Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001868293 | SCV002277925 | likely pathogenic | Leber congenital amaurosis 2; Retinitis pigmentosa 20 | 2021-06-04 | criteria provided, single submitter | clinical testing | This variant has not been reported in the literature in individuals with RPE65-related conditions. ClinVar contains an entry for this variant (Variation ID: 560496). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with serine at codon 467 of the RPE65 protein (p.Pro467Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. 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 RPE65 protein function. 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. This variant disrupts the p.Pro467 amino acid residue in RPE65. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30996589, 31273949). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004702311 | SCV005203856 | pathogenic | Leber congenital amaurosis | 2024-07-02 | criteria provided, single submitter | clinical testing | Variant summary: RPE65 c.1399C>T (p.Pro467Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250854 control chromosomes. c.1399C>T has been reported in the literature in the compound heterozygous state in individuals affected with Leber Congenital Amaurosis (e.g. Haer-Wigman_2017, Yang_2019). These data indicate that the variant may be associated with disease. At least one in vitro study in HEK293 cells showed that this variant resulted in absent catalytic activity (e.g. Yang_2019). Another missense variant affecting this amino acid (p.Pro467Ala CV ID 1069898) has been determined to be pathogenic, supporting the critical relevance of codon 457 to RPE65 protein function. The following publications have been ascertained in the context of this evaluation (PMID: 28224992, 31580392). ClinVar contains an entry for this variant (Variation ID: 560496). Based on the evidence outlined above, the variant was classified as pathogenic. |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000678615 | SCV000804703 | uncertain significance | Leber congenital amaurosis 2 | 2016-09-01 | no assertion criteria provided | clinical testing |