VCV000189616.13 - ClinVar

NM_005249.5(FOXG1):c.577G>A (p.Ala193Thr)

Germline

Classification

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

Pathogenic/Likely pathogenic

5 out of 6 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.577G>A (p.Ala193Thr)

Variation ID: 189616 Accession: VCV000189616.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q12 14: 28767856 (GRCh38) [ NCBI UCSC ] 14: 29237062 (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	Feb 25, 2025	May 30, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_005249.5:c.577G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005240.3:p.Ala193Thr	missense
NC_000014.9:g.28767856G>A
NC_000014.8:g.29237062G>A
NG_009367.1:g.5776G>A

Protein change

A193T

Other names

NM_005249.5(FOXG1):c.577G>A
p.Ala193Thr

Canonical SPDI

NC_000014.9:28767855:G:A

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: CA199438 dbSNP: rs786205005 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	862	887

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 (1)	criteria provided, single submitter	May 30, 2024	RCV004558428.1
Rett syndrome, congenital variant	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jan 20, 2018	RCV000170078.13
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Jul 5, 2016	RCV000624178.2

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.	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.
Pathogenic (Jul 05, 2016) C Contributing to aggregate classification	criteria provided, single submitter (Ambry exome assertion method (8-5-2015)) Method: clinical testing	Inborn genetic diseases Affected status: yes Allele origin: germline	Ambry Genetics Accession: SCV000741670.3 First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023	Number of individuals with the variant: 1 Sex: female Ethnicity/Population group: Hispanic/Mexican
Likely pathogenic (Jan 20, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Rett syndrome, congenital variant Affected status: yes Allele origin: germline	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV002026246.1 First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021	Publications: PubMed (1) PubMed: 28661489
Likely pathogenic (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Rett syndrome, congenital variant (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004048384.1 First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023	Comment: The missense variant p.Ala193Thr in FOXG1 has been reported to be de novo in individuals affected with FOXG1-related disorders including Rett syndrome (Van der Aa … (more) The missense variant p.Ala193Thr in FOXG1 has been reported to be de novo in individuals affected with FOXG1-related disorders including Rett syndrome (Van der Aa N et. al., 2011). The p.Ala193Thr variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been submitted to ClinVar as Pathogenic/Likely Pathogenic, but no details are available for independent assessment. The amino acid Ala at position 193 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The amino acid change p.Ala193Thr in FOXG1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. (less) Clinical Features: Microcephaly (present) , Hypotonia (present) , Attention deficit hyperactivity disorder (present) , Cerebral hypomyelination (present) Comment on clinical features: Age: 1 year/ female Clinical indications: - Microcephaly - Hypotonia - ADHD - ? Hypomyelinating disorder
Pathogenic (May 30, 2024) C Contributing to aggregate classification	criteria provided, single submitter (McKnight et al. (Hum Mutat. 2022)) Method: curation	FOXG1 disorder (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Centre for Population Genomics, CPG Accession: SCV005046884.1 First in ClinVar: Jun 09, 2024 Last updated: Jun 09, 2024	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/7bf23976-8dbb-4cdd-9e85-abcb4c31b426 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: This variant has been identified as a de novo occurrence in at least 2 individuals with FOXG1 disorder, without confirmation of paternity and maternity (PM6_Strong). PMID: 22190898, PMID: 28661489 Has been observed in at least 5 individuals with phenotypes consistent with FOXG1 disorder (PS4). PMID:22190898 PMID:27029630 PMID:31199603 PMID:24766421 PMID:26344814 PMID:18571142 PMID:21441262 PMID:28661489 PMID:24836831 Occurs in the well-characterized Forkhead functional domain of FOXG1 (PM1). Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). This variant is absent from gnomAD (PM2_Supporting). (less)
Pathogenic (Jun 08, 2017) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Rett syndrome, congenital variant Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000650054.5 First in ClinVar: Dec 26, 2017 Last updated: Feb 25, 2025	Comment: This sequence change replaces alanine with threonine at codon 193 of the FOXG1 protein (p.Ala193Thr). The alanine residue is highly conserved and there is a … (more) This sequence change replaces alanine with threonine at codon 193 of the FOXG1 protein (p.Ala193Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in individuals affected with FOXG1-related disorders including Rett syndrome (PMID: ¬†22190898, 27029630, 24836831).¬†¬†ClinVar contains an entry for this variant (Variation ID: 189616). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (May 18, 2012) N Not contributing to aggregate classification	no assertion criteria provided Method: curation	Rett syndrome, congenital variant Affected status: yes Allele origin: de novo	RettBASE Accession: SCV000222389.1 First in ClinVar: Apr 23, 2015 Last updated: Apr 23, 2015	Publications: PubMed (1) PubMed: 22190898 Number of individuals with the variant: 1 Family history: No Sex: male Comment on evidence: Rett syndrome - congenital

Comment:

The missense variant p.Ala193Thr in FOXG1 has been reported to be de novo in individuals affected with FOXG1-related disorders including Rett syndrome (Van der Aa N et. al., 2011). The p.Ala193Thr variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been submitted to ClinVar as Pathogenic/Likely Pathogenic, but no details are available for independent assessment. The amino acid Ala at position 193 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The amino acid change p.Ala193Thr in FOXG1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely 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: This variant has been identified as a de novo occurrence in at least 2 individuals with FOXG1 disorder, without confirmation of paternity and maternity (PM6_Strong). PMID: 22190898, PMID: 28661489 Has been observed in at least 5 individuals with phenotypes consistent with FOXG1 disorder (PS4). PMID:22190898 PMID:27029630 PMID:31199603 PMID:24766421 PMID:26344814 PMID:18571142 PMID:21441262 PMID:28661489 PMID:24836831 Occurs in the well-characterized Forkhead functional domain of FOXG1 (PM1). Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). This variant is absent from gnomAD (PM2_Supporting).

Comment:

This sequence change replaces alanine with threonine at codon 193 of the FOXG1 protein (p.Ala193Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in individuals affected with FOXG1-related disorders including Rett syndrome (PMID: ¬†22190898, 27029630, 24836831).¬†¬†ClinVar contains an entry for this variant (Variation ID: 189616). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been 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
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
Analysis of FOXG1 Is Highly Recommended in Male and Female Patients with Rett Syndrome.	Van der Aa N	Molecular syndromology	2011	PMID: 22190898
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/7bf23976-8dbb-4cdd-9e85-abcb4c31b426	-	-	-	-

Text-mined citations for rs786205005 ...

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 26, 2025

ClinVar Genomic variation as it relates to human health

NM_005249.5(FOXG1):c.577G>A (p.Ala193Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs786205005 ...