Submissions for variant NM_005249.5(FOXG1):c.821G>C (p.Arg274Pro)

dbSNP: rs869312700

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002002475	SCV002237020	pathogenic	Rett syndrome, congenital variant	2021-01-06	criteria provided, single submitter	clinical testing	This variant has been observed in individual(s) with clinical features of FOXG1-related conditions (Invitae). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg274 amino acid residue in FOXG1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28554332). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 is not present in population databases (ExAC no frequency). This sequence change replaces arginine with proline at codon 274 of the FOXG1 protein (p.Arg274Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV002002475	SCV003920953	pathogenic	Rett syndrome, congenital variant	2022-10-03	criteria provided, single submitter	clinical testing