VCV000425040.34 - ClinVar

NM_005249.5(FOXG1):c.685A>C (p.Ile229Leu)

Germline

Top reviewed classifications are shown here.

Submission summary:

3 submissions

3 submitters

3 conditions

Reviewed by expert panel

Likely pathogenic

Feb 2022 by ClinGen Rett a… FDA Recognized Database

for FOXG1 disorder

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_005249.5(FOXG1):c.685A>C (p.Ile229Leu)

Variation ID: 425040 Accession: VCV000425040.34

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q12 14: 28767964 (GRCh38) [ NCBI UCSC ] 14: 29237170 (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	May 8, 2017	Oct 20, 2024	Feb 18, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_005249.5:c.685A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005240.3:p.Ile229Leu	missense
NC_000014.9:g.28767964A>C
NC_000014.8:g.29237170A>C
NG_009367.1:g.5884A>C

Protein change

I229L

Other names

NM_005249.5(FOXG1):c.685A>C
p.Ile229Leu

Canonical SPDI

NC_000014.9:28767963:A:C

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: CA16621657 dbSNP: rs1064797186 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	801	826

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	Aug 9, 2016	RCV000503039.7
not provided	Uncertain significance (1)	criteria provided, single submitter	Jan 1, 2017	RCV000487770.24
FOXG1 disorder	Likely pathogenic (1)	reviewed by expert panel	Feb 18, 2022	RCV002260643.3

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 (Feb 18, 2022)	reviewed by expert panel (ClinGen RettAS ACMG Specifications V2) Method: curation	FOXG1 disorder (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel FDA Recognized Database Accession: SCV002540692.1 First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/8f7a9d2e-ff03-406d-88b5-34d80f6d48d0 Comment: The p.Ile229Leu variant occurs in the well-characterized Forkhead functional domain of the FOXG1 gene (PMID 18571142, 28661489) (PM1). The p.Ile229Leu variant in FOXG1 occurs in … (more) The p.Ile229Leu variant occurs in the well-characterized Forkhead functional domain of the FOXG1 gene (PMID 18571142, 28661489) (PM1). The p.Ile229Leu variant in FOXG1 occurs in the de novo state (biological parentage unconfirmed) in an individual with intellectual disability and seizures (Genetic Services Laboratory, University of Chicago internal data)(PM6). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance (PP3). The p.Ile229Leu variant in FOXG1 is absent in gnomAD (PM2_supporting). In summary, the p.Ile229Leu variant in FOXG1 is classified as likely pathogenic for FOXG1 disorder based on the ACMG/AMP criteria (PM1, PM6, PP3, PM2_supporting). (less)
Likely pathogenic (Aug 09, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Rett syndrome, congenital variant Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000594859.1 First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017
Uncertain significance (Jan 01, 2017)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV000574971.32 First in ClinVar: May 08, 2017 Last updated: Oct 20, 2024	Number of individuals with the variant: 1

Comment:

The p.Ile229Leu variant occurs in the well-characterized Forkhead functional domain of the FOXG1 gene (PMID 18571142, 28661489) (PM1). The p.Ile229Leu variant in FOXG1 occurs in the de novo state (biological parentage unconfirmed) in an individual with intellectual disability and seizures (Genetic Services Laboratory, University of Chicago internal data)(PM6). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance (PP3). The p.Ile229Leu variant in FOXG1 is absent in gnomAD (PM2_supporting). In summary, the p.Ile229Leu variant in FOXG1 is classified as likely pathogenic for FOXG1 disorder based on the ACMG/AMP criteria (PM1, PM6, PP3, PM2_supporting).

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
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/8f7a9d2e-ff03-406d-88b5-34d80f6d48d0	-	-	-	-

Text-mined citations for rs1064797186 ...

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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_005249.5(FOXG1):c.685A>C (p.Ile229Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1064797186 ...