ClinVar Genomic variation as it relates to human health
NM_001349338.3(FOXP1):c.1574G>A (p.Arg525Gln)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001349338.3(FOXP1):c.1574G>A (p.Arg525Gln)
Variation ID: 521111 Accession: VCV000521111.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p13 3: 70972633 (GRCh38) [ NCBI UCSC ] 3: 71021784 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 15, 2018 Apr 15, 2024 Sep 12, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001349338.3:c.1574G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001336267.1:p.Arg525Gln missense NM_001244808.3:c.1571G>A NP_001231737.1:p.Arg524Gln missense NM_001244810.2:c.1531-453G>A intron variant NM_001244812.3:c.1346G>A NP_001231741.1:p.Arg449Gln missense NM_001244813.3:c.1274G>A NP_001231742.1:p.Arg425Gln missense NM_001244814.3:c.1574G>A NP_001231743.1:p.Arg525Gln missense NM_001244815.2:c.1274G>A NP_001231744.2:p.Arg425Gln missense NM_001244816.2:c.1574G>A NP_001231745.1:p.Arg525Gln missense NM_001349337.2:c.1271G>A NP_001336266.2:p.Arg424Gln missense NM_001349340.3:c.1574G>A NP_001336269.1:p.Arg525Gln missense NM_001349341.3:c.1571G>A NP_001336270.1:p.Arg524Gln missense NM_001349342.3:c.1274G>A NP_001336271.1:p.Arg425Gln missense NM_001349343.3:c.1271G>A NP_001336272.1:p.Arg424Gln missense NM_001349344.3:c.1271G>A NP_001336273.1:p.Arg424Gln missense NM_001370548.1:c.1271G>A NP_001357477.1:p.Arg424Gln missense NM_032682.6:c.1574G>A NP_116071.2:p.Arg525Gln missense NR_146142.3:n.2090G>A non-coding transcript variant NR_146143.3:n.2087G>A non-coding transcript variant NC_000003.12:g.70972633C>T NC_000003.11:g.71021784C>T NG_028243.1:g.616357G>A - Protein change
- R525Q, R524Q, R424Q, R449Q, R425Q
- Other names
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- Canonical SPDI
- NC_000003.12:70972632:C:T
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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
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
807 | 884 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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 (1) |
criteria provided, single submitter
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Jun 6, 2016 | RCV000624175.3 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Aug 4, 2022 | RCV000679989.7 | |
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Sep 12, 2022 | RCV001573746.9 |
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
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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
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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
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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
(Aug 11, 2020)
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criteria provided, single submitter
Method: clinical testing
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MENTAL RETARDATION WITH LANGUAGE IMPAIRMENT AND AUTISTIC FEATURES
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001431899.1
First in ClinVar: Sep 14, 2020 Last updated: Sep 14, 2020 |
Comment:
Variant summary: FOXP1 c.1574G>A (p.Arg525Gln) results in a conservative amino acid change located in the Fork Head domain (IPR001766) of the encoded protein sequence. Four … (more)
Variant summary: FOXP1 c.1574G>A (p.Arg525Gln) results in a conservative amino acid change located in the Fork Head domain (IPR001766) 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 251486 control chromosomes. c.1574G>A has been reported in the literature in three patients who all presented with global developmental delay, autism spectrum disorder, and characteristic dysmorphic features, with other phenotypic features being unique to particular patients (Bekheirnia_2017, Myers_2017, Johnson_2018). Two of these patients had confirmed de novo inheritance of the variant, while one was missing maternal sample, however paternal and unaffected full siblings samples were negative for the variant. A functional study reported that despite normal nuclear localization of the variant protein in vitro, the ability to transcriptionally repress the SV40 promoter was severely diminished compared to wild-type (Johnson_2018). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Sep 15, 2021)
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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: SCV001905601.1
First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021 |
Clinical Features:
Strabismus (present) , Delayed speech and language development (present) , Intellectual disability, mild (present) , Global developmental delay (present) , Nocturnal enuresis (present)
Sex: female
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Pathogenic
(Jun 06, 2016)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000741551.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Intellectual disability (present) , Expressive language delay (present) , Short stature (present) , Heart murmur (present) , Delayed puberty (present) , Microcephaly (present) , Narrow … (more)
Intellectual disability (present) , Expressive language delay (present) , Short stature (present) , Heart murmur (present) , Delayed puberty (present) , Microcephaly (present) , Narrow forehead (present) , Abnormal hair whorl (present) , Highly arched eyebrow (present) , Synophrys (present) , Blepharophimosis (present) , Slender nose (present) , Underdeveloped nasal alae (present) , Smooth philtrum (present) , Thin upper lip vermilion (present) , Dental crowding (present) , Short nail (present) , Failure to thrive (present) , Behavioral abnormality (present) , Self-injurious behavior (present) , Frontal upsweep of hair (present) , Long palpebral fissure (present) , Prominence of the zygomatic bone (present) , Small earlobe (present) , Decreased testosterone in males (present) (less)
Sex: male
Ethnicity/Population group: Caucasian
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Pathogenic
(Dec 30, 2021)
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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: SCV002050436.2
First in ClinVar: Jan 08, 2022 Last updated: Mar 04, 2023 |
Comment:
Published functional studies suggest a damaging effect (loss of DNA-binding ability) (Johnson et al., 2018); Not observed in large population cohorts (Lek et al., 2016); … (more)
Published functional studies suggest a damaging effect (loss of DNA-binding ability) (Johnson et al., 2018); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25326635, 28884888, 27657687, 30385778) (less)
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Pathogenic
(-)
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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:
unknown
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Baylor Genetics
Accession: SCV000807426.3
First in ClinVar: Sep 17, 2018 Last updated: Mar 18, 2023 |
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Pathogenic
(Sep 12, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003525338.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects FOXP1 function (PMID: 30385778). Advanced modeling … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects FOXP1 function (PMID: 30385778). 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. ClinVar contains an entry for this variant (Variation ID: 521111). This missense change has been observed in individual(s) with clinical features of FOXP1-related conditions (PMID: 27657687, 30385778). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 525 of the FOXP1 protein (p.Arg525Gln). (less)
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Pathogenic
(Aug 04, 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: yes
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812418.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
This sequence change in FOXP1 is predicted to replace arginine with glutamine at codon 525, p.(Arg525Gln). The arginine residue is highly conserved (100 vertebrates, UCSC), … (more)
This sequence change in FOXP1 is predicted to replace arginine with glutamine at codon 525, p.(Arg525Gln). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in Fork-head DNA-binding domain a region, amino acids 465-555, that is defined as a mutational hotspot and critical functional domain (PMID: 31199603). There is a small physicochemical difference between arginine and glutamine. This variant is absent from gnomAD v2.1 and v3.1. This variant has been identified as a de novo occurrence with confirmed parental relationships in one individual and as a de novo occurrence with unconfirmed parental relationships in two individuals with syndromic intellectual disability (PMID: 27657687, 30385778; DECIPHER). This variant has also been reported in an additional four probands with unknown/unconfirmed de novo status and consistent phenotypes resembling FOXP1 syndrome (PMID: 30385778, 34588003; ClinVar: SCV000741551.2, SCV001905601.1). A luciferase assay in HEK293 cells showed diminished transcriptional repression indicating that this variant impacts protein function (PMID: 30385778). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PS2/PM6_Strong, PM1, PS3_Supporting, PS4_Supporting, PM2_Supporting, PP3. (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001800061.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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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: SCV001951272.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Individuals with FOXP1 syndrome present with a complex neurobehavioral profile with high rates of ADHD, anxiety, repetitive behaviors, and sensory symptoms. | Trelles MP | Molecular autism | 2021 | PMID: 34588003 |
Pathogenic missense mutation pattern of forkhead box genes in neurodevelopmental disorders. | Han L | Molecular genetics & genomic medicine | 2019 | PMID: 31199603 |
Characterization of a recurrent missense mutation in the forkhead DNA-binding domain of FOXP1. | Johnson TB | Scientific reports | 2018 | PMID: 30385778 |
FOXP1 haploinsufficiency: Phenotypes beyond behavior and intellectual disability? | Myers A | American journal of medical genetics. Part A | 2017 | PMID: 28884888 |
Whole-exome sequencing in the molecular diagnosis of individuals with congenital anomalies of the kidney and urinary tract and identification of a new causative gene. | Bekheirnia MR | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 27657687 |
Text-mined citations for rs1553663084 ...
HelpRecord last updated Apr 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.