ClinVar Genomic variation as it relates to human health
NM_005249.5(FOXG1):c.256del (p.Gln86fs)
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_005249.5(FOXG1):c.256del (p.Gln86fs)
Variation ID: 189612 Accession: VCV000189612.21
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 14q12 14: 28767529 (GRCh38) [ NCBI UCSC ] 14: 29236735 (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 23, 2015 Mar 16, 2024 Mar 25, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005249.5:c.250delC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_005249.5:c.256del 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.256delC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_005249.3:c.256del NC_000014.9:g.28767535del NC_000014.8:g.29236741del NG_009367.1:g.5455del - Protein change
- Q86fs
- Other names
- NM_005249.5(FOXG1):c.256del
- p.Gln86fs
- Canonical SPDI
- NC_000014.9:28767528:CCCCCCC:CCCCCC
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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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FOXG1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
782 | 807 |
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 (6) |
criteria provided, multiple submitters, no conflicts
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Apr 11, 2023 | RCV000170073.18 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 14, 2022 | RCV000187475.5 | |
Pathogenic (2) |
reviewed by expert panel
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Mar 25, 2021 | RCV001507052.5 |
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
(Mar 25, 2021)
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reviewed by expert panel
Method: curation
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FOXG1 disorder
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV001712010.1 First in ClinVar: Jun 08, 2021 Last updated: Jun 08, 2021 |
Comment:
The p.Gln86Argfs variant in FOXG1 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where … (more)
The p.Gln86Argfs variant in FOXG1 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Gln86Argfs variant in FOXG1 has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with FOXG1 disorder (PMID 22739344, 2634418) (PM6_strong, PP4). This variant has been observed in at least 3 other individuals with FOXG1 disorder (PMID 22739344, 26344814) (PS4_moderate). The c.256delC variant in FOXG1 is absent from gnomAD (PM2_supporting). In summary, the p.Gln86Argfs variant in FOXG1 is classified as Pathogenic for FOXG1 disorder based on the ACMG/AMP criteria (PVS1, PM6_strong, PS4_moderate, PM2_supporting, PP4). (less)
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Pathogenic
(Oct 30, 2014)
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criteria provided, single submitter
Method: clinical testing
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Rett syndrome, congenital variant
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000247413.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Rett syndrome, congenital variant
Affected status: yes
Allele origin:
germline
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Centogene AG - the Rare Disease Company
Accession: SCV001426430.1
First in ClinVar: Aug 06, 2020 Last updated: Aug 06, 2020 |
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Pathogenic
(Mar 14, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000241068.8
First in ClinVar: Aug 07, 2015 Last updated: Mar 04, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with … (more)
Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26344814, 22739344, 28661489, 31316448, 31019990, 30533527, 34964776, 33106377, 32860008, 31238879) (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Rett syndrome, congenital variant
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002026223.2
First in ClinVar: Nov 29, 2021 Last updated: Dec 17, 2023 |
Comment:
Criteria applied: PVS1,PS2,PS4; dedicated FOXG1 criteria, Version 3.0.0
Clinical Features:
Severe global developmental delay (present) , Dysplastic corpus callosum (present) , Microcephaly (present) , Spastic tetraparesis (present) , Focal-onset seizure (present)
Sex: male
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Pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Rett syndrome, congenital variant
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000676980.8
First in ClinVar: Oct 05, 2015 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 189612). This premature translational stop signal … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 189612). This premature translational stop signal has been observed in individual(s) with FOXG1-related conditions (PMID: 22739344, 26344814). 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 poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Gln86Argfs*106) 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)
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Pathogenic
(Mar 13, 2024)
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criteria provided, single submitter
Method: curation
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FOXG1 disorder
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV004800980.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The heterozygous p.Gln86ArgfsTer106 variant in FOXG1 was identified by our study in one individual with congenital fibrosis of the extraocular muscles, gastroesophageal reflux,and fine motor … (more)
The heterozygous p.Gln86ArgfsTer106 variant in FOXG1 was identified by our study in one individual with congenital fibrosis of the extraocular muscles, gastroesophageal reflux,and fine motor delay, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Engle lab (https://kirbyneuro.org/EngleLab/). We believe this is a phenotype expansion for FOXG1-related disorders. The p.Gln86ArgfsTer106 variant in FOXG1 has been previously reported in 9 unrelated individuals with FOXG1-related disease (PMID: 32860008, PMID: 33106377, PMID: 30533527, PMID: 31316448, PMID: 28661489, PMID: 31238879, PMID: 22739344, PMID: 26344814). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant was found to be de novo in 5 individuals with confirmed paternity and maternity (PMID: 30533527, PMID: 28661489, PMID: 22739344, PMID: 26344814) and is assumed de novo in one individual, but maternity and paternity have not been confirmed (PMID: 31316448). The phenotype of individuals heterozygous for this variant is highly specific for FOXG1-related disease based on the presence of core phenotypic consistent with disease, as defined in the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel (PMID: 31238879, PMID: 26344814, PMID: 31316448, PMID: 28661489, PMID: 22739344). This variant has also been reported in ClinVar (Variation ID: 189612) and has been interpreted as pathogenic by multiple submitters. This variant was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 86 and leads to a premature termination codon 106 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the FOXG1 gene is an established disease mechanism in FOXG1-related disease. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FOXG1-related disease. ACMG/AMP Criteria applied: PVS1, PS2_VeryStrong, PS4, PM2_Supporting, PP4 (Richards 2015). (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Rett syndrome, congenital variant
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Lifecell International Pvt. Ltd
Accession: SCV003921118.1
First in ClinVar: May 06, 2023 Last updated: May 06, 2023 |
Comment:
A Heterozygous Frameshift variant c.250delC in Exon 1 of the FOXG1 gene that results in the amino acid substitution p.Gln86fs*106 was identified. The observed variant … (more)
A Heterozygous Frameshift variant c.250delC in Exon 1 of the FOXG1 gene that results in the amino acid substitution p.Gln86fs*106 was identified. The observed variant is novel in gnomAD exomes and genomes. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic(Variant ID 189612). This variant has been previously reported by Celini et al., 2016. Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. (less)
Ethnicity/Population group: Asian
Geographic origin: India
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Pathogenic
(Feb 15, 2013)
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no assertion criteria provided
Method: curation
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Rett syndrome, congenital variant
Affected status: yes
Allele origin:
de novo
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RettBASE
Accession: SCV000222383.1
First in ClinVar: Apr 23, 2015 Last updated: Apr 23, 2015 |
Number of individuals with the variant: 1
Family history: No
Sex: male
Tissue: blood
Comment on evidence:
Rett syndrome - atypical
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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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The hyperkinetic movement disorder of FOXG1-related epileptic-dyskinetic encephalopathy. | Cellini E | Developmental medicine and child neurology | 2016 | PMID: 26344814 |
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 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/3adb4e57-42ba-4d85-a85d-339b6d6df8fc | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/4dd8f576-545f-470c-81ce-51862fe5e694 | - | - | - | - |
Text-mined citations for rs786205001 ...
HelpRecord last updated Mar 30, 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.