Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV003235331 | SCV003933677 | likely pathogenic | FOXG1 disorder | 2023-04-14 | reviewed by expert panel | curation | The p.Leu189Val variant occurs in the well-characterized Forkhead functional domain of the FOXG1 gene (PM1). The p.Leu189Val variant in FOXG1 is absent from gnomAD (PM2_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). A pathogenic missense variant (p.Leu189Phe) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 28661489, GeneDx internal database)(PM5). In summary, the p.Leu189Val variant in FOXG1 is classified as likely pathogenic for a FOXG1-related disorder based on the ACMG/AMP criteria (PM1, PM2_supporting, PP3, PM5). |
Center for Human Genetics, |
RCV000659679 | SCV000781524 | uncertain significance | Rett syndrome, congenital variant | 2016-11-01 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000659679 | SCV001375956 | uncertain significance | Rett syndrome, congenital variant | 2019-10-20 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with FOXG1-related conditions (PMID: 25914188). ClinVar contains an entry for this variant (Variation ID: 547390). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Leu189 amino acid residue in FOXG1. Other variant(s) that disrupt this residue have been observed in individuals with FOXG1-related conditions (PMID:28661489), which suggests that this may be a clinically significant amino acid residue. 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. This sequence change replaces leucine with valine at codon 189 of the FOXG1 protein (p.Leu189Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. |
Baylor Genetics | RCV000659679 | SCV001527210 | likely pathogenic | Rett syndrome, congenital variant | 2018-04-11 | criteria provided, single submitter | clinical testing | This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in a female patient with global developmental delay without regression, microcephaly, diffuse hypotonia, hand dyskinesia, unsteady gait, sleep disturbance, unprovoked shrieking spells, mild hypomyelination, and small corpus callosum [PMID 25914188] |