Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003764627 | SCV004697407 | pathogenic | RPE65-related recessive retinopathy | 2024-02-20 | reviewed by expert panel | curation | NM_000329.3(RPE65):c.907A>T (p.Lys303Ter) is a nonsense 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 absent from gnomAD v2.1.1 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts) with infantile onset (1 pt), night blindness (0.5 pts), reduced visual acuity (0.5 pts), absence of electroretinogram responses from rods (0.5 pts) and cones, nystagmus (1 pt), loss of color vision (1 pt), severely constricted visual fields (1 pt), optic nerve head pallor (0.5 pts), attenuation of retinal arterioles (0.5 pts) with pigmentary changes, macular atrophy (0.5 pts), and significant improvement of dark-adapted vision following RPE65 gene therapy (8 pts), which together are highly specific for RPE65-related recessive retinopathy (15.5 total pts, PMID: 14962443, PMID: 22323828, PP4_Moderate). 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, and PP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023). |
| Gene |
RCV000085231 | SCV000329700 | pathogenic | not provided | 2016-01-22 | criteria provided, single submitter | clinical testing | The K303X variant in the RPE65 gene has been reported previously in the compound heterozygous state, opposite of a second RPE65 variant, in individuals affected with an RPE65-related disorder (Al-Khayer et al., 2004; Jacobson et al., 2005; Stone, et al., 2007). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The K303X variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we interpret K303X as a pathogenic variant. |
| Fulgent Genetics, |
RCV002490403 | SCV002799533 | pathogenic | Leber congenital amaurosis 2; Retinitis pigmentosa 20; Retinitis pigmentosa 87 with choroidal involvement | 2022-03-23 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV002513174 | SCV003296255 | pathogenic | Leber congenital amaurosis 2; Retinitis pigmentosa 20 | 2023-09-29 | criteria provided, single submitter | clinical testing | This premature translational stop signal has been observed in individual(s) with Leber congenital amaurosis (LCA) (PMID: 14962443). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 29872). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys303*) 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). |
| Baylor Genetics | RCV000022753 | SCV004209294 | pathogenic | Leber congenital amaurosis 2 | 2022-08-08 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000022753 | SCV000044042 | pathogenic | Leber congenital amaurosis 2 | 2004-02-01 | no assertion criteria provided | literature only | |
| Retina International | RCV000085231 | SCV000117368 | not provided | not provided | no assertion provided | not provided |