Total submissions: 1
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000646225 | SCV000767985 | uncertain significance | Axenfeld-Rieger syndrome type 3 | 2017-12-23 | criteria provided, single submitter | clinical testing | This sequence change replaces proline with serine at codon 79 of the FOXC1 protein (p.Pro79Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with FOXC1-related disease. 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. Different missense substitutions at this codon (p.Pro79Leu, p.Pro79Thr, and p.Pro79Arg) have been reported in individuals affected with anterior segment dysgenesis and Axenfeld-Rieger syndrome (PMID: 11170889, 16936096), and at least one (p.Pro79Thr) has been determined to be pathogenic (PMID: 14506133, 27124303, 11589884). This suggests that the proline residue is critical for FOXC1 protein function and that other missense substitutions at this position may also be pathogenic. 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. |