The in-frame deletion p.K250del in FOXP3 (NM_014009.4) has been observed in multiple affected individuals with IPEX syndrome (Gambineri E et al,Wildin RS et al,Hashimura Y et al). The variant has been submitted to ClinVar as Pathogenic.The p.K250del variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant results in a deletion of a lysine at position 250 of the FOXP3 gene. However, as this is an in-frame deletion, it is not expected to result in either a truncated protein product or loss of protein through nonsense-mediated mRNA decay. The nucleotide c.748 in FOXP3 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_014009.4(FOXP3):c.748_750del (p.Lys250del)
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/Likely 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.748_750del (p.Lys250del)
Variation ID: 499890 Accession: VCV000499890.12
- Type and length
-
Deletion, 3 bp
- Location
-
Cytogenetic: Xp11.23 X: 49255495-49255497 (GRCh38) [ NCBI UCSC ] X: 49111956-49111958 (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 Apr 2, 2018 Feb 14, 2024 Aug 14, 2021 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_014009.4:c.748_750del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_054728.2:p.Lys250del inframe deletion NM_001114377.2:c.643_645del NP_001107849.1:p.Lys215del inframe deletion NM_014009.3:c.748_750delAAG NC_000023.11:g.49255497_49255499del NC_000023.10:g.49111958_49111960del NG_007392.1:g.14331_14333del NG_021311.2:g.25033_25035del LRG_62:g.14331_14333del LRG_62t1:c.748_750del - Protein change
- K250del, K215del
- Other names
- -
- Canonical SPDI
- NC_000023.11:49255494:CTTCT:CT
-
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 |
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. |
|---|---|---|---|---|
| Likely pathogenic (1) |
criteria provided, single submitter
|
Mar 1, 2017 | RCV000595405.4 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Aug 14, 2021 | RCV001380271.12 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Mar 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000705614.2
First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Insulin-dependent diabetes mellitus secretory diarrhea syndrome
(X-linked recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004100522.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
Comment:
The in-frame deletion p.K250del in FOXP3 (NM_014009.4) has been observed in multiple affected individuals with IPEX syndrome (Gambineri E et al,Wildin RS et al,Hashimura Y … (more)
The in-frame deletion p.K250del in FOXP3 (NM_014009.4) has been observed in multiple affected individuals with IPEX syndrome (Gambineri E et al,Wildin RS et al,Hashimura Y et al). The variant has been submitted to ClinVar as Pathogenic.The p.K250del variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant results in a deletion of a lysine at position 250 of the FOXP3 gene. However, as this is an in-frame deletion, it is not expected to result in either a truncated protein product or loss of protein through nonsense-mediated mRNA decay. The nucleotide c.748 in FOXP3 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Anemia (present) , Proteinuria (present) , Hypoalbuminemia (present) , Hypercholesterolemia (present) , Nephrotic syndrome (present) , Hemolytic anemia (present) , Venous thrombosis (present)
|
|
|
Pathogenic
(Aug 14, 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: SCV001578271.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect FOXP3 protein function (PMID: 16920951, 17586580). This variant … (more)
For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect FOXP3 protein function (PMID: 16920951, 17586580). This variant has been observed in individual(s) with clinical features of immunodysregulation, polyendocrinopathy, and enteropathy (IPEX) syndrome (PMID: 29907148, 19189134, 12161590, 30443250, Invitae). This variant is also known as delE251. ClinVar contains an entry for this variant (Variation ID: 499890). This variant is not present in population databases (ExAC no frequency). This variant, c.748_750del, results in the deletion of 1 amino acid(s) of the FOXP3 protein (p.Lys250del), but otherwise preserves the integrity of the reading frame. (less)
|
|
|
Likely benign
(-)
|
Flagged submission
flagged submission
(K & H Uppaluri Personalized Medicine Clinic Variant Classification & Assertion Criteria_Updated V.1)
Method: research
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
|
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: SCV002605326.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 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 rs1557116163, yet. (less)
|
|
| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect FOXP3 protein function (PMID: 16920951, 17586580). This variant has been observed in individual(s) with clinical features of immunodysregulation, polyendocrinopathy, and enteropathy (IPEX) syndrome (PMID: 29907148, 19189134, 12161590, 30443250, Invitae). This variant is also known as delE251. ClinVar contains an entry for this variant (Variation ID: 499890). This variant is not present in population databases (ExAC no frequency). This variant, c.748_750del, results in the deletion of 1 amino acid(s) of the FOXP3 protein (p.Lys250del), but otherwise preserves the integrity of the reading frame.
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 rs1557116163, yet.
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:
The in-frame deletion p.K250del in FOXP3 (NM_014009.4) has been observed in multiple affected individuals with IPEX syndrome (Gambineri E et al,Wildin RS et al,Hashimura Y et al). The variant has been submitted to ClinVar as Pathogenic.The p.K250del variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant results in a deletion of a lysine at position 250 of the FOXP3 gene. However, as this is an in-frame deletion, it is not expected to result in either a truncated protein product or loss of protein through nonsense-mediated mRNA decay. The nucleotide c.748 in FOXP3 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect FOXP3 protein function (PMID: 16920951, 17586580). This variant has been observed in individual(s) with clinical features of immunodysregulation, polyendocrinopathy, and enteropathy (IPEX) syndrome (PMID: 29907148, 19189134, 12161590, 30443250, Invitae). This variant is also known as delE251. ClinVar contains an entry for this variant (Variation ID: 499890). This variant is not present in population databases (ExAC no frequency). This variant, c.748_750del, results in the deletion of 1 amino acid(s) of the FOXP3 protein (p.Lys250del), but otherwise preserves the integrity of the reading frame.
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 rs1557116163, yet.
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 |
| 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 |
| A case of Metaplastic atrophic gastritis in immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) syndrome. | Luo Y | BMC pediatrics | 2018 | PMID: 29907148 |
| 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 |
| FOXP3: genetic and epigenetic implications for autoimmunity. | Katoh H | Journal of autoimmunity | 2013 | PMID: 23313429 |
| Minimal change nephrotic syndrome associated with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. | Hashimura Y | Pediatric nephrology (Berlin, Germany) | 2009 | PMID: 19189134 |
| FOXP3 is a homo-oligomer and a component of a supramolecular regulatory complex disabled in the human XLAAD/IPEX autoimmune disease. | Li B | International immunology | 2007 | PMID: 17586580 |
| 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 |
| Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. | Wildin RS | Journal of medical genetics | 2002 | PMID: 12161590 |
| The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. | Bennett CL | Nature genetics | 2001 | PMID: 11137993 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FOXP3 | - | - | - | - |
| click to load more click to collapse | ||||
Text-mined citations for rs1557116163 ...
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.