rs727503935

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2_SupportingPS4_SupportingPM1PM6

This summary comes from the ClinGen Evidence Repository: The p.Gly224Ser variant in FOXG1 is located in the well-characterized Forkhead functional domain (PMID 18571142, 28661489)(PM1). The p.Gly224Ser variant in FOXG1 occurs in the de novo state (biological parentage unconfirmed) in an individual with gross motor delay and infantile spasms (GeneDx internal database)(PM6). The p.Gly224Ser variant in FOXG1 is absent in gnomAD (PM2_supporting). The p.Gly224Ser variant has been observed in 2 individuals with neurodevelopmental disease (GeneDx internal database, University of Chicago internal database)(PS4_supporting). In summary, the p.Gly224Ser variant in FOXG1 is classified as likely pathogenic based on the ACMG/AMP criteria (PM1, PM6, PM2_supporting, PS4_supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA234034/MONDO:0100040/016

Frequency

Genomes: not found (cov: 32)

Consequence

FOXG1
NM_005249.5 missense

Scores

11
6
2

Clinical Significance

Likely pathogenic reviewed by expert panel P:6

Conservation

PhyloP100: 7.97
Variant links:
Genes affected
FOXG1 (HGNC:3811): (forkhead box G1) This locus encodes a member of the fork-head transcription factor family. The encoded protein, which functions as a transcriptional repressor, is highly expressed in neural tissues during brain development. Mutations at this locus have been associated with Rett syndrome and a diverse spectrum of neurodevelopmental disorders defined as part of the FOXG1 syndrome. This gene is disregulated in many types of cancer and is the target of multiple microRNAs that regulate the proliferation of tumor cells. [provided by RefSeq, Jul 2020]
LINC01551 (HGNC:19828): (long intergenic non-protein coding RNA 1551)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PS4
For more information check the summary or visit ClinGen Evidence Repository.
PM1
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PM6
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FOXG1NM_005249.5 linkuse as main transcriptc.670G>A p.Gly224Ser missense_variant 1/1 ENST00000313071.7 NP_005240.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FOXG1ENST00000313071.7 linkuse as main transcriptc.670G>A p.Gly224Ser missense_variant 1/1 NM_005249.5 ENSP00000339004 P1
FOXG1ENST00000706482.1 linkuse as main transcriptc.670G>A p.Gly224Ser missense_variant 2/2 ENSP00000516406 P1
LINC01551ENST00000675861.1 linkuse as main transcriptn.374+1936G>A intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:6
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Rett syndrome, congenital variant Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 18, 2023This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 224 of the FOXG1 protein (p.Gly224Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of FOXG1-related conditions (PMID: 30533527; external communication). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 167092). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FOXG1 protein function. Experimental studies have shown that this missense change affects FOXG1 function (PMID: 35163265). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitterclinical testingEquipe Genetique des Anomalies du Developpement, Université de BourgogneMar 30, 2017- -
Likely pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoMar 25, 2016- -
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Apr 09, 2014- -
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxDec 13, 2016A G224S variant that is likely pathogenic has been identified in the FOXG1 gene. The G224S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The G224S variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G224S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, the G224S variant occurs within the forkhead binding domain where all previously reported missense variants in FOXG1 have been identified and multiple missense variants in nearby residues have been reported in Human Gene Mutation Database in association with FOXG1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -
FOXG1 disorder Pathogenic:1
Likely pathogenic, reviewed by expert panelcurationClinGen Rett and Angelman-like Disorders Variant Curation Expert PanelFeb 18, 2022The p.Gly224Ser variant in FOXG1 is located in the well-characterized Forkhead functional domain (PMID 18571142, 28661489)(PM1). The p.Gly224Ser variant in FOXG1 occurs in the de novo state (biological parentage unconfirmed) in an individual with gross motor delay and infantile spasms (GeneDx internal database)(PM6). The p.Gly224Ser variant in FOXG1 is absent in gnomAD (PM2_supporting). The p.Gly224Ser variant has been observed in 2 individuals with neurodevelopmental disease (GeneDx internal database, University of Chicago internal database)(PS4_supporting). In summary, the p.Gly224Ser variant in FOXG1 is classified as likely pathogenic based on the ACMG/AMP criteria (PM1, PM6, PM2_supporting, PS4_supporting). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.33
D
BayesDel_noAF
Pathogenic
0.23
CADD
Pathogenic
34
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.98
D
Eigen
Uncertain
0.60
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.96
D
M_CAP
Pathogenic
0.80
D
MetaRNN
Pathogenic
0.94
D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Benign
1.6
L
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-5.5
D
REVEL
Pathogenic
0.80
Sift
Uncertain
0.013
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.82
MutPred
0.57
Gain of catalytic residue at I229 (P = 0.0159);
MVP
1.0
ClinPred
0.99
D
GERP RS
3.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.7
Varity_R
0.90
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs727503935; hg19: chr14-29237155; API