Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003235523 | SCV003933689 | likely pathogenic | FOXG1 disorder | 2023-04-14 | reviewed by expert panel | curation | The p.Ile207Thr variant in FOXG1 occurs in the de novo state (biological parentage confirmed) in an individual with a neurological disorder (Ambry internal database) (PS2). The p.Ile207Thr variant occurs in the well-characterized Forkhead functional domain of the FOXG1 (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Ile207Thr variant in FOXG1 is absent from gnomAD (PM2_supporting). In summary, the p.Ile207Thr variant in FOXG1 is classified as a likely pathogenic variant based on the ACMG/AMP criteria (PS2, PM1, PP3, PM2_supporting). |
| Ambry Genetics | RCV001266076 | SCV001444248 | likely pathogenic | Inborn genetic diseases | 2018-11-21 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001338819 | SCV001532514 | uncertain significance | Rett syndrome, congenital variant | 2020-07-12 | criteria provided, single submitter | clinical testing | This variant has not been reported in the literature in individuals with FOXG1-related conditions. This sequence change replaces isoleucine with threonine at codon 207 of the FOXG1 protein (p.Ile207Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). 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 and their clinical significance is uncertain. 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. |
| 3billion | RCV001338819 | SCV002012114 | likely pathogenic | Rett syndrome, congenital variant | 2021-10-02 | criteria provided, single submitter | clinical testing | Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with supporting evidence (ClinVar ID: VCV000985267.2, PS1_P). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.96, 3Cnet: 0.999, PP3). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. |
| Gene |
RCV004778038 | SCV005389294 | pathogenic | not provided | 2024-03-06 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge |