Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001041992 | SCV001205647 | pathogenic | Leber congenital amaurosis 2; Retinitis pigmentosa 20 | 2024-01-17 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 408 of the RPE65 protein (p.Leu408Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with RPE65-related retinal dystrophy (PMID: 19431183, 26364624; Invitae). ClinVar contains an entry for this variant (Variation ID: 98834). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RPE65 protein function. Experimental studies have shown that this missense change affects RPE65 function (PMID: 19431183, 24849605, 26427455). For these reasons, this variant has been classified as Pathogenic. |
| SIB Swiss Institute of Bioinformatics | RCV001089894 | SCV001245401 | likely pathogenic | Leber congenital amaurosis 2 | 2020-02-14 | criteria provided, single submitter | curation | This variant is interpreted as likely pathogenic for Leber congenital amaurosis 2, autosomal recessive. The following ACMG Tag(s) were applied: PM2, PP3, PS3. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002509207 | SCV002819761 | likely pathogenic | Leber congenital amaurosis | 2022-12-23 | criteria provided, single submitter | clinical testing | Variant summary: RPE65 c.1223T>C (p.Leu408Pro) 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 250850 control chromosomes. c.1223T>C has been reported in the literature in at-least one individual affected with Leber Congenital Amaurosis (example, Stone_2007, Philp_2009). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <6% of normal RPE65 Isomerohydrolase activity in vitro (Philp_2009). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Retina International | RCV000085159 | SCV000117296 | not provided | not provided | no assertion provided | not provided |