Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000255576 | SCV000322419 | pathogenic | not provided | 2022-10-12 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect (reduced capacity for DNA binding and transactivation) (Saleem RA et al., 2003); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 14578375, 27535533, 28513611) |
Invitae | RCV000416497 | SCV003439266 | pathogenic | Axenfeld-Rieger syndrome type 3 | 2023-12-06 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 86 of the FOXC1 protein (p.Leu86Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Axenfeld-Rieger syndrome (PMID: 14578375, 17197537, 28513611). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 265478). 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 FOXC1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects FOXC1 function (PMID: 14506133, 14578375, 32631953). For these reasons, this variant has been classified as Pathogenic. |
Genetics and Molecular Pathology, |
RCV000416497 | SCV000494253 | likely pathogenic | Axenfeld-Rieger syndrome type 3 | 2016-03-11 | no assertion criteria provided | clinical testing | Missense; predicted to affect function by multiple algorithms (SIFT, PolyPhen), demonstrates reduced transactivation (Saleem et al., 2003), hightly conserved region, conservation throughout FOX gene family |