ClinVar Miner

Submissions for variant NM_005249.5(FOXG1):c.670G>A (p.Gly224Ser) (rs727503935)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000153265 SCV000202741 likely pathogenic not provided 2014-04-09 criteria provided, single submitter clinical testing
GeneDx RCV000153265 SCV000492334 likely pathogenic not provided 2016-12-13 criteria provided, single submitter clinical testing A G224S variant that is likely pathogenic has been identified in the FOXG1 gene. The G224S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The G224S variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G224S 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 across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, the G224S variant occurs within the forkhead binding domain where all previously reported missense variants in FOXG1 have been identified and multiple missense variants in nearby residues have been reported in 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.
Genetic Services Laboratory, University of Chicago RCV000500932 SCV000594858 likely pathogenic Rett syndrome, congenital variant 2016-03-25 criteria provided, single submitter clinical testing
Invitae RCV000500932 SCV000650056 uncertain significance Rett syndrome, congenital variant 2017-01-24 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 224 of the FOXG1 protein (p.Gly224Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a FOXG1-related disease. ClinVar contains an entry for this variant (Variation ID: 167092). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000500932 SCV000700153 likely pathogenic Rett syndrome, congenital variant 2017-03-30 criteria provided, single submitter clinical testing

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