This variant has been previously reported as a hemizygous change in patients with Immunodysregulation, Polyendocrinopathy, and Enteropathy, X-Linked (IPEX) Syndrome (PMID: 18931102, 24982679, 28289675, 29241729, 30443250). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.1010G>A (p.Arg337Gln) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1010G>A (p.Arg337Gln) variant is classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_014009.4(FOXP3):c.1010G>A (p.Arg337Gln)
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/Likely pathogenic/Likely risk allele
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_014009.4(FOXP3):c.1010G>A (p.Arg337Gln)
Variation ID: 935864 Accession: VCV000935864.14
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xp11.23 X: 49253160 (GRCh38) [ NCBI UCSC ] X: 49109621 (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 Jul 16, 2020 Feb 14, 2024 Feb 14, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_014009.4:c.1010G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_054728.2:p.Arg337Gln missense NM_001114377.2:c.905G>A NP_001107849.1:p.Arg302Gln missense NC_000023.11:g.49253160C>T NC_000023.10:g.49109621C>T NG_007392.1:g.16668G>A NG_021311.2:g.22696C>T LRG_62:g.16668G>A LRG_62t1:c.1010G>A - Protein change
- R302Q, R337Q
- Other names
- -
- Canonical SPDI
- NC_000023.11:49253159:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- 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 |
334 | 499 | |
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/Likely risk allele (5) |
criteria provided, multiple submitters, no conflicts
|
Jul 18, 2022 | RCV001204541.11 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 21, 2019 | RCV002504237.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 14, 2023 | RCV003389067.1 |
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
(Sep 25, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
IMMUNODYSREGULATION, POLYENDOCRINOPATHY, AND ENTEROPATHY, X-LINKED
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV001445930.1
First in ClinVar: Nov 21, 2020 Last updated: Nov 21, 2020 |
Comment:
This variant has been previously reported as a hemizygous change in patients with Immunodysregulation, Polyendocrinopathy, and Enteropathy, X-Linked (IPEX) Syndrome (PMID: 18931102, 24982679, 28289675, 29241729, … (more)
This variant has been previously reported as a hemizygous change in patients with Immunodysregulation, Polyendocrinopathy, and Enteropathy, X-Linked (IPEX) Syndrome (PMID: 18931102, 24982679, 28289675, 29241729, 30443250). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.1010G>A (p.Arg337Gln) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1010G>A (p.Arg337Gln) variant is classified as Pathogenic. (less)
|
|
|
Pathogenic
(Dec 20, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Insulin-dependent diabetes mellitus secretory diarrhea syndrome
Affected status: yes
Allele origin:
de novo
|
Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital
Accession: SCV001499933.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Number of individuals with the variant: 1
Age: 0-9 years
Sex: male
Ethnicity/Population group: East Asia
Geographic origin: China
|
|
|
Pathogenic
(Jul 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Insulin-dependent diabetes mellitus secretory diarrhea syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002570853.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
Variant summary: FOXP3 c.1010G>A (p.Arg337Gln) results in a conservative amino acid change located in the Fork head domain of the encoded protein sequence. Four of … (more)
Variant summary: FOXP3 c.1010G>A (p.Arg337Gln) results in a conservative amino acid change located in the Fork head domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 180275 control chromosomes. c.1010G>A has been reported in the literature in individuals affected with Insulin-Dependent Diabetes Mellitus Secretory Diarrhea Syndrome. These data indicate that the variant may be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Likely risk allele
(-)
|
criteria provided, single submitter
(K & H Uppaluri Personalized Medicine Clinic Variant Classification & Assertion Criteria_Updated V.1)
Method: research
|
Insulin-dependent diabetes mellitus secretory diarrhea syndrome
(X-linked recessive inheritance)
Affected status: unknown
Allele origin:
unknown
|
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic
Accession: SCV002605323.1
First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022 |
Comment:
Potent mutations in FOXP3 gene are associated with a rare X linked condition called IPEX. It presents with immune dysregulation, secretory diarrhea, polyendocrinopathy which includes … (more)
Potent mutations in FOXP3 gene are associated with a rare X linked condition called IPEX. It presents with immune dysregulation, secretory diarrhea, polyendocrinopathy which includes diabtes type 1, thyroiditis, growth hormone deficiency and hypoadrenalism. It is associated with pancreatic beta cell destruction.However no sufficient evidence is found to ascertain the role of this particular variant rs2066044949, yet. (less)
|
|
|
Pathogenic
(Aug 21, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV002817280.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
This variant was reported to be maternally inherited in multiple patients with clinical features of IPEX (PMID: 18931102, 27167055, 28289675, 24982679, 23771172, 28488220, 25911531, 30951839, … (more)
This variant was reported to be maternally inherited in multiple patients with clinical features of IPEX (PMID: 18931102, 27167055, 28289675, 24982679, 23771172, 28488220, 25911531, 30951839, 30443250). This variant appears to have occurred de novo in one mother of an affected patient (PMID: 28289675). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Computational tools yielded predictions that this amino acid change may be damaging to the protein. This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. (less)
|
|
|
Pathogenic
(Feb 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodevelopmental disorder
Affected status: yes
Allele origin:
germline
|
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes
Accession: SCV004101228.1
First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023 |
|
|
|
Likely pathogenic
(Sep 13, 2019)
|
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: SCV001375751.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more)
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individuals with clinical features of IPEX syndrome (PMID: 18931102, 30443250, 24982679, 25911531, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 337 of the FOXP3 protein (p.Arg337Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. (less)
|
Comment:
Comment:
Variant summary: FOXP3 c.1010G>A (p.Arg337Gln) results in a conservative amino acid change located in the Fork head domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 180275 control chromosomes. c.1010G>A has been reported in the literature in individuals affected with Insulin-Dependent Diabetes Mellitus Secretory Diarrhea Syndrome. These data indicate that the variant may be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Potent mutations in FOXP3 gene are associated with a rare X linked condition called IPEX. It presents with immune dysregulation, secretory diarrhea, polyendocrinopathy which includes diabtes type 1, thyroiditis, growth hormone deficiency and hypoadrenalism. It is associated with pancreatic beta cell destruction.However no sufficient evidence is found to ascertain the role of this particular variant rs2066044949, yet.
Comment:
This variant was reported to be maternally inherited in multiple patients with clinical features of IPEX (PMID: 18931102, 27167055, 28289675, 24982679, 23771172, 28488220, 25911531, 30951839, 30443250). This variant appears to have occurred de novo in one mother of an affected patient (PMID: 28289675). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Computational tools yielded predictions that this amino acid change may be damaging to the protein. This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individuals with clinical features of IPEX syndrome (PMID: 18931102, 30443250, 24982679, 25911531, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 337 of the FOXP3 protein (p.Arg337Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine.
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:
This variant has been previously reported as a hemizygous change in patients with Immunodysregulation, Polyendocrinopathy, and Enteropathy, X-Linked (IPEX) Syndrome (PMID: 18931102, 24982679, 28289675, 29241729, 30443250). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.1010G>A (p.Arg337Gln) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1010G>A (p.Arg337Gln) variant is classified as Pathogenic.
Comment:
Variant summary: FOXP3 c.1010G>A (p.Arg337Gln) results in a conservative amino acid change located in the Fork head domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 180275 control chromosomes. c.1010G>A has been reported in the literature in individuals affected with Insulin-Dependent Diabetes Mellitus Secretory Diarrhea Syndrome. These data indicate that the variant may be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Potent mutations in FOXP3 gene are associated with a rare X linked condition called IPEX. It presents with immune dysregulation, secretory diarrhea, polyendocrinopathy which includes diabtes type 1, thyroiditis, growth hormone deficiency and hypoadrenalism. It is associated with pancreatic beta cell destruction.However no sufficient evidence is found to ascertain the role of this particular variant rs2066044949, yet.
Comment:
This variant was reported to be maternally inherited in multiple patients with clinical features of IPEX (PMID: 18931102, 27167055, 28289675, 24982679, 23771172, 28488220, 25911531, 30951839, 30443250). This variant appears to have occurred de novo in one mother of an affected patient (PMID: 28289675). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Computational tools yielded predictions that this amino acid change may be damaging to the protein. This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individuals with clinical features of IPEX syndrome (PMID: 18931102, 30443250, 24982679, 25911531, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 337 of the FOXP3 protein (p.Arg337Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| A Structure-Guided Delineation of FOXP3 Regulation Mechanism in IPEX. | Ma T | Advances in experimental medicine and biology | 2021 | PMID: 33523441 |
| Clinical and genetic analysis in a Chinese cohort of children and adolescents with diabetes/persistent hyperglycemia. | Ding Y | Journal of diabetes investigation | 2021 | PMID: 32531870 |
| IPEX as a Consequence of Alternatively Spliced FOXP3. | Mailer RK | Frontiers in pediatrics | 2020 | PMID: 33194927 |
| 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 |
| FOXP3 mutations causing early-onset insulin-requiring diabetes but without other features of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. | Hwang JL | Pediatric diabetes | 2018 | PMID: 29193502 |
| Humoral Immunodeficiency with Hypotonia, Feeding Difficulties, Enteropathy, and Mild Eczema Caused by a Classical FOXP3 Mutation. | Tuijnenburg P | Frontiers in pediatrics | 2017 | PMID: 28289675 |
| Clinical, Genetic, and Biochemical Characteristics of Early-Onset Diabetes in the Finnish Population. | Huopio H | The Journal of clinical endocrinology and metabolism | 2016 | PMID: 27167055 |
| Renal involvement in the immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) disorder. | Sheikine Y | Pediatric nephrology (Berlin, Germany) | 2015 | PMID: 25911531 |
| Clinical Case of Immune Dysregulation, Polyendocrinopaty, Enteropathy, X-Linked (IPEX) Syndrome with Severe Immune Deficiency and Late Onset of Endocrinopathy and Enteropathy. | Savova R | Case reports in medicine | 2014 | PMID: 24982679 |
| FOXP3: genetic and epigenetic implications for autoimmunity. | Katoh H | Journal of autoimmunity | 2013 | PMID: 23313429 |
| Clinical heterogeneity in patients with FOXP3 mutations presenting with permanent neonatal diabetes. | Rubio-Cabezas O | Diabetes care | 2009 | PMID: 18931102 |
| The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. | Bennett CL | Nature genetics | 2001 | PMID: 11137993 |
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Text-mined citations for rs2066044949 ...
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.