Submissions for variant NM_005249.5(FOXG1):c.573G>A (p.Met191Ile)

dbSNP: rs1555321311

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV003235269	SCV003933696	likely pathogenic	FOXG1 disorder	2023-04-14	reviewed by expert panel	curation	The p.Met191Ile variant occurs in the well-characterized Forkhead functional domain of the FOXG1 gene (PM1). The p.Met191Ile variant in FOXG1 is absent from gnomAD (PM2_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). A pathogenic missense variant (p.Met191Arg) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 26364767, 26993267) (PM5). In summary, the p.Met191Ile variant in FOXG1 is classified as likely pathogenic for a FOXG1-related disorder based on the ACMG/AMP criteria (PM1, PM2_supporting, PP3, PM5).
GeneDx	RCV000522911	SCV000621505	likely pathogenic	not provided	2017-10-20	criteria provided, single submitter	clinical testing	A novel M191I variant that is likely pathogenic has been identified in the FOXG1 gene. The M191I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. A different missense substitution at the same position (M191R) has been reported previously in association with FOXG1-related disorders (McMahon et al., 2015; Trump et al., 2016). The M191I variant is not observed in large population cohorts (Lek et al., 2016). The M191I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a positionthat is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense variants in nearby residues (N187D, A188G, L189V, A193T) have been reported in the 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001297654	SCV001486682	likely pathogenic	Rett syndrome, congenital variant	2022-06-27	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FOXG1-related conditions. ClinVar contains an entry for this variant (Variation ID: 452682). 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. This variant disrupts the p.Met191 amino acid residue in FOXG1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26364767). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 191 of the FOXG1 protein (p.Met191Ile).