The frameshift duplication p.Q86Pfs*35 in FOXG1 (NM_005249.5) has been observed in individual(s) with congenital variant of Rett syndrome (Le Guen T et al). The observed variant has been reported to ClinVar as Pathogenic. The p.Q86Pfs*35 variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This pathogenic mutation is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_005249.5(FOXG1):c.256dup (p.Gln86fs)
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.
(11)
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
11
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_005249.5(FOXG1):c.256dup (p.Gln86fs)
Variation ID: 189613 Accession: VCV000189613.61
- Type and length
-
Duplication, 1 bp
- Location
-
Cytogenetic: 14q12 14: 28767528-28767529 (GRCh38) [ NCBI UCSC ] 14: 29236734-29236735 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 23, 2015 Oct 20, 2024 Jul 16, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_005249.5:c.256dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005240.3:p.Gln86fs frameshift NM_005249.5:c.256dupC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_005249.3:c.256dupC NM_005249.4:c.256dup NC_000014.9:g.28767535dup NC_000014.8:g.29236741dup NG_009367.1:g.5455dup - Protein change
- Q86fs
- Other names
-
NM_005249.5(FOXG1):c.256dup
p.Gln86fs
- Canonical SPDI
- NC_000014.9:28767528:CCCCCCC:CCCCCCCC
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| FOXG1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
802 | 827 | |
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 (5) |
criteria provided, multiple submitters, no conflicts
|
Jul 16, 2024 | RCV000170074.16 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 5, 2023 | RCV000187488.30 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 10, 2021 | RCV001814085.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 10, 2024 | RCV004558425.1 | |
|
FOXG1-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Apr 18, 2024 | RCV004751321.1 |
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
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Rett syndrome, congenital variant
Affected status: yes
Allele origin:
de novo
|
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV002575065.1
First in ClinVar: Oct 01, 2022 Last updated: Oct 01, 2022 |
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Rett syndrome, congenital variant
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002820305.1
First in ClinVar: Jan 21, 2023 Last updated: Jan 21, 2023 |
Comment:
The frameshift duplication p.Q86Pfs*35 in FOXG1 (NM_005249.5) has been observed in individual(s) with congenital variant of Rett syndrome (Le Guen T et al). The observed … (more)
The frameshift duplication p.Q86Pfs*35 in FOXG1 (NM_005249.5) has been observed in individual(s) with congenital variant of Rett syndrome (Le Guen T et al). The observed variant has been reported to ClinVar as Pathogenic. The p.Q86Pfs*35 variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This pathogenic mutation is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Global developmental delay (present) , Seizure (present) , Abnormal facial shape (present)
|
|
|
Pathogenic
(May 10, 2024)
|
criteria provided, single submitter
Method: curation
|
FOXG1 disorder
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Centre for Population Genomics, CPG
Accession: SCV005046891.1
First in ClinVar: Jun 09, 2024 Last updated: Jun 09, 2024 |
Comment:
This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert … (more)
This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as pathogenic. At least the following criteria are met: Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). Has been observed in at least 5 individuals with phenotypes consistent with FOXG1 disorder (PS4). PMID:20734096 PMID:30533527 PMID:22739344 PMID:22129046 PMID:22968132 PMID:31454984 PMID:28661489 PMID:22670136 PMID:26993267 This variant is absent from gnomAD (PM2_Supporting). (less)
|
|
|
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: SCV001446572.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Global developmental delay (present) , Hypotonia (present) , Microcephaly (present) , Horizontal nystagmus (present) , Strabismus (present) , Kyphosis (present)
Sex: male
|
|
|
Pathogenic
(Jul 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Abnormality of the nervous system
Affected status: yes
Allele origin:
de novo
|
Kariminejad - Najmabadi Pathology & Genetics Center
Accession: SCV001755294.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
|
|
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Pathogenic
(Mar 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000241082.11
First in ClinVar: Aug 07, 2015 Last updated: Mar 18, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency … (more)
Frameshift variant predicted to result in protein truncation 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: 20734096, 30533527, 31316448, 34120799, 31577544, 22968132, 22129046, 26993267, 22739344, 28661489, 35148845) (less)
|
|
|
Pathogenic
(Apr 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Rett syndrome, congenital variant
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001203682.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the FOXG1 protein in which other variant(s) (p.Ser472Ilefs*15) have … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the FOXG1 protein in which other variant(s) (p.Ser472Ilefs*15) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 189613). This variant is also known as c.256_257dupC. This premature translational stop signal has been observed in individual(s) with congenital variant of Rett syndrome (PMID: 20734096). In at least one individual the variant was observed to be de novo. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Gln86Profs*35) in the FOXG1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 404 amino acid(s) of the FOXG1 protein. (less)
|
|
|
Pathogenic
(Jul 16, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Rett syndrome, congenital variant
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002026222.2
First in ClinVar: Nov 29, 2021 Last updated: Oct 13, 2024 |
Comment:
Criteria applied: PVS1,PS4
Clinical Features:
Spasticity (present) , Seizure (present) , Intellectual disability (present) , Hypotonia (present) , Tall stature (present) , Cerebral palsy (present) , Microcephaly (present) , Severe … (more)
Spasticity (present) , Seizure (present) , Intellectual disability (present) , Hypotonia (present) , Tall stature (present) , Cerebral palsy (present) , Microcephaly (present) , Severe global developmental delay (present) (less)
Sex: male
|
|
|
Pathogenic
(Mar 01, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001249820.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Feb 15, 2013)
|
no assertion criteria provided
Method: curation
|
Rett syndrome, congenital variant
Affected status: yes
Allele origin:
de novo
|
RettBASE
Accession: SCV000222384.1
First in ClinVar: Apr 23, 2015 Last updated: Apr 23, 2015 |
Observation 1:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - congenital
Observation 2:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - congenital
Observation 3:
Number of individuals with the variant: 1
Family history: No
Sex: male
Tissue: blood
Comment on evidence:
Rett syndrome - congenital
Observation 4:
Number of individuals with the variant: 1
Family history: No
Sex: female
Tissue: blood
Comment on evidence:
Rett syndrome - classical
|
|
|
Pathogenic
(Apr 18, 2024)
|
no assertion criteria provided
Method: clinical testing
|
FOXG1-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005362608.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The FOXG1 c.256dupC variant is predicted to result in a frameshift and premature protein termination (p.Gln86Profs*35). This variant has been reported as a de novo … (more)
The FOXG1 c.256dupC variant is predicted to result in a frameshift and premature protein termination (p.Gln86Profs*35). This variant has been reported as a de novo finding in multiple individuals with congenital variant Rett syndrome (see for example, Le Guen et al. 2011. PubMed ID: 20734096; Takahashi et al. 2011. PubMed ID: 22129046; Khan and Kirmani. 2020. PubMed ID: 31577544). This variant has also been reported in the heterozygous state in an individual with early infantile epileptic encephalopathy (Trump et al. 2016. PubMed ID: 26993267). Another variant resulting in a frameshift at the same codon, c.256del (p.Gln86fs*106), has been classified as pathogenic by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/189612/). Taken together, the c.256dupC (p.Gln86Profs*35) variant is interpreted as pathogenic. (less)
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Comment:
Comment:
This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as pathogenic. At least the following criteria are met: Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). Has been observed in at least 5 individuals with phenotypes consistent with FOXG1 disorder (PS4). PMID:20734096 PMID:30533527 PMID:22739344 PMID:22129046 PMID:22968132 PMID:31454984 PMID:28661489 PMID:22670136 PMID:26993267 This variant is absent from gnomAD (PM2_Supporting).
Comment:
Frameshift variant predicted to result in protein truncation 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: 20734096, 30533527, 31316448, 34120799, 31577544, 22968132, 22129046, 26993267, 22739344, 28661489, 35148845)
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the FOXG1 protein in which other variant(s) (p.Ser472Ilefs*15) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 189613). This variant is also known as c.256_257dupC. This premature translational stop signal has been observed in individual(s) with congenital variant of Rett syndrome (PMID: 20734096). In at least one individual the variant was observed to be de novo. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Gln86Profs*35) in the FOXG1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 404 amino acid(s) of the FOXG1 protein.
Comment:
Criteria applied: PVS1,PS4
Comment:
The FOXG1 c.256dupC variant is predicted to result in a frameshift and premature protein termination (p.Gln86Profs*35). This variant has been reported as a de novo finding in multiple individuals with congenital variant Rett syndrome (see for example, Le Guen et al. 2011. PubMed ID: 20734096; Takahashi et al. 2011. PubMed ID: 22129046; Khan and Kirmani. 2020. PubMed ID: 31577544). This variant has also been reported in the heterozygous state in an individual with early infantile epileptic encephalopathy (Trump et al. 2016. PubMed ID: 26993267). Another variant resulting in a frameshift at the same codon, c.256del (p.Gln86fs*106), has been classified as pathogenic by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/189612/). Taken together, the c.256dupC (p.Gln86Profs*35) 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:
The frameshift duplication p.Q86Pfs*35 in FOXG1 (NM_005249.5) has been observed in individual(s) with congenital variant of Rett syndrome (Le Guen T et al). The observed variant has been reported to ClinVar as Pathogenic. The p.Q86Pfs*35 variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This pathogenic mutation is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as pathogenic. At least the following criteria are met: Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). Has been observed in at least 5 individuals with phenotypes consistent with FOXG1 disorder (PS4). PMID:20734096 PMID:30533527 PMID:22739344 PMID:22129046 PMID:22968132 PMID:31454984 PMID:28661489 PMID:22670136 PMID:26993267 This variant is absent from gnomAD (PM2_Supporting).
Comment:
Frameshift variant predicted to result in protein truncation 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: 20734096, 30533527, 31316448, 34120799, 31577544, 22968132, 22129046, 26993267, 22739344, 28661489, 35148845)
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the FOXG1 protein in which other variant(s) (p.Ser472Ilefs*15) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 189613). This variant is also known as c.256_257dupC. This premature translational stop signal has been observed in individual(s) with congenital variant of Rett syndrome (PMID: 20734096). In at least one individual the variant was observed to be de novo. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Gln86Profs*35) in the FOXG1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 404 amino acid(s) of the FOXG1 protein.
Comment:
Criteria applied: PVS1,PS4
Comment:
The FOXG1 c.256dupC variant is predicted to result in a frameshift and premature protein termination (p.Gln86Profs*35). This variant has been reported as a de novo finding in multiple individuals with congenital variant Rett syndrome (see for example, Le Guen et al. 2011. PubMed ID: 20734096; Takahashi et al. 2011. PubMed ID: 22129046; Khan and Kirmani. 2020. PubMed ID: 31577544). This variant has also been reported in the heterozygous state in an individual with early infantile epileptic encephalopathy (Trump et al. 2016. PubMed ID: 26993267). Another variant resulting in a frameshift at the same codon, c.256del (p.Gln86fs*106), has been classified as pathogenic by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/189612/). Taken together, the c.256dupC (p.Gln86Profs*35) variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 14q12 microdeletions excluding FOXG1 give rise to a congenital variant Rett syndrome-like phenotype. | Ellaway CJ | European journal of human genetics : EJHG | 2013 | PMID: 22968132 |
| 14q12 and severe Rett-like phenotypes: new clinical insights and physical mapping of FOXG1-regulatory elements. | Allou L | European journal of human genetics : EJHG | 2012 | PMID: 22739344 |
| FOXG1 mutations in Japanese patients with the congenital variant of Rett syndrome. | Takahashi S | Clinical genetics | 2012 | PMID: 22129046 |
| A FOXG1 mutation in a boy with congenital variant of Rett syndrome. | Le Guen T | Neurogenetics | 2011 | PMID: 20734096 |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/140a4b68-da0e-4fbb-bfdb-f0769ec20c1f | - | - | - | - |
Text-mined citations for rs786205001 ...
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.