This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS3,PM4,PM2,PP3. This variant arose de novo in at least one reported proband.
ClinVar Genomic variation as it relates to human health
NM_001349338.3(FOXP1):c.1573C>T (p.Arg525Ter)
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
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NM_001349338.3(FOXP1):c.1573C>T (p.Arg525Ter)
Variation ID: 18428 Accession: VCV000018428.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p13 3: 70972634 (GRCh38) [ NCBI UCSC ] 3: 71021785 (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 Feb 19, 2017 Oct 20, 2024 Apr 7, 2022 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001349338.3:c.1573C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001336267.1:p.Arg525Ter nonsense NM_001244808.3:c.1570C>T NP_001231737.1:p.Arg524Ter nonsense NM_001244810.2:c.1531-454C>T intron variant NM_001244812.3:c.1345C>T NP_001231741.1:p.Arg449Ter nonsense NM_001244813.3:c.1273C>T NP_001231742.1:p.Arg425Ter nonsense NM_001244814.3:c.1573C>T NP_001231743.1:p.Arg525Ter nonsense NM_001244815.2:c.1273C>T NP_001231744.2:p.Arg425Ter nonsense NM_001244816.2:c.1573C>T NP_001231745.1:p.Arg525Ter nonsense NM_001349337.2:c.1270C>T NP_001336266.2:p.Arg424Ter nonsense NM_001349340.3:c.1573C>T NP_001336269.1:p.Arg525Ter nonsense NM_001349341.3:c.1570C>T NP_001336270.1:p.Arg524Ter nonsense NM_001349342.3:c.1273C>T NP_001336271.1:p.Arg425Ter nonsense NM_001349343.3:c.1270C>T NP_001336272.1:p.Arg424Ter nonsense NM_001349344.3:c.1270C>T NP_001336273.1:p.Arg424Ter nonsense NM_001370548.1:c.1270C>T NP_001357477.1:p.Arg424Ter nonsense NM_032682.6:c.1573C>T NP_116071.2:p.Arg525Ter nonsense NR_146142.3:n.2089C>T non-coding transcript variant NR_146143.3:n.2086C>T non-coding transcript variant NC_000003.12:g.70972634G>A NC_000003.11:g.71021785G>A NG_028243.1:g.616356C>T - Protein change
- R525*, R424*, R425*, R524*, R449*
- Other names
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- Canonical SPDI
- NC_000003.12:70972633: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 | ||
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| 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. |
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| FOXP1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
837 | 915 | |
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 (4) |
criteria provided, multiple submitters, no conflicts
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Apr 7, 2022 | RCV000005214.12 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 2, 2022 | RCV000760393.6 | |
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INTELLECTUAL DEVELOPMENTAL DISORDER WITH LANGUAGE IMPAIRMENT AND AUTISTIC FEATURES
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Pathogenic (1) |
no assertion criteria provided
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Nov 12, 2010 | RCV003761738.6 |
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
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447011.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Delayed speech and language development (present) , Hypotonia (present) , Global developmental delay (present) , Oral motor hypotonia (present)
Sex: male
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Pathogenic
(Jan 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability-severe speech delay-mild dysmorphism syndrome
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001367889.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS3,PM4,PM2,PP3. This variant arose de novo in at least … (more)
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS3,PM4,PM2,PP3. This variant arose de novo in at least one reported proband. (less)
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Pathogenic
(Apr 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability-severe speech delay-mild dysmorphism syndrome
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003824521.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Feb 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability-severe speech delay-mild dysmorphism syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557600.2
First in ClinVar: Aug 08, 2022 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with FOXP1-related intellectual disability syndrome (MIM#613670). Dominant negative is also a suggested mechanism of disease. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been well reported as pathogenic, and observed in individuals with FOXP1-related intellectual disability syndrome (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic, and observed in many individuals with FOXP1-related intellectual disability syndrome, where the variant was proven to be de novo (ClinVar, DECIPHER, PMID: 28735298). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Jul 09, 2017)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability-severe speech delay-mild dysmorphism syndrome
Affected status: yes
Allele origin:
de novo
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Genetic Diagnostic Laboratory, University of Szeged
Accession: SCV000583530.1
First in ClinVar: Feb 19, 2017 Last updated: Feb 19, 2017 |
Number of individuals with the variant: 1
Clinical Features:
Megalencephaly (present) , Profound global developmental delay (present) , Intellectual disability, severe (present) , Prominent forehead (present) , Frontal upsweep of hair (present) , Wide … (more)
Megalencephaly (present) , Profound global developmental delay (present) , Intellectual disability, severe (present) , Prominent forehead (present) , Frontal upsweep of hair (present) , Wide nasal bridge (present) , Low-set ears (present) , Abnormality of skin adnexa morphology (present) , Partial agenesis of the corpus callosum (present) , Cavum septum pellucidum (present) (less)
Family history: yes
Age: 0-9 years
Sex: female
Ethnicity/Population group: Hungarian
Geographic origin: Hungary
Segregation observed: yes
Method: TruSight One Clinical exome sequencing kit
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Pathogenic
(Mar 02, 2022)
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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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GeneDx
Accession: SCV000890265.3
First in ClinVar: Mar 19, 2019 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense-mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed … (more)
Nonsense variant predicted to result in protein truncation or nonsense-mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31785789, 33218123, 25525159, 26647308, 28735298, 30385778, 20950788, 28135719, 30181650) (less)
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Pathogenic
(Nov 12, 2010)
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no assertion criteria provided
Method: literature only
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INTELLECTUAL DEVELOPMENTAL DISORDER WITH LANGUAGE IMPAIRMENT AND AUTISTIC FEATURES
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000025392.6
First in ClinVar: Apr 04, 2013 Last updated: Oct 20, 2024 |
Comment on evidence:
In a French Canadian boy (patient B, R0024121) with intellectual developmental disorder with language impairment and autistic features (IDDLA; 613670), Hamdan et al. (2010) identified … (more)
In a French Canadian boy (patient B, R0024121) with intellectual developmental disorder with language impairment and autistic features (IDDLA; 613670), Hamdan et al. (2010) identified a de novo heterozygous 1573C-T transition in the FOXP1 gene, resulting in an arg525-to-ter (R525X) substitution. The mutation was predicted to abolish the last 152 residues of the protein, including part of the forkhead DNA-binding (FHD) domain and a conserved nuclear localization signal. The mutation was not found in 570 controls. In vitro functional expression studies in HEK293 cells showed that the R525X mutant impaired the transcriptional repression ability of FOXP1, consistent with a loss of function. Sollis et al. (2016) showed that the R525X mutant protein formed large cytoplasmic aggregates and was excluded from the nuclei in cellular transfection studies; these findings suggested misfolding of the aberrant protein. The R525X variant showed a complete loss of interaction with wildtype FOXP1 and FOXP2 (605317) and was unable to self-associate, suggesting haploinsufficiency as the pathogenic mechanism. (less)
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Comment:
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with FOXP1-related intellectual disability syndrome (MIM#613670). Dominant negative is also a suggested mechanism of disease. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been well reported as pathogenic, and observed in individuals with FOXP1-related intellectual disability syndrome (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic, and observed in many individuals with FOXP1-related intellectual disability syndrome, where the variant was proven to be de novo (ClinVar, DECIPHER, PMID: 28735298). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
Nonsense variant predicted to result in protein truncation or nonsense-mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31785789, 33218123, 25525159, 26647308, 28735298, 30385778, 20950788, 28135719, 30181650)
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 was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS3,PM4,PM2,PP3. This variant arose de novo in at least one reported proband.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with FOXP1-related intellectual disability syndrome (MIM#613670). Dominant negative is also a suggested mechanism of disease. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been well reported as pathogenic, and observed in individuals with FOXP1-related intellectual disability syndrome (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic, and observed in many individuals with FOXP1-related intellectual disability syndrome, where the variant was proven to be de novo (ClinVar, DECIPHER, PMID: 28735298). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
Nonsense variant predicted to result in protein truncation or nonsense-mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31785789, 33218123, 25525159, 26647308, 28735298, 30385778, 20950788, 28135719, 30181650)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| FOXP1-related intellectual disability syndrome: a recognisable entity. | Meerschaut I | Journal of medical genetics | 2017 | PMID: 28735298 |
| Identification and functional characterization of de novo FOXP1 variants provides novel insights into the etiology of neurodevelopmental disorder. | Sollis E | Human molecular genetics | 2016 | PMID: 26647308 |
| De novo mutations in FOXP1 in cases with intellectual disability, autism, and language impairment. | Hamdan FF | American journal of human genetics | 2010 | PMID: 20950788 |
Text-mined citations for rs112795301 ...
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.