Submissions for variant NM_005249.5(FOXG1):c.670G>A (p.Gly224Ser)

dbSNP: rs727503935

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV002260625	SCV002540696	likely pathogenic	FOXG1 disorder	2022-02-18	reviewed by expert panel	curation	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).
Eurofins Ntd Llc (ga)	RCV000153265	SCV000202741	likely pathogenic	not provided	2014-04-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000153265	SCV000492334	likely pathogenic	not provided	2016-12-13	criteria provided, single submitter	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.
Genetic Services Laboratory, University of Chicago	RCV000500932	SCV000594858	likely pathogenic	Rett syndrome, congenital variant	2016-03-25	criteria provided, single submitter	clinical testing
Invitae	RCV000500932	SCV000650056	pathogenic	Rett syndrome, congenital variant	2023-08-18	criteria provided, single submitter	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.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000500932	SCV000700153	likely pathogenic	Rett syndrome, congenital variant	2017-03-30	criteria provided, single submitter	clinical testing