Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 15 of 21). (P) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Multiple variants predicted to result in NMD have been reported pathogenic (ClinVar, Decipher). (P) 0807 - Variant has not previously been reported in a clinical context. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
ClinVar Genomic variation as it relates to human health
NM_001349338.3(FOXP1):c.1241del (p.Leu414fs)
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
4
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.1241del (p.Leu414fs)
Variation ID: 1805564 Accession: VCV001805564.6
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 3p13 3: 70977935 (GRCh38) [ NCBI UCSC ] 3: 71027086 (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 Dec 24, 2022 Oct 8, 2024 Oct 19, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001349338.3:c.1241del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001336267.1:p.Leu414fs frameshift NM_001244808.3:c.1241del NP_001231737.1:p.Leu414fs frameshift NM_001244810.2:c.1241del NP_001231739.1:p.Leu414fs frameshift NM_001244812.3:c.1013del NP_001231741.1:p.Leu338fs frameshift NM_001244813.3:c.941del NP_001231742.1:p.Leu314fs frameshift NM_001244814.3:c.1241del NP_001231743.1:p.Leu414fs frameshift NM_001244815.2:c.941del NP_001231744.2:p.Leu314fs frameshift NM_001244816.2:c.1241del NP_001231745.1:p.Leu414fs frameshift NM_001349337.2:c.938del NP_001336266.2:p.Leu313fs frameshift NM_001349339.1:c.1241delT NP_001336268.1:p.Leu414Argfs frameshift NM_001349340.3:c.1241del NP_001336269.1:p.Leu414fs frameshift NM_001349341.3:c.1238del NP_001336270.1:p.Leu413fs frameshift NM_001349342.3:c.941del NP_001336271.1:p.Leu314fs frameshift NM_001349343.3:c.938del NP_001336272.1:p.Leu313fs frameshift NM_001349344.3:c.938del NP_001336273.1:p.Leu313fs frameshift NM_001370548.1:c.941del NP_001357477.1:p.Leu314fs frameshift NM_032682.5:c.1241del NM_032682.5:c.1241delT NM_032682.6:c.1241del NP_116071.2:p.Leu414fs frameshift NR_146142.3:n.1757del non-coding transcript variant NR_146143.3:n.1754del non-coding transcript variant NC_000003.12:g.70977935del NC_000003.11:g.71027086del NG_028243.1:g.611055del - Protein change
- L313fs, L314fs, L338fs, L413fs, L414fs
- Other names
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- Canonical SPDI
- NC_000003.12:70977934: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 | ||
|---|---|---|---|---|---|---|
| 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 |
841 | 920 | |
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 (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 19, 2023 | RCV002571475.5 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 25, 2020 | RCV002471982.2 | |
|
FOXP1-related disorder
|
Pathogenic (1) |
no assertion criteria provided
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Dec 18, 2023 | RCV003943412.2 |
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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|---|---|---|---|---|---|
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Pathogenic
(May 25, 2020)
|
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: SCV002767683.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease … (more)
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 15 of 21). (P) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Multiple variants predicted to result in NMD have been reported pathogenic (ClinVar, Decipher). (P) 0807 - Variant has not previously been reported in a clinical context. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (less)
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Pathogenic
(Aug 03, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003473133.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with FOXP1-related conditions (PMID: 30564305, … (more)
For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with FOXP1-related conditions (PMID: 30564305, 34109629). This sequence change creates a premature translational stop signal (p.Leu414Argfs*60) in the FOXP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FOXP1 are known to be pathogenic (PMID: 28735298). This variant is not present in population databases (gnomAD no frequency). (less)
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Pathogenic
(Oct 19, 2023)
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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: SCV005327589.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Frameshift 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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34109629, 30564305) (less)
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Pathogenic
(Dec 18, 2023)
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no assertion criteria provided
Method: clinical testing
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FOXP1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004759334.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The FOXP1 c.1241delT variant is predicted to result in a frameshift and premature protein termination (p.Leu414Argfs*60). This variant was reported as de novo variant in … (more)
The FOXP1 c.1241delT variant is predicted to result in a frameshift and premature protein termination (p.Leu414Argfs*60). This variant was reported as de novo variant in two individuals with autism spectrum disorder (Guo et al 2018. PubMed ID: 30564305; Braden et al 2021. PubMed ID: 34109629). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in FOXP1 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with FOXP1-related conditions (PMID: 30564305, 34109629). This sequence change creates a premature translational stop signal (p.Leu414Argfs*60) in the FOXP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FOXP1 are known to be pathogenic (PMID: 28735298). This variant is not present in population databases (gnomAD no frequency).
Comment:
Frameshift 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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34109629, 30564305)
Comment:
The FOXP1 c.1241delT variant is predicted to result in a frameshift and premature protein termination (p.Leu414Argfs*60). This variant was reported as de novo variant in two individuals with autism spectrum disorder (Guo et al 2018. PubMed ID: 30564305; Braden et al 2021. PubMed ID: 34109629). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in FOXP1 are expected to be pathogenic. This variant is interpreted 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:
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 15 of 21). (P) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Multiple variants predicted to result in NMD have been reported pathogenic (ClinVar, Decipher). (P) 0807 - Variant has not previously been reported in a clinical context. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Comment:
For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with FOXP1-related conditions (PMID: 30564305, 34109629). This sequence change creates a premature translational stop signal (p.Leu414Argfs*60) in the FOXP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FOXP1 are known to be pathogenic (PMID: 28735298). This variant is not present in population databases (gnomAD no frequency).
Comment:
Frameshift 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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34109629, 30564305)
Comment:
The FOXP1 c.1241delT variant is predicted to result in a frameshift and premature protein termination (p.Leu414Argfs*60). This variant was reported as de novo variant in two individuals with autism spectrum disorder (Guo et al 2018. PubMed ID: 30564305; Braden et al 2021. PubMed ID: 34109629). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in FOXP1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Severe speech impairment is a distinguishing feature of FOXP1-related disorder. | Braden RO | Developmental medicine and child neurology | 2021 | PMID: 34109629 |
| Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model. | Guo H | Molecular autism | 2018 | PMID: 30564305 |
| FOXP1-related intellectual disability syndrome: a recognisable entity. | Meerschaut I | Journal of medical genetics | 2017 | PMID: 28735298 |
Text-mined citations for this variant ...
HelpRecord last updated Dec 07, 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.