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
Consequence
NM_005249.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FOXG1 | NM_005249.5 | c.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 |
---|---|---|---|---|---|---|---|---|---|---|
FOXG1 | ENST00000313071.7 | c.670G>A | p.Gly224Ser | missense_variant | 1/1 | NM_005249.5 | ENSP00000339004 | P1 | ||
FOXG1 | ENST00000706482.1 | c.670G>A | p.Gly224Ser | missense_variant | 2/2 | ENSP00000516406 | P1 | |||
LINC01551 | ENST00000675861.1 | n.374+1936G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 34
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Rett syndrome, congenital variant Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 18, 2023 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Mar 30, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 25, 2016 | - - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 09, 2014 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 13, 2016 | 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. - |
FOXG1 disorder Pathogenic:1
Likely pathogenic, reviewed by expert panel | curation | ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel | Feb 18, 2022 | 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). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at