ClinVar Genomic variation as it relates to human health
NM_007315.4(STAT1):c.1154C>T (p.Thr385Met)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_007315.4(STAT1):c.1154C>T (p.Thr385Met)
Variation ID: 144006 Accession: VCV000144006.34
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q32.2 2: 190986921 (GRCh38) [ NCBI UCSC ] 2: 191851647 (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 Oct 7, 2016 Apr 15, 2024 Aug 31, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_007315.4:c.1154C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009330.1:p.Thr385Met missense NM_001384880.1:c.1094C>T NP_001371809.1:p.Thr365Met missense NM_001384881.1:c.1160C>T NP_001371810.1:p.Thr387Met missense NM_001384882.1:c.1148C>T NP_001371811.1:p.Thr383Met missense NM_001384883.1:c.1055C>T NP_001371812.1:p.Thr352Met missense NM_001384884.1:c.1160C>T NP_001371813.1:p.Thr387Met missense NM_001384885.1:c.995C>T NP_001371814.1:p.Thr332Met missense NM_001384886.1:c.1154C>T NP_001371815.1:p.Thr385Met missense NM_001384887.1:c.1061C>T NP_001371816.1:p.Thr354Met missense NM_001384888.1:c.1124C>T NP_001371817.1:p.Thr375Met missense NM_001384889.1:c.1154C>T NP_001371818.1:p.Thr385Met missense NM_001384890.1:c.1064C>T NP_001371819.1:p.Thr355Met missense NM_001384891.1:c.1190C>T NP_001371820.1:p.Thr397Met missense NM_139266.3:c.1154C>T NP_644671.1:p.Thr385Met missense NC_000002.12:g.190986921G>A NC_000002.11:g.191851647G>A NG_008294.1:g.32330C>T LRG_111:g.32330C>T LRG_111t1:c.1154C>T LRG_111p1:p.Thr385Met P42224:p.Thr385Met - Protein change
- T385M, T332M, T352M, T354M, T355M, T365M, T375M, T383M, T387M, T397M
- Other names
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- Canonical SPDI
- NC_000002.12:190986920: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
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The frequency of the allele represented by this VCV record.
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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 | ||
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HI score
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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. |
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STAT1 | No evidence available | No evidence available |
GRCh38 GRCh37 |
617 | 660 |
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. |
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Pathogenic (2) |
criteria provided, single submitter
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Mar 8, 2018 | RCV000133515.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 31, 2023 | RCV000698604.8 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV000735313.3 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV000735320.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 1, 2019 | RCV001027623.2 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jun 8, 2022 | RCV001090648.19 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 21, 2022 | RCV003156074.2 |
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. |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Chronic oral candidiasis
Delayed speech and language development Liver abscess Hypothyroidism Primary hypothyroidism Severe T-cell immunodeficiency Short stature
Affected status: yes
Allele origin:
germline
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Center for Personalized Medicine, Children's Hospital Los Angeles
Accession: SCV000854466.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Sex: female
Ethnicity/Population group: Non-Hispanic, Non-Hispanic
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Bronchiectasis
Chronic diarrhea Cognitive impairment Combined immunodeficiency Failure to thrive Hypothyroidism
Affected status: yes
Allele origin:
germline
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Center for Personalized Medicine, Children's Hospital Los Angeles
Accession: SCV000854474.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Sex: female
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Pathogenic
(Jan 01, 2019)
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criteria provided, single submitter
Method: research
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Inherited Immunodeficiency Diseases
Affected status: yes
Allele origin:
de novo
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NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV001190194.1
First in ClinVar: Mar 26, 2020 Last updated: Mar 26, 2020 |
Observation 1:
Clinical Features:
Abnormality of head or neck (present) , B lymphocytopenia (present) , Oral ulcer (present) , Recurrent fungal infections (present)
Observation 2:
Clinical Features:
Abnormality of the respiratory system (present) , Bronchiectasis (present) , Hemolytic anemia (present) , IgA deficiency (present) , IgG deficiency (present) , IgM deficiency (present) … (more)
Abnormality of the respiratory system (present) , Bronchiectasis (present) , Hemolytic anemia (present) , IgA deficiency (present) , IgG deficiency (present) , IgM deficiency (present) , Recurrent aphthous stomatitis (present) , Recurrent lower respiratory tract infections (present) (less)
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal unknown)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446929.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Recurrent skin infections (present) , Dystrophic toenail (present) , Recurrent infections (present) , Oral mucosa leukoplakia (present) , Skin erosion (present) , Hyperkeratosis (present)
Sex: female
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Pathogenic
(Mar 08, 2018)
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criteria provided, single submitter
Method: clinical testing
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Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome
Affected status: yes
Allele origin:
de novo
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Baylor Genetics
Accession: SCV001530648.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing in multiple patients with … (more)
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing in multiple patients with autosomal dominant immunodeficiency [PMID 22730530, 27379765, 26604104, 28597685, 23541320, 24239102, 27577878, 23534974, 26743090] (less)
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Pathogenic
(Dec 21, 2022)
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criteria provided, single submitter
Method: clinical testing
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See cases
Affected status: yes
Allele origin:
de novo
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Center for Personalized Medicine, Children's Hospital Los Angeles
Accession: SCV003845355.1
First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023 |
Clinical Features:
Chronic oral candidiasis (present) , Delayed speech and language development (present) , Liver abscess (present) , Hypothyroidism (present) , Primary hypothyroidism (present) , Severe T-cell … (more)
Chronic oral candidiasis (present) , Delayed speech and language development (present) , Liver abscess (present) , Hypothyroidism (present) , Primary hypothyroidism (present) , Severe T-cell immunodeficiency (present) , Short stature (present) (less)
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Pathogenic
(Jun 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226740.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP2, PP3, PM2, PS2, PS3, PS4
Number of individuals with the variant: 1
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Pathogenic
(Aug 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency
Immunodeficiency 31B Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome
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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Invitae
Accession: SCV000827277.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects STAT1 function (PMID: 22730530, 23534974, 23541320, … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects STAT1 function (PMID: 22730530, 23534974, 23541320, 23709754, 26604104). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 144006). This missense change has been observed in individual(s) with autosomal dominant chronic mucocutaneous candidiasis (PMID: 22730530, 23541320, 23709754, 24239102, 25042743, 26604104, 26743090, 27379765, 28597685). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 385 of the STAT1 protein (p.Thr385Met). (less)
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Pathogenic
(Mar 01, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001246318.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 3
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Pathogenic
(Sep 01, 2013)
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no assertion criteria provided
Method: literature only
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IMMUNODEFICIENCY 31C
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000188590.3
First in ClinVar: Aug 25, 2014 Last updated: Oct 07, 2016 |
Comment on evidence:
In a 13-year-old Ukrainian boy with IMD31C (614162), Soltesz et al. (2013) identified a c.1154C-T transition in exon 14 of the STAT1 gene. The mutation … (more)
In a 13-year-old Ukrainian boy with IMD31C (614162), Soltesz et al. (2013) identified a c.1154C-T transition in exon 14 of the STAT1 gene. The mutation resulted in a thr385-to-met (T385M) substitution in the DNA-binding domain of STAT1 that caused a gain of STAT1 phosphorylation due to loss of dephosphorylation. The boy had exhibited severe chronic mucocutaneous candidiasis with oral obstruction and dysphagia from infancy. His symptoms were usually controlled by oral antifungal medication, and manifestations in the fingernails subsided after age 10 years. The boy's 9-year-old sister and mother were healthy. Uzel et al. (2013) identified a heterozygous T385M mutation in 2 unrelated children with IMD31C (614162). One patient presented in infancy with mucocutaneous candidiasis, and the other presented in early childhood with dermatitis, recurrent infections, and enteropathy, but only had 1 episode of mild candidiasis. In vitro functional expression studies showed that the mutation resulted in increased STAT1 phosphorylation, activation, and increased DNA binding in response to IFNG stimulation, consistent with a gain of function. Transfected cells also showed decreased STAT1 dephosphorylation compared to wildtype, indicating prolonged activation. Flow cytometric analysis of patient lymphocytes confirmed increased IFNG-induced STAT1 hyperphosphorylation. Sampaio et al. (2013) identified a de novo heterozygous T385M mutation in the STAT1 gene in a 21-year-old Caucasian man with a lifetime history of recurrent infections and bone fractures in childhood. He developed mucocutaneous candidiasis at age 7 days, a mycobacterial infection at age 4, and severe disseminated histoplasmosis at age 12. In vitro functional expression studies indicated that the mutation resulted in enhanced IFNG-induced STAT1 phosphorylation and increased DNA binding in B cells compared to wildtype, consistent with a gain of function. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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A gain-of-function mutation of STAT1: A novel genetic factor contributing to chronic mucocutaneous candidiasis. | Eslami N | Acta microbiologica et immunologica Hungarica | 2017 | PMID: 28597685 |
Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders. | Stray-Pedersen A | The Journal of allergy and clinical immunology | 2017 | PMID: 27577878 |
Severe Early-Onset Combined Immunodeficiency due to Heterozygous Gain-of-Function Mutations in STAT1. | Baris S | Journal of clinical immunology | 2016 | PMID: 27379765 |
Progressive Multifocal Leukoencephalopathy in Primary Immune Deficiencies: Stat1 Gain of Function and Review of the Literature. | Zerbe CS | Clinical infectious diseases : an official publication of the Infectious Diseases Society of America | 2016 | PMID: 26743090 |
The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1. | Depner M | Journal of clinical immunology | 2016 | PMID: 26604104 |
Gain-of-function mutations in signal transducer and activator of transcription 1 (STAT1): chronic mucocutaneous candidiasis accompanied by enamel defects and delayed dental shedding. | Frans G | The Journal of allergy and clinical immunology | 2014 | PMID: 25042743 |
Fatal combined immunodeficiency associated with heterozygous mutation in STAT1. | Sharfe N | The Journal of allergy and clinical immunology | 2014 | PMID: 24239102 |
New and recurrent gain-of-function STAT1 mutations in patients with chronic mucocutaneous candidiasis from Eastern and Central Europe. | Soltész B | Journal of medical genetics | 2013 | PMID: 23709754 |
Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis. | Sampaio EP | The Journal of allergy and clinical immunology | 2013 | PMID: 23541320 |
Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation-polyendocrinopathy-enteropathy-X-linked-like syndrome. | Uzel G | The Journal of allergy and clinical immunology | 2013 | PMID: 23534974 |
Text-mined citations for rs587777630 ...
HelpRecord last updated Apr 15, 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.