Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003764787 | SCV004697419 | likely pathogenic | RPE65-related recessive retinopathy | 2024-01-31 | reviewed by expert panel | curation | NM_000329.3(RPE65):c.1418T>A is a missense variant that substitutes valine with arginine at position 473. This variant has been reported in at least 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMID: 9501220, SCV001430890.1). This variant has also been reported in at least 1 probands with early-onset severe retinal dystrophy who was compound heterozygous with the p.Pro363Thr variant confirmed in trans (1 point, VCEP member-provided data), which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2 total points, PM3_Strong). At least one patient harboring the variant exhibits a phenotype including nondetectable ERG responses from rods (0.5 pts) and cones ( 1 pt), nyctalopia (0.5 pts), decreased central visual acuity (1 pt), symptomatic onset between birth and age 5 years (1 pt), light staring (1 pt), and positive response to RPE65 gene therapy (8 pts), which together are highly specific for RPE65-related recessive retinopathy (13 total points, VCEP member-provided data, PP4_Moderate). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.992, which is above the ClinGen LCA/eoRD VCEP PP3_Mod threshold of >0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). In summary, this variant meets the criteria to be classified as a Likely Pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM3_Strong, PP4_Moderate, PM2_Supporting, and PP3_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). |
| Foundation for Research in Genetics and Endocrinology, |
RCV004786365 | SCV001430890 | likely pathogenic | Retinitis pigmentosa 20 | 2020-08-20 | criteria provided, single submitter | clinical testing | A homozygous missense variation in exon 13 of the RPE65 gene that results in the amino acid substitution of Aspartic acid for Valine at codon 473 was detected. The observed variant c.1418T>A (p.Val473Asp) lies in the retinal pigment epithelial membrane protein domain of the RPE65 protein (Morimura et al. 1998) and has previously been reported in homozygous state in a patient affected with leber congenital amaurosis. The variant has not been reported in the 1000 genomes and gnomAD databases. The in silico prediction of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic. |
| Neuberg Centre For Genomic Medicine, |
RCV001250706 | SCV004048441 | likely pathogenic | Leber congenital amaurosis 2 | criteria provided, single submitter | clinical testing | The observed variant c.1418T>A (p.Val473Asp) has previously been reported in homozygous state in a patient affected with leber congenital amaurosis and it lies in the retinal pigment epithelial membrane protein domain of the RPE65 protein (Morimura et al. 1998). The p.Val473Asp variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Likely pathogenic. The amino acid Val at position 473 is changed to a Asp changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Val473Asp in RPE65 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. | |
| Baylor Genetics | RCV001250706 | SCV004209287 | likely pathogenic | Leber congenital amaurosis 2 | 2023-11-27 | criteria provided, single submitter | clinical testing | |
| Retina International | RCV000085173 | SCV000117310 | not provided | not provided | no assertion provided | not provided | ||
| Laboratory of Genetics in Ophthalmology, |
RCV001250706 | SCV001425584 | likely pathogenic | Leber congenital amaurosis 2 | no assertion criteria provided | research |