VCV000453289.14 - ClinVar

NM_005249.5(FOXG1):c.624C>A (p.Tyr208Ter)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic

3 out of 5 submissions contributed to this classification

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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_005249.5(FOXG1):c.624C>A (p.Tyr208Ter)

Variation ID: 453289 Accession: VCV000453289.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q12 14: 28767903 (GRCh38) [ NCBI UCSC ] 14: 29237109 (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	Dec 26, 2017	Feb 15, 2026	Aug 25, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_005249.5:c.624C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005240.3:p.Tyr208Ter	nonsense
NC_000014.9:g.28767903C>A
NC_000014.8:g.29237109C>A
NG_009367.1:g.5823C>A

Protein change

Y208*

Other names

Canonical SPDI

NC_000014.9:28767902:C:A

Global minor allele frequency (GMAF) Help The 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

ClinGen: CA389475504 dbSNP: rs267606826 VarSome

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
Gene	OMIM	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	934	961

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.
FOXG1 disorder	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Aug 25, 2025	RCV000550163.14
Abnormal optic nerve morphology Axial hypotonia Global developmental delay Stereotypic movement disorder Strabismus	Pathogenic (1)	no assertion criteria provided	-	RCV001003977.2

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.	Expand all rows Collapse all rows 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.
Pathogenic (Aug 05, 2016) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	FOXG1 disorder	Undiagnosed Diseases Network, NIH Accession: SCV000622146.2 First in ClinVar: Dec 26, 2017 Last updated: Apr 13, 2025	Comment: show This terminating amino acid change (p.Y208X) has been reported in at least one affected individual (PMID 19578037). (less) Observation: 1 Collection method: clinical testing Allele origin: de novo Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: de novo Affected status: yes Clinical Features: Strabismus (present) , Spasticity (present) , Sleep disturbance (present) , Short stature (present) , Recurrent urinary tract infections (present) , Protruding ear (present) , Proportionate short stature (present) , Postnatal microcephaly (present) , Phimosis (present) , Pectus excavatum (present) , Partial agenesis of the corpus callosum (present) , Oculomotor apraxia (present) , Nystagmus (present) , Mild short stature (present) , Microcephaly (present) , Intellectual disability (present) , Infra-orbital crease (present) , Hypoplasia of the corpus callosum (present) , Global developmental delay (present) , Generalized hypotonia (present) , Gastroesophageal reflux (present) , Flaring of rib cage (present) , Failure to thrive (present) , Esotropia (present) , Dystonia (present) , Drooling (present) , Delayed CNS myelination (present) , Decreased body weight (present) , Aplasia/Hypoplasia of the corpus callosum (present) , Aplasia/Hypoplasia involving the central nervous system (present) , Absent speech (present) , Abnormality of the corpus callosum (present) , Abnormality of brain morphology (present) , Abnormal CNS myelination (present) Zygosity: Single Heterozygote Family history: no Age: 0-9 years Sex: male Ethnicity/Population group: White Platform type: exome sequencing Platform name: HiSeq Testing laboratory: Baylor Genetics Date variant was reported to submitter: 2016-08-05

Pathogenic (Aug 25, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	FOXG1 disorder	Daryl Scott Lab, Baylor College of Medicine Accession: SCV006555471.1 First in ClinVar: Oct 18, 2025 Last updated: Oct 18, 2025	Comment: show PVS1, PS2, PM2 (less) Observation: 1 Collection method: clinical testing Allele origin: de novo Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: de novo Affected status: yes Zygosity: Single Heterozygote

Pathogenic (Mar 05, 2020) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	FOXG1 disorder	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001399979.7 First in ClinVar: Jul 16, 2020 Last updated: Feb 15, 2026	Publications: PubMed (2) PubMed: 19578037‚ 28661489 Comment: show For these reasons, this variant has been classified as Pathogenic. This nonsense change has been observed in individual(s) with clinical features of Rett syndrome (PMID: 28661489, 19578037). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 453289). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the FOXG1 gene (p.Tyr208*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 282 amino acids of the FOXG1 protein. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Jan 01, 2019) N Not contributing to aggregate classification	no assertion criteria provided	Rett syndrome, congenital variant	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille Accession: SCV001427498.1 First in ClinVar: Aug 13, 2020 Last updated: Aug 13, 2020	Publications: PubMed (1) PubMed: 25741868 Observation: 1 Collection method: clinical testing Allele origin: de novo Affected status: yes Observation 1 Collection method: clinical testing Allele origin: de novo Affected status: yes

Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	Abnormal optic nerve morphology Strabismus Global developmental delay Axial hypotonia Motor stereotypies	NIHR Bioresource Rare Diseases, University of Cambridge Accession: SCV001162003.2 First in ClinVar: Feb 27, 2020 Last updated: Apr 13, 2025	Publications: PubMed (1) PubMed: 32581362 Observation: 1 Collection method: research Allele origin: unknown Affected status: yes more Observation 1 Collection method: research Allele origin: unknown Affected status: yes Number of individuals with the variant: 1 Sex: female

Comment:

For these reasons, this variant has been classified as Pathogenic. This nonsense change has been observed in individual(s) with clinical features of Rett syndrome (PMID: 28661489, 19578037). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 453289). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the FOXG1 gene (p.Tyr208*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 282 amino acids of the FOXG1 protein.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Whole-genome sequencing of patients with rare diseases in a national health system.	Turro E	Nature	2020	PMID: 32581362
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
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.	Richards S	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25741868
Novel FOXG1 mutations associated with the congenital variant of Rett syndrome.	Mencarelli MA	Journal of medical genetics	2010	PMID: 19578037

Text-mined citations for rs267606826 ...

These 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 Feb 15, 2026