VCV002429880.2 - ClinVar

NM_005249.5(FOXG1):c.578C>T (p.Ala193Val)

Germline

Classification

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

Pathogenic/Likely pathogenic

2 out of 2 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.578C>T (p.Ala193Val)

Variation ID: 2429880 Accession: VCV002429880.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q12 14: 28767857 (GRCh38) [ NCBI UCSC ] 14: 29237063 (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	Feb 18, 2023	Jan 13, 2025	Oct 2, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_005249.5:c.578C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005240.3:p.Ala193Val	missense
NC_000014.9:g.28767857C>T
NC_000014.8:g.29237063C>T
NG_009367.1:g.5777C>T

Protein change

A193V

Other names

Canonical SPDI

NC_000014.9:28767856:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

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: CA389475406 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	867	892

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.
Rett syndrome, congenital variant	Likely pathogenic (1)	criteria provided, single submitter	May 12, 2020	RCV003127319.1
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Oct 2, 2024	RCV004978768.1

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.
Likely pathogenic (May 12, 2020) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Rett syndrome, congenital variant Affected status: yes Allele origin: de novo	Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine Accession: SCV003803880.1 First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023	Sex: female
Pathogenic (Oct 02, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV005584198.1 First in ClinVar: Jan 13, 2025 Last updated: Jan 13, 2025	Publications: PubMed (2) PubMed: 22190898‚ 24836831 Comment: The c.578C>T (p.A193V) alteration is located in exon 1 (coding exon 1) of the FOXG1 gene. This alteration results from a C to T substitution … (more) The c.578C>T (p.A193V) alteration is located in exon 1 (coding exon 1) of the FOXG1 gene. This alteration results from a C to T substitution at nucleotide position 578, causing the alanine (A) at amino acid position 193 to be replaced by a valine (V). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Another alteration at the same codon, c.577G>A (p.A193T), has been reported in multiple individuals with features consistent with congenital variant of Rett syndrome (Van der Aa, 2011; Seltzer, 2014) This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)

Comment:

The c.578C>T (p.A193V) alteration is located in exon 1 (coding exon 1) of the FOXG1 gene. This alteration results from a C to T substitution at nucleotide position 578, causing the alanine (A) at amino acid position 193 to be replaced by a valine (V). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Another alteration at the same codon, c.577G>A (p.A193T), has been reported in multiple individuals with features consistent with congenital variant of Rett syndrome (Van der Aa, 2011; Seltzer, 2014) This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Epilepsy and outcome in FOXG1-related disorders.	Seltzer LE	Epilepsia	2014	PMID: 24836831
Analysis of FOXG1 Is Highly Recommended in Male and Female Patients with Rett Syndrome.	Van der Aa N	Molecular syndromology	2011	PMID: 22190898

Text-mined citations for this variant ...

Record last updated Feb 16, 2025

ClinVar Genomic variation as it relates to human health

NM_005249.5(FOXG1):c.578C>T (p.Ala193Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...