Variant summary: FOXP3 c.1189C>T (p.Arg397Trp) results in a non-conservative amino acid change located in the Fork head domain (IPR001766) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 182711 control chromosomes (gnomAD). c.1189C>T has been reported in the literature in multiple individuals affected with Insulin-Dependent Diabetes Mellitus Secretory Diarrhea Syndrome (Wildin_2001, Xavier-DaSilva_2015, Gambineri_2018, Quinlan Jones_2019, Shangaris_2021). These data indicate that the variant is associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_014009.4(FOXP3):c.1189C>T (p.Arg397Trp)
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.
(4)
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
4
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_014009.4(FOXP3):c.1189C>T (p.Arg397Trp)
Variation ID: 11407 Accession: VCV000011407.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xp11.23 X: 49251441 (GRCh38) [ NCBI UCSC ] X: 49107902 (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 14, 2024 Dec 3, 2021 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_014009.4:c.1189C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_054728.2:p.Arg397Trp missense NM_001114377.2:c.1084C>T NP_001107849.1:p.Arg362Trp missense NC_000023.11:g.49251441G>A NC_000023.10:g.49107902G>A NG_007392.1:g.18387C>T NG_021311.2:g.20977G>A LRG_62:g.18387C>T LRG_62t1:c.1189C>T Q9BZS1:p.Arg397Trp - Protein change
- R397W, R362W
- Other names
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- Canonical SPDI
- NC_000023.11:49251440: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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Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD), exomes 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
- 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. |
|||
| FOXP3 | - | - |
GRCh38 GRCh37 |
332 | 497 | |
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, multiple submitters, no conflicts
|
Dec 3, 2021 | RCV000012160.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 2, 2020 | RCV001290142.2 |
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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|---|---|---|---|---|---|
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Pathogenic
(Dec 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
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Insulin-dependent diabetes mellitus secretory diarrhea syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002050717.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
Variant summary: FOXP3 c.1189C>T (p.Arg397Trp) results in a non-conservative amino acid change located in the Fork head domain (IPR001766) of the encoded protein sequence. Five … (more)
Variant summary: FOXP3 c.1189C>T (p.Arg397Trp) results in a non-conservative amino acid change located in the Fork head domain (IPR001766) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 182711 control chromosomes (gnomAD). c.1189C>T has been reported in the literature in multiple individuals affected with Insulin-Dependent Diabetes Mellitus Secretory Diarrhea Syndrome (Wildin_2001, Xavier-DaSilva_2015, Gambineri_2018, Quinlan Jones_2019, Shangaris_2021). These data indicate that the variant is associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
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Pathogenic
(Mar 02, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hydrops fetalis
Affected status: yes
Allele origin:
maternal
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Genetics - Synnovis, NHS South East Genomic Laboratory Hub
Accession: SCV001468505.1
First in ClinVar: Jan 30, 2021 Last updated: Jan 30, 2021 |
Comment:
This variant detected in two affected male fetuses and not detected in an unaffected male fetus (consecutive pregnancies). The same variant reported by Xavier-da-Silva (2015) … (more)
This variant detected in two affected male fetuses and not detected in an unaffected male fetus (consecutive pregnancies). The same variant reported by Xavier-da-Silva (2015) in a fetus presenting with hydrops at 27 weeks' gestation and in a term newborn who developed diabetes mellitus during the first hours of life. Levy-Lahad & Wildin (2001) also reported this variant in three siblings presenting with IPEX manifestations at birth. In all previously reported cases, the pathological process began during intrauterine life; furthermore, there are no survivors described. (less)
Sex: male
Comment on evidence:
Prenatal
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Pathogenic
(Jul 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Insulin-dependent diabetes mellitus secretory diarrhea syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002236466.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This variant has been observed in individuals with clinical features of IPEX syndrome (PMID: 11137992, 11295725, 25546394, 30293990, 30443250, 31130284). It has also been observed … (more)
This variant has been observed in individuals with clinical features of IPEX syndrome (PMID: 11137992, 11295725, 25546394, 30293990, 30443250, 31130284). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11407). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with tryptophan at codon 397 of the FOXP3 protein (p.Arg397Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects FOXP3 protein function (PMID: 16920951, 22590469, 28778586, 28783662). 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 FOXP3 protein function. (less)
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Pathogenic
(Apr 01, 2001)
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no assertion criteria provided
Method: literature only
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IMMUNODYSREGULATION, POLYENDOCRINOPATHY, AND ENTEROPATHY, X-LINKED
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000032394.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
Wildin et al. (2001) identified an arg397-to-trp mutation in the FOXP3 gene (due to 1189C-T) as the cause of IPEX (304790) in one of the … (more)
Wildin et al. (2001) identified an arg397-to-trp mutation in the FOXP3 gene (due to 1189C-T) as the cause of IPEX (304790) in one of the patients previously reported by Levy-Lahad and Wildin (2001). The infant died at age 5 weeks with insulin-dependent diabetes mellitus, enteropathy, hypothyroidism, thrombocytopenia, and peritonitis. (less)
|
Comment:
Comment:
This variant detected in two affected male fetuses and not detected in an unaffected male fetus (consecutive pregnancies). The same variant reported by Xavier-da-Silva (2015) in a fetus presenting with hydrops at 27 weeks' gestation and in a term newborn who developed diabetes mellitus during the first hours of life. Levy-Lahad & Wildin (2001) also reported this variant in three siblings presenting with IPEX manifestations at birth. In all previously reported cases, the pathological process began during intrauterine life; furthermore, there are no survivors described.
Comment:
This variant has been observed in individuals with clinical features of IPEX syndrome (PMID: 11137992, 11295725, 25546394, 30293990, 30443250, 31130284). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11407). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with tryptophan at codon 397 of the FOXP3 protein (p.Arg397Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects FOXP3 protein function (PMID: 16920951, 22590469, 28778586, 28783662). 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 FOXP3 protein function.
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:
Variant summary: FOXP3 c.1189C>T (p.Arg397Trp) results in a non-conservative amino acid change located in the Fork head domain (IPR001766) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 182711 control chromosomes (gnomAD). c.1189C>T has been reported in the literature in multiple individuals affected with Insulin-Dependent Diabetes Mellitus Secretory Diarrhea Syndrome (Wildin_2001, Xavier-DaSilva_2015, Gambineri_2018, Quinlan Jones_2019, Shangaris_2021). These data indicate that the variant is associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This variant detected in two affected male fetuses and not detected in an unaffected male fetus (consecutive pregnancies). The same variant reported by Xavier-da-Silva (2015) in a fetus presenting with hydrops at 27 weeks' gestation and in a term newborn who developed diabetes mellitus during the first hours of life. Levy-Lahad & Wildin (2001) also reported this variant in three siblings presenting with IPEX manifestations at birth. In all previously reported cases, the pathological process began during intrauterine life; furthermore, there are no survivors described.
Comment:
This variant has been observed in individuals with clinical features of IPEX syndrome (PMID: 11137992, 11295725, 25546394, 30293990, 30443250, 31130284). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11407). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with tryptophan at codon 397 of the FOXP3 protein (p.Arg397Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects FOXP3 protein function (PMID: 16920951, 22590469, 28778586, 28783662). 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 FOXP3 protein function.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| A hemizygous mutation in the FOXP3 gene (IPEX syndrome) resulting in recurrent X-linked fetal hydrops: a case report. | Shangaris P | BMC medical genomics | 2021 | PMID: 33637067 |
| Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population. | Monies D | American journal of human genetics | 2019 | PMID: 31130284 |
| Molecular autopsy by trio exome sequencing (ES) and postmortem examination in fetuses and neonates with prenatally identified structural anomalies. | Quinlan-Jones E | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30293990 |
| Clinical, Immunological, and Molecular Heterogeneity of 173 Patients With the Phenotype of Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked (IPEX) Syndrome. | Gambineri E | Frontiers in immunology | 2018 | PMID: 30443250 |
| Suppression by human FOXP3(+) regulatory T cells requires FOXP3-TIP60 interactions. | Bin Dhuban K | Science immunology | 2017 | PMID: 28783662 |
| Analyses of a Mutant Foxp3 Allele Reveal BATF as a Critical Transcription Factor in the Differentiation and Accumulation of Tissue Regulatory T Cells. | Hayatsu N | Immunity | 2017 | PMID: 28778586 |
| Fetal-onset IPEX: report of two families and review of literature. | Xavier-da-Silva MM | Clinical immunology (Orlando, Fla.) | 2015 | PMID: 25546394 |
| Comparative Genomics Reveals Key Gain-of-Function Events in Foxp3 during Regulatory T Cell Evolution. | Andersen KG | Frontiers in immunology | 2012 | PMID: 22590469 |
| Analysis of FOXP3 reveals multiple domains required for its function as a transcriptional repressor. | Lopes JE | Journal of immunology (Baltimore, Md. : 1950) | 2006 | PMID: 16920951 |
| Neonatal diabetes mellitus, enteropathy, thrombocytopenia, and endocrinopathy: Further evidence for an X-linked lethal syndrome. | Levy-Lahad E | The Journal of pediatrics | 2001 | PMID: 11295725 |
| X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. | Wildin RS | Nature genetics | 2001 | PMID: 11137992 |
| - | - | - | - | DOI: 10.1016/j.clim.2014.12.007 |
| - | - | - | - | DOI: 10.1067/mpd.2001.111502 |
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Text-mined citations for rs28935477 ...
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.