rs727503935

Variant names:

• chr14-28767949-G-A
• rs727503935
• NM_005249.5:c.670G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3 PM2_Supporting PS4_Moderate PM1 PS3_Supporting PM6

This summary comes from the ClinGen Evidence Repository: The p.Gly224Ser variant occurs in the well-characterized Forkhead functional domain of the FOXG1 gene (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 (Internal database - GeneDx) (PM6). Functional study has shown that this variant impacts protein function (PMID:35163265) (PS3_supporting). Computational prediction analysis tools suggest a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Gly224Ser variant in FOXG1 is absent from gnomAD v4.1.0 (PM2_Supporting). The p.Gly224Ser variant has been observed in 3 individuals with neurodevelopmental disease (PMID:30533527, Internal database - GeneDx, Internal database - University of Chicago) (PS4_moderate). In summary, this variant meets the criteria to be classified as Likely Pathogenic based on ACMG/AMP criteria (PM1, PM6, PS3_supporting, PP3_supporting, PM2_supporting, PS4_moderate). (FOXG1 specification v3.0.0; approved on 12/18/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA234034/MONDO:0100040/035

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOXG1 NM_005249.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 7.97

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)

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• 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.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXG1	NM_005249.5	c.670G>A	p.Gly224Ser	missense_variant	Exon 1 of 1	ENST00000313071.7	NP_005240.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXG1	ENST00000313071.7	c.670G>A	p.Gly224Ser	missense_variant	Exon 1 of 1	6	NM_005249.5	ENSP00000339004.3
FOXG1	ENST00000706482.1	c.670G>A	p.Gly224Ser	missense_variant	Exon 2 of 2			ENSP00000516406.1
LINC01551	ENST00000675861.1	n.374+1936G>A		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Rett syndrome, congenital variant Pathogenic:3

Aug 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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. -

Mar 25, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 30, 2017

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Dec 13, 2016

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A 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. -

Apr 09, 2014

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rett syndrome Pathogenic:1

Dec 24, 2024

Centre for Population Genomics, CPG

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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 likely 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: 30533527, GeneDx GTR Lab ID: 26957). Occurs in the well-characterized Forkhead functional domain of FOXG1 (PM1). This variant is absent from gnomAD (PM2_Supporting). -

FOXG1 disorder Pathogenic:1

Dec 18, 2024

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The p.Gly224Ser variant occurs in the well-characterized Forkhead functional domain of the FOXG1 gene (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 (Internal database - GeneDx) (PM6). Functional study has shown that this variant impacts protein function (PMID: 35163265) (PS3_supporting). Computational prediction analysis tools suggest a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Gly224Ser variant in FOXG1 is absent from gnomAD v4.1.0 (PM2_Supporting). The p.Gly224Ser variant has been observed in 3 individuals with neurodevelopmental disease (PMID: 30533527, Internal database - GeneDx, Internal database - University of Chicago) (PS4_moderate). In summary, this variant meets the criteria to be classified as Likely Pathogenic based on ACMG/AMP criteria (PM1, PM6, PS3_supporting, PP3_supporting, PM2_supporting, PS4_moderate). (FOXG1 specification v3.0.0; approved on 12/18/2024) -

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
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

Other links and lift over

dbSNP: rs727503935; hg19: chr14-29237155;