NM_005249.5(FOXG1):c.577G>A (p.Ala193Thr) AND Rett syndrome, congenital variant

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jan 20, 2018
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000170078.13

Allele description [Variation Report for NM_005249.5(FOXG1):c.577G>A (p.Ala193Thr)]

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

Gene:

FOXG1:forkhead box G1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q12

Genomic location:

Preferred name:

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

Other names:

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

HGVS:

NC_000014.9:g.28767856G>A
NG_009367.1:g.5776G>A
NM_005249.5:c.577G>AMANE SELECT
NP_005240.3:p.Ala193Thr
NC_000014.8:g.29237062G>A
NM_005249.4:c.577G>A

Protein change:

A193T

Links:

dbSNP: rs786205005

NCBI 1000 Genomes Browser:

rs786205005

Molecular consequence:

NM_005249.5:c.577G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Rett syndrome, congenital variant
Identifiers:: MedGen: C3150705; Orphanet: 3095; OMIM: 613454

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000222389	RettBASE	no assertion criteria provided	Pathogenic (May 18, 2012)	de novo	curation	PubMed (1) [See all records that cite this PMID]
SCV000650054	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 8, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002026246	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 20, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28661489, 25741868
SCV004048384	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	yes	1	not provided	not provided	1	No	curation
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Analysis of FOXG1 Is Highly Recommended in Male and Female Patients with Rett Syndrome.

Van der Aa N, Van den Bergh M, Ponomarenko N, Verstraete L, Ceulemans B, Storm K.

Mol Syndromol. 2011 Sep;1(6):290-293. Epub 2011 Aug 9.

PubMed [citation]

PMID:: 22190898
PMCID:: PMC3214958

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (4)

Details of each submission

From RettBASE, SCV000222389.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	No	curation	PubMed (1)

Description

"Rett syndrome - congenital"

PubMed [ID: 22190898]

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000650054.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV002026246.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV004048384.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 25, 2025

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