The c.1540C>T;p.(Arg514Cys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 217265; PMID: 26647308) - PS4.The variant is located in a mutational hot spot and/or critical and well-established functional domain (Forkhead domain) - PM1. This variant is not present in population databases (rs869025203, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (PMID: 28741757 - c.1541G>A (p.Arg514His) - ) - .PM5. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
ClinVar Genomic variation as it relates to human health
NM_001349338.3(FOXP1):c.1540C>T (p.Arg514Cys)
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.
(12)
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
12
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001349338.3(FOXP1):c.1540C>T (p.Arg514Cys)
Variation ID: 217265 Accession: VCV000217265.23
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3p13 3: 70972667 (GRCh38) [ NCBI UCSC ] 3: 71021818 (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 Feb 20, 2016 Oct 20, 2024 Dec 18, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001349338.3:c.1540C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001336267.1:p.Arg514Cys missense NM_001244808.3:c.1537C>T NP_001231737.1:p.Arg513Cys missense NM_001244810.2:c.1531-487C>T intron variant NM_001244812.3:c.1312C>T NP_001231741.1:p.Arg438Cys missense NM_001244813.3:c.1240C>T NP_001231742.1:p.Arg414Cys missense NM_001244814.3:c.1540C>T NP_001231743.1:p.Arg514Cys missense NM_001244815.2:c.1240C>T NP_001231744.2:p.Arg414Cys missense NM_001244816.2:c.1540C>T NP_001231745.1:p.Arg514Cys missense NM_001349337.2:c.1237C>T NP_001336266.2:p.Arg413Cys missense NM_001349340.3:c.1540C>T NP_001336269.1:p.Arg514Cys missense NM_001349341.3:c.1537C>T NP_001336270.1:p.Arg513Cys missense NM_001349342.3:c.1240C>T NP_001336271.1:p.Arg414Cys missense NM_001349343.3:c.1237C>T NP_001336272.1:p.Arg413Cys missense NM_001349344.3:c.1237C>T NP_001336273.1:p.Arg413Cys missense NM_001370548.1:c.1237C>T NP_001357477.1:p.Arg413Cys missense NM_032682.6:c.1540C>T NP_116071.2:p.Arg514Cys missense NR_146142.3:n.2056C>T non-coding transcript variant NR_146143.3:n.2053C>T non-coding transcript variant NC_000003.12:g.70972667G>A NC_000003.11:g.71021818G>A NG_028243.1:g.616323C>T Q9H334:p.Arg514Cys - Protein change
- R514C, R413C, R414C, R438C, R513C
- Other names
- -
- Canonical SPDI
- NC_000003.12:70972666: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.
- -
-
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. |
|||
| FOXP1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
840 | 919 | |
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 (4) |
criteria provided, multiple submitters, no conflicts
|
Jan 5, 2022 | RCV000207490.10 | |
| Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Dec 18, 2023 | RCV001267938.13 | |
|
FOXP1-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
Jan 6, 2023 | RCV003417726.4 |
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INTELLECTUAL DEVELOPMENTAL DISORDER WITH LANGUAGE IMPAIRMENT AND AUTISTIC FEATURES
|
Pathogenic (1) |
no assertion criteria provided
|
Oct 16, 2024 | RCV004701260.2 |
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
(Jan 01, 2015)
|
criteria provided, single submitter
Method: clinical testing, in vitro
|
Mental retardation with language impairment and with or without autistic features
Affected status: yes, not applicable
Allele origin:
de novo,
not applicable
|
Language and Genetics Department, Max Planck Institute for Psycholinguistics
Accession: SCV000246200.1
First in ClinVar: Feb 20, 2016 Last updated: Feb 20, 2016 |
Observation 1:
Number of individuals with the variant: 1
Zygosity: Single Heterozygote
Sex: male
Geographic origin: Netherlands
Observation 2:
Method: fluorescence microscopy
Result:
disrupts cellular localization; disrupts transcriptional repression activity
|
|
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Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446455.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Delayed speech and language development (present) , Hyperactivity (present) , Global developmental delay (present) , Dysphagia (present) , Trigonocephaly (present)
Sex: male
|
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Pathogenic
(Jan 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Intellectual disability-severe speech delay-mild dysmorphism syndrome
Affected status: yes
Allele origin:
germline
|
DASA
Accession: SCV002061152.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
Comment:
The c.1540C>T;p.(Arg514Cys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 217265; PMID: 26647308) - PS4.The … (more)
The c.1540C>T;p.(Arg514Cys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 217265; PMID: 26647308) - PS4.The variant is located in a mutational hot spot and/or critical and well-established functional domain (Forkhead domain) - PM1. This variant is not present in population databases (rs869025203, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (PMID: 28741757 - c.1541G>A (p.Arg514His) - ) - .PM5. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. (less)
Number of individuals with the variant: 1
Sex: female
Geographic origin: Brazil
|
|
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Pathogenic
(Dec 29, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002051538.2
First in ClinVar: Jan 08, 2022 Last updated: Feb 11, 2022 |
Comment:
PS3, PM2, PM6, PS4_Moderate
|
|
|
Pathogenic
(May 06, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Intellectual disability-severe speech delay-mild dysmorphism syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767206.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with intellectual disability with language impairment and with or without autistic features (MIM#613670). Loss of function leading to haploinsufficiency has been demonstrated, however some variants have also been shown to bind to wild type FOXP1 and affect wild type function and localisation (PMID: 26647308). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional forkhead domain. Moreover, the affected residue is a DNA binding site (Decipher; NCBI conserved domain). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.(Arg514His) variant is de novo in three unrelated individuals with mild to severe intellectual disability (PMID: 28741757). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is de novo in two individuals with intellectual disability (ClinVar, PMID: 26647308). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Mutant constructs transfected into HEK293T cells resulted in reduced protein expression with subsequent mis-localisation and reduced transcriptional repression ability of the protein (PMID: 26647308). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Jan 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV003194978.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated … (more)
Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26647308, 31199603, 28741757, 34109629, 31981491) (less)
|
|
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Pathogenic
(Jan 06, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
FOXP1-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004106266.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The FOXP1 c.1540C>T variant is predicted to result in the amino acid substitution p.Arg514Cys. This variant has been reported de novo in individuals with global … (more)
The FOXP1 c.1540C>T variant is predicted to result in the amino acid substitution p.Arg514Cys. This variant has been reported de novo in individuals with global developmental disorder, intellectual disability, and/or speech and language delay (Sollis et al. 2015. PubMed ID: 26647308; Braden et al. 2021. PubMed ID: 34109629). Function studies have shown that this variant impacts protein function (Sollis et al. 2015. PubMed ID: 26647308; Estruch et al. 2018. PMID: 29365100). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare, and is interpreted as pathogenic in ClinVar by several laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/217265/). This variant is interpreted as pathogenic. (less)
|
|
|
Pathogenic
(Dec 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003525557.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 514 of the FOXP1 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 514 of the FOXP1 protein (p.Arg514Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with intellectual disability syndrome (PMID: 26647308). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 217265). 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 FOXP1 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg514 amino acid residue in FOXP1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28741757). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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|
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Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001808292.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021 |
|
|
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Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001952578.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(Oct 16, 2024)
|
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
|
OMIM
Accession: SCV000502987.6
First in ClinVar: Feb 20, 2016 Last updated: Oct 20, 2024 |
Comment on evidence:
In a 7-year-old Dutch boy (patient 2) with intellectual developmental disorder with language impairment and pervasive developmental disorder (IDDLA; 613670), Sollis et al. (2016) identified … (more)
In a 7-year-old Dutch boy (patient 2) with intellectual developmental disorder with language impairment and pervasive developmental disorder (IDDLA; 613670), Sollis et al. (2016) identified a de novo heterozygous c.1540C-T transition (chr3.71,021,818C-T, GRCh37) in the FOXP1 gene, resulting in an arg514-to-cys (R514C) substitution at a conserved residue in the DNA-binding domain. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. In vitro cellular expression studies showed that the mutant protein had abnormal localization and formed cytoplasmic and nuclear aggregates. Luciferase reporter assays showed that the mutant protein had a significant loss of repressive activity, suggesting it would be unable to properly regulate transcription of target genes. The R514C variant retained the ability to interact with wildtype FOXP1 and FOXP2 (605317) and led to mislocalization of the wildtype proteins in nuclear aggregates, suggesting a possible dominant-negative effect. (less)
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Likely pathogenic
(Nov 02, 2023)
|
no assertion criteria provided
Method: clinical testing
|
Intellectual disability-severe speech delay-mild dysmorphism syndrome
Affected status: yes
Allele origin:
germline
|
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas
Accession: SCV004101077.1
First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023 |
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Comment:
Comment:
PS3, PM2, PM6, PS4_Moderate
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with intellectual disability with language impairment and with or without autistic features (MIM#613670). Loss of function leading to haploinsufficiency has been demonstrated, however some variants have also been shown to bind to wild type FOXP1 and affect wild type function and localisation (PMID: 26647308). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional forkhead domain. Moreover, the affected residue is a DNA binding site (Decipher; NCBI conserved domain). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.(Arg514His) variant is de novo in three unrelated individuals with mild to severe intellectual disability (PMID: 28741757). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is de novo in two individuals with intellectual disability (ClinVar, PMID: 26647308). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Mutant constructs transfected into HEK293T cells resulted in reduced protein expression with subsequent mis-localisation and reduced transcriptional repression ability of the protein (PMID: 26647308). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26647308, 31199603, 28741757, 34109629, 31981491)
Comment:
The FOXP1 c.1540C>T variant is predicted to result in the amino acid substitution p.Arg514Cys. This variant has been reported de novo in individuals with global developmental disorder, intellectual disability, and/or speech and language delay (Sollis et al. 2015. PubMed ID: 26647308; Braden et al. 2021. PubMed ID: 34109629). Function studies have shown that this variant impacts protein function (Sollis et al. 2015. PubMed ID: 26647308; Estruch et al. 2018. PMID: 29365100). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare, and is interpreted as pathogenic in ClinVar by several laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/217265/). This variant is interpreted as pathogenic.
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 514 of the FOXP1 protein (p.Arg514Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with intellectual disability syndrome (PMID: 26647308). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 217265). 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 FOXP1 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg514 amino acid residue in FOXP1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28741757). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
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 c.1540C>T;p.(Arg514Cys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 217265; PMID: 26647308) - PS4.The variant is located in a mutational hot spot and/or critical and well-established functional domain (Forkhead domain) - PM1. This variant is not present in population databases (rs869025203, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (PMID: 28741757 - c.1541G>A (p.Arg514His) - ) - .PM5. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
Comment:
PS3, PM2, PM6, PS4_Moderate
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with intellectual disability with language impairment and with or without autistic features (MIM#613670). Loss of function leading to haploinsufficiency has been demonstrated, however some variants have also been shown to bind to wild type FOXP1 and affect wild type function and localisation (PMID: 26647308). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional forkhead domain. Moreover, the affected residue is a DNA binding site (Decipher; NCBI conserved domain). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The p.(Arg514His) variant is de novo in three unrelated individuals with mild to severe intellectual disability (PMID: 28741757). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is de novo in two individuals with intellectual disability (ClinVar, PMID: 26647308). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Mutant constructs transfected into HEK293T cells resulted in reduced protein expression with subsequent mis-localisation and reduced transcriptional repression ability of the protein (PMID: 26647308). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26647308, 31199603, 28741757, 34109629, 31981491)
Comment:
The FOXP1 c.1540C>T variant is predicted to result in the amino acid substitution p.Arg514Cys. This variant has been reported de novo in individuals with global developmental disorder, intellectual disability, and/or speech and language delay (Sollis et al. 2015. PubMed ID: 26647308; Braden et al. 2021. PubMed ID: 34109629). Function studies have shown that this variant impacts protein function (Sollis et al. 2015. PubMed ID: 26647308; Estruch et al. 2018. PMID: 29365100). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare, and is interpreted as pathogenic in ClinVar by several laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/217265/). This variant is interpreted as pathogenic.
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 514 of the FOXP1 protein (p.Arg514Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with intellectual disability syndrome (PMID: 26647308). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 217265). 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 FOXP1 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg514 amino acid residue in FOXP1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28741757). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Targeted next generation sequencing in Italian patients with Usher syndrome: phenotype-genotype correlations. | Eandi CM | Scientific reports | 2017 | PMID: 29142287 |
| Equivalent missense variant in the FOXP2 and FOXP1 transcription factors causes distinct neurodevelopmental disorders. | Sollis E | Human mutation | 2017 | PMID: 28741757 |
| Usher's Syndrome Type II: A Comparative Study of Genetic Mutations and Vestibular System Evaluation. | Magliulo G | Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery | 2017 | PMID: 28653555 |
| 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 |
| Usher syndrome: an effective sequencing approach to establish a genetic and clinical diagnosis. | Lenarduzzi S | Hearing research | 2015 | PMID: 25575603 |
| Experience of targeted Usher exome sequencing as a clinical test. | Besnard T | Molecular genetics & genomic medicine | 2014 | PMID: 24498627 |
| Molecular and in silico analyses of the full-length isoform of usherin identify new pathogenic alleles in Usher type II patients. | Baux D | Human mutation | 2007 | PMID: 17405132 |
Text-mined citations for rs869025203 ...
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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 27, 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.