ClinVar Genomic variation as it relates to human health
NM_005249.5(FOXG1):c.506del (p.Gly169fs)
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.506del (p.Gly169fs)
Variation ID: 471470 Accession: VCV000471470.22
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 14q12 14: 28767780 (GRCh38) [ NCBI UCSC ] 14: 29236986 (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 26, 2017 Apr 20, 2024 Sep 19, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005249.5:c.506del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005240.3:p.Gly169fs frameshift NM_005249.5:c.506delG MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_005249.3:c.506del NM_005249.4:c.506del NC_000014.9:g.28767785del NC_000014.8:g.29236991del NG_009367.1:g.5705del - Protein change
- G169fs
- Other names
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- Canonical SPDI
- NC_000014.9:28767779:GGGGGG:GGGGG
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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
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
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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 (7) |
criteria provided, multiple submitters, no conflicts
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Sep 19, 2023 | RCV000541926.17 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 28, 2018 | RCV001267590.2 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 6, 2022 | RCV001288608.5 |
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
(Feb 20, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics Inc
Accession: SCV001475861.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in … (more)
The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity. (less)
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Pathogenic
(Jan 20, 2018)
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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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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002026233.1
First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021 |
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Pathogenic
(Dec 13, 2021)
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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 Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV002764708.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Number of individuals with the variant: 1
Clinical Features:
Global developmental delay (present) , Seizure (present) , Secondary microcephaly (present) , Encephalopathy (present)
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Pathogenic
(Sep 28, 2018)
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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: SCV001445772.2
First in ClinVar: Nov 21, 2020 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Osteoporosis (present) , Nystagmus (present) , Microcephaly (present) , Hyperparathyroidism (present) , Movement disorder (present) , Progressive microcephaly (present) , Exotropia (present) , Dysautonomia (present) … (more)
Osteoporosis (present) , Nystagmus (present) , Microcephaly (present) , Hyperparathyroidism (present) , Movement disorder (present) , Progressive microcephaly (present) , Exotropia (present) , Dysautonomia (present) , Hypocalcemia (present) , Apnea (present) , Esotropia (present) , Dysphagia (present) , Corpus callosum, agenesis of (present) , High, narrow palate (present) , Recurrent fractures (present) , Epicanthus (present) , Muscular hypotonia (present) , Flexion contracture (present) , Posteriorly rotated ears (present) (less)
Sex: male
Ethnicity/Population group: Caucasian
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Pathogenic
(Jun 06, 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: SCV001791914.3
First in ClinVar: Aug 21, 2021 Last updated: Mar 04, 2023 |
Comment:
Reported previously in a patient with myoclonic seizures, tonic seizures, and drop seizures (Seltzer et al., 2014); Frameshift variant predicted to result in protein truncation … (more)
Reported previously in a patient with myoclonic seizures, tonic seizures, and drop seizures (Seltzer et al., 2014); 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: 27640358, 25356899, 24836831, 30792901, 33644862, 34788679) (less)
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Pathogenic
(Feb 10, 2022)
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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: SCV000650053.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 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.Tyr400*) 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.Tyr400*) have been determined to be pathogenic (PMID: 19564653). 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: 471470). This premature translational stop signal has been observed in individual(s) with epilepsy, gross motor delays and no language abilities (PMID: 24836831). 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.Gly169Alafs*23) in the FOXG1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 321 amino acid(s) of the FOXG1 protein. (less)
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Pathogenic
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Rett syndrome, congenital variant
Affected status: unknown
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV004801467.1
First in ClinVar: Mar 23, 2024 Last updated: Mar 23, 2024 |
Comment:
The FOXG1 c.506delG p.(Gly169AlafsTer23) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss … (more)
The FOXG1 c.506delG p.(Gly169AlafsTer23) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant has been identified in a de novo state in individuals with a phenotype consistent with Rett syndrome, congenital variant (Seltzer et al. 2014; Hamdan et al. 2014). This variant is not observed in version 2.1.1 of the Genome Aggregation Database. The variant was identified in a de novo state in the proband. Based on the available evidence, the c.506delG p.(Gly169AlafsTer23) variant is classified as pathogenic for Rett syndrome, congenital variant. (less)
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Pathogenic
(Sep 19, 2023)
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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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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV004847222.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Method: Exome sequencing
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Rett syndrome, congenital variant
Affected status: yes
Allele origin:
unknown
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Service de Génétique Moléculaire, Hôpital Robert Debré
Accession: SCV001432346.1
First in ClinVar: Sep 16, 2020 Last updated: Sep 16, 2020 |
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Pathogenic
(-)
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no assertion criteria provided
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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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV001787118.1
First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Sex: male
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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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Clinical whole genome sequencing as a first-tier test at a resource-limited dysmorphology clinic in Mexico. | Scocchia A | NPJ genomic medicine | 2019 | PMID: 30792901 |
FOXG1 syndrome: genotype-phenotype association in 83 patients with FOXG1 variants. | Mitter D | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 28661489 |
De novo mutations in moderate or severe intellectual disability. | Hamdan FF | PLoS genetics | 2014 | PMID: 25356899 |
Epilepsy and outcome in FOXG1-related disorders. | Seltzer LE | Epilepsia | 2014 | PMID: 24836831 |
Phenotypic variability in Rett syndrome associated with FOXG1 mutations in females. | Philippe C | Journal of medical genetics | 2010 | PMID: 19564653 |
Text-mined citations for rs1452295073 ...
HelpRecord last updated May 01, 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.