Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000416550 | SCV000647085 | pathogenic | Axenfeld-Rieger syndrome type 3 | 2017-05-25 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. A different truncation downstream of this variant (c.816_817delinsG) has been determined to be pathogenic (PMID: 20881294). This suggests that deletion of this region of the FOXC1 protein is causative of disease. This variant has been reported to be de novo in an individual affected with Axenfeld-Rieger syndrome with developmental glaucoma (PMID: 16638984). ClinVar contains an entry for this variant (Variation ID: 375429). While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change results in a premature translational stop signal in the FOXC1 gene (p.Leu240Valfs*65). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 314 amino acids of the FOXC1 protein. |
| Human Developmental Genetics Laboratory, |
RCV000416550 | SCV002538959 | pathogenic | Axenfeld-Rieger syndrome type 3 | 2022-06-23 | criteria provided, single submitter | research | |
| Victorian Clinical Genetics Services, |
RCV000416550 | SCV002767748 | pathogenic | Axenfeld-Rieger syndrome type 3 | 2020-10-19 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 5-Pathogenic. Following criteria are met: 0102 - Loss of function is a likely mechanism of disease in this gene and is associated with Axenfeld-Rieger syndrome, type 3 (MIM #602482), anterior segment dysgenesis 3 (MIM #601631), congenital glaucoma (PMID: 31836490) and juvenile open angle glaucoma (PMID: 31836490). While some missense variants have been functionally proven, evidence for truncating variants are currently limited (PMID: 19513095). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Variants in FOXC1 have been reported to demonstrate inter- and intra-familial expressivity (PMIDs: 19513095; 31836490). 0204 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with at least 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other protein-truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. There are more than 4 protein-truncating variants located downstream of the current variant (ClinVar; Decipher). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been identified in individuals with Axenfeld-Rieger malformations (ClinVar; PMID: 16638984). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed) (Maternal VCGS #20G001795; Paternal VCGS #20G001796). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| Genetics and Molecular Pathology, |
RCV000416550 | SCV000494261 | pathogenic | Axenfeld-Rieger syndrome type 3 | 2015-06-11 | no assertion criteria provided | clinical testing | Frame-shift introducing premature terminating codon (PTC) effecting functional haploinufficiency; clinical significance consistent with FOXC1 PTC variants found upstream and down stream of this position - each regarded as pathogenic in published literature. |