Submissions for variant NM_005249.5(FOXG1):c.268G>T (p.Ala90Ser)

dbSNP: rs906816341

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV003448907	SCV004176719	benign	FOXG1 disorder	2023-12-06	reviewed by expert panel	curation	The allele frequency of the p.Ala90Ser variant in FOXG1 is 0.01457% in Admixed American sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Ala90Ser variant is observed in 10 unaffected individuals (internal database - GeneDx) (BS2). Computational analysis prediction tools suggest that the p.Ala90Ser variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In summary, the p.Ala90Ser variant in FOXG1 is classified as Benign based on the ACMG/AMP criteria (BS1, BS2, BP4).
GeneDx	RCV001698373	SCV000533036	likely benign	not provided	2019-02-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001364359	SCV001560503	uncertain significance	Rett syndrome, congenital variant	2023-12-21	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 90 of the FOXG1 protein (p.Ala90Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. 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: 390253). 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.
CeGaT Center for Human Genetics Tuebingen	RCV001698373	SCV001961430	likely benign	not provided	2021-07-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002522566	SCV003616820	uncertain significance	Inborn genetic diseases	2022-05-16	criteria provided, single submitter	clinical testing	The c.268G>T (p.A90S) alteration is located in exon 1 (coding exon 1) of the FOXG1 gene. This alteration results from a G to T substitution at nucleotide position 268, causing the alanine (A) at amino acid position 90 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.