Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000255136 | SCV000322175 | pathogenic | not provided | 2016-05-10 | criteria provided, single submitter | clinical testing | The N187K variant, resulting from a different nucleotide substitution (c.561 C>A), has been reported previously as a de novo variant in a patient referred for clinical whole exome sequencing (Farwell et al., 2015). Additionally, the N187K variant has been identified as a de novo variant in another patient with epilepsy at GeneDx. The N187K variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The N187K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution alters a conserved position predicted to occur within the forkhead binding domain of the FOXG1 protein where all previously reported missense variants in FOXG1 have been identified. A different missense variant in the same codon (N187D) as well as missense variants in nearby residues (L189V, M191R) have been reported in the Human Gene Mutation Database in association with FOXG1-related disorders (Stenson et al., 2014). |
Ambry Genetics | RCV000624779 | SCV000740873 | pathogenic | Inborn genetic diseases | 2015-04-16 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV001859479 | SCV002243734 | pathogenic | Rett syndrome, congenital variant | 2023-03-27 | criteria provided, single submitter | clinical testing | 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FOXG1 protein function. ClinVar contains an entry for this variant (Variation ID: 265363). This missense change has been observed in individual(s) with clinical features of FOXG1-related conditions (PMID: 28628100, 28661489). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 187 of the FOXG1 protein (p.Asn187Lys). |