Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003766145 | SCV004697402 | pathogenic | RPE65-related recessive retinopathy | 2024-02-20 | reviewed by expert panel | curation | NM_000329.3(RPE65):c.893delA (p.Lys298fs) is a frameshift variant that introduces a premature stop codon into exon 9 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00002294, with 7 alleles / 129102 total alleles in the European (non-Finnish) population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). At least two probands harboring this variant exhibit a phenotype including undetectable ERG responses from rods (0.5 pts) and cones (1 pt), nystagmus (1 pt), retinal pigment epithelial mottling (0.5 pts), and reduced visual acuity (1 pt), which together are specific for RPE65-related recessive retinopathy (4 total points, PMID: 35129589, PP4). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 pts, PMID: 35129589, PM3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PVS1, PM2_Supporting, PM3_Supporting, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). |
| Gene |
RCV000414568 | SCV000490776 | pathogenic | not provided | 2024-04-08 | criteria provided, single submitter | clinical testing | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 17848510, 17964524, 10766140, 16123401, 18055820, 31964843, 36460718, 24154662, 11462243) |
| Blueprint Genetics | RCV001074534 | SCV001240123 | pathogenic | Retinal dystrophy | 2018-02-05 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001225799 | SCV001398091 | pathogenic | Leber congenital amaurosis 2; Retinitis pigmentosa 20 | 2024-01-16 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Lys298Serfs*27) in the RPE65 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RPE65 are known to be pathogenic (PMID: 9326941, 9501220, 9843205, 18632300). This variant is present in population databases (rs757246161, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with Leber congenital amaurosis (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 372493). For these reasons, this variant has been classified as Pathogenic. |
| Baylor Genetics | RCV003470359 | SCV004209232 | pathogenic | Leber congenital amaurosis 2 | 2024-03-30 | criteria provided, single submitter | clinical testing | |
| Retina International | RCV000414568 | SCV000117365 | not provided | not provided | no assertion provided | not provided | ||
| Natera, |
RCV001275330 | SCV001460404 | pathogenic | Leber congenital amaurosis | 2020-09-16 | no assertion criteria provided | clinical testing |