Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000488983 | SCV000577572 | likely pathogenic | not provided | 2017-01-25 | criteria provided, single submitter | clinical testing | The R127L variant has been published in a parent and child diagnosed with Axenfeld-Rieger syndrome (Du et al., 2016). The R127L variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R127L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species in the forkhead domain of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Based on the currently available information this variant is likely pathogenic |
| Invitae | RCV000532837 | SCV000647081 | likely pathogenic | Axenfeld-Rieger syndrome type 3 | 2017-12-14 | criteria provided, single submitter | clinical testing | A different missense substitution at this codon (p.Arg127His) has been determined to be pathogenic (PMID: 11740218). This suggests that the arginine residue is critical for FOXC1 protein function and that other missense substitutions at this position may also be pathogenic. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. This variant has been reported to segregate with disease in several families affected with Axenfeld Rieger syndrome (PMID: 24914578) and aniridia and peters anomaly (Invitae). ClinVar contains an entry for this variant (Variation ID: 426978). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with leucine at codon 127 of the FOXC1 protein (p.Arg127Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. |