Submissions for variant NM_005249.5(FOXG1):c.645C>G (p.Phe215Leu)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414314	SCV000491602	pathogenic	not provided	2016-10-20	criteria provided, single submitter	clinical testing	The F215L pathogenic variant due to a C to G transversion at nucleotide 645 in the FOXG1 gene hasnot been reported previously as a pathogenic variant nor as a benign variant, to our knowledge.However, a female with congenital variant of Rett syndrome was found to be heterozygous for the denovo F215L variant due to a T to C transition at the same nucleotide position, denoted c.643C>T inthe publication due to alternate nomenclature (Mencarelli et al., 2010). The F215L variant was notobserved in approximately 6500 individuals of European and African American ancestry in theNHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.Although the F215L variant is a conservative amino acid substitution, it occurs at a position withinthe Fork-head DNA binding domain that is conserved across species and in silico analysis predicts thisvariant is probably damaging to the protein structure/function. We interpret F215L as a pathogenicvariant.
Invitae	RCV001069733	SCV001234923	pathogenic	Rett syndrome, congenital variant	2022-06-28	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 215 of the FOXG1 protein (p.Phe215Leu). For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 373043). This missense change has been observed in individual(s) with Rett syndrome (PMID: 19578037). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency).

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