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25359994, 30942636, 25038750, 31770611, 33046446, 28960754, 29330115, 26280891)
Comment:
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).
Comment:
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]
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:
segregates with the phenotype in an affected family
Comment:
Observed in a patient and their parent with autoimmune enteropathy (Slowik et al., 2014); Published functional studies demonstrate variant results in a gain of function effect (Flanagan SE et al., 2014; Milner JD et al., 2015); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25359994, 30942636, 25038750, 31770611, 33046446, 28960754, 29330115, 26280891)
Comment:
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).
Comment:
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]
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Pediatric-onset Evans syndrome: Heterogeneous presentation and high frequency of monogenic disorders including LRBA and CTLA4 mutations. | Besnard C | Clinical immunology (Orlando, Fla.) | 2018 | PMID: 29330115 |
| Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations. | Milner JD | Blood | 2015 | PMID: 25359994 |
| Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease. | Flanagan SE | Nature genetics | 2014 | PMID: 25038750 |
Text-mined citations for rs869312892 ...
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 Oct 20, 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.