Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV003235088 | SCV003933693 | uncertain significance | FOXG1 disorder | 2023-04-14 | reviewed by expert panel | curation | The p.Asn227Lys variant occurs in the well-characterized Forkhead functional domain of the FOXG1 gene (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Asn227Lys variant in FOXG1 is absent from gnomAD (PM2_supporting). The p.Asn227Lys variant was observed in an individual with microcephaly, rocking movements, absent speech, epilepsy, bruxism, severe scoliosis, and who is non-ambulatory. However, this individual's parents were not available for segregation analysis and this individual was evaluated once at the age of 13 years old (PMID 19578037) (PP4_not met). In summary, the p.Asn227Lys variant in FOXG1 is classified as a variant of uncertain significance based on the ACMG/AMP criteria (PM1, PP3, PM2_supporting). |
Institute of Human Genetics, |
RCV000170086 | SCV002026255 | likely pathogenic | Rett syndrome, congenital variant | 2018-01-20 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV000170086 | SCV002177809 | uncertain significance | Rett syndrome, congenital variant | 2021-09-21 | criteria provided, single submitter | clinical testing | This variant disrupts the p.Asn227 amino acid residue in FOXG1. Other variant(s) that disrupt this residue have been observed in individuals with FOXG1-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. 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: 189623). This missense change has been observed in individual(s) with Rett syndrome, congenital variant (PMID: 19578037). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with lysine at codon 227 of the FOXG1 protein (p.Asn227Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. 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. |
Centre for Population Genomics, |
RCV003235088 | SCV005046861 | uncertain significance | FOXG1 disorder | 2024-05-10 | criteria provided, single submitter | curation | This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as a variant of uncertain significance. At least the following criteria are met: met Occurs in the well-characterized Forkhead functional domain of FOXG1 (PM1). Computational prediction analysis tools suggests a deleterious impact (REVEL score>= 0.75) (PP3). This variant is absent from gnomAD v4 (PM2_Supporting). |
Rett |
RCV000170086 | SCV000222402 | uncertain significance | Rett syndrome, congenital variant | 2010-07-13 | no assertion criteria provided | curation |