Submissions for variant NM_005249.5(FOXG1):c.131A>C (p.His44Pro)

gnomAD frequency: 0.00001  dbSNP: rs1555321183

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522323	SCV000616929	uncertain significance	not provided	2017-07-06	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the FOXG1 gene. The H44P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The H44P variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The H44P 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 in mammals. However, the H44P variant does not occur within the forkhead binding domain where all previously reported missense variants in FOXG1 have been identified. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001857939	SCV002297686	uncertain significance	Rett syndrome, congenital variant	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 44 of the FOXG1 protein (p.His44Pro). 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: 449126). 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 not expected to disrupt FOXG1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002384002	SCV002691805	uncertain significance	Inborn genetic diseases	2017-06-07	criteria provided, single submitter	clinical testing	The p.H44P variant (also known as c.131A>C), located in coding exon 1 of the FOXG1 gene, results from an A to C substitution at nucleotide position 131. The histidine at codon 44 is replaced by proline, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.