Submissions for variant NM_005249.5(FOXG1):c.344C>T (p.Ala115Val)

dbSNP: rs796052454

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV004584204	SCV005068292	benign	FOXG1 disorder	2024-02-23	reviewed by expert panel	curation	The allele frequency of the p.Ala115Val variant in FOXG1 is 0.061% in South Asian sub population in gnomAD v2, which is high enough to be classified as benign based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BA1). Computational analysis prediction tools suggest that the p.Ala115Val variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). The p.Ala115Val variant is observed in at least 2 unaffected individuals (internal database - GeneDx) (BS2). The p.Ala115Val variant is found in a patient with an alternate molecular basis of disease (internal database - GeneDx) (BP5). In summary, the p.Ala115Val variant in FOXG1 is classified as benign based on the ACMG/AMP criteria (BA1, BP4, BS2, BP5).
GeneDx	RCV000187440	SCV000241032	likely benign	not specified	2014-01-27	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852456	SCV002111197	uncertain significance	Rett syndrome, congenital variant	2023-04-06	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 205470). This variant has not been reported in the literature in individuals affected with FOXG1-related conditions. This variant is present in population databases (rs796052454, gnomAD 0.06%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 115 of the FOXG1 protein (p.Ala115Val).
PreventionGenetics, part of Exact Sciences	RCV003907655	SCV004719659	likely benign	FOXG1-related disorder	2021-10-10	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).