Total submissions: 10
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV003764793 | SCV004697400 | pathogenic | RPE65-related recessive retinopathy | 2024-02-20 | reviewed by expert panel | curation | NM_000329.3(RPE65):c.304G>T (p.Glu102Ter) is a nonsense variant that introduces a premature stop codon into exon 4 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 0.00004117, with 9 alleles / 113674 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 one proband harboring this variant exhibits a phenotype including childhood onset, nystagmus (1 pt), nyctalopia, reduced visual acuity (1 pt), undetectable electroretinogram responses from rods (0.5 pts) and cones (1 pt), and decreased peripheral vision (1 pt), which together are specific for RPE65-related recessive retinopathy (4.5 total pts, PMID: 11095629, 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: 15512997, PM3_Supporting). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the homozygous state (PMID: 15512997, PP1). 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, PP1, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). |
Ce |
RCV000085192 | SCV000574761 | pathogenic | not provided | 2021-06-01 | criteria provided, single submitter | clinical testing | |
Fulgent Genetics, |
RCV000763389 | SCV000894093 | pathogenic | Leber congenital amaurosis 2; Retinitis pigmentosa 20 | 2018-10-31 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000763389 | SCV001224972 | pathogenic | Leber congenital amaurosis 2; Retinitis pigmentosa 20 | 2023-12-20 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Glu102*) 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 (rs62642584, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with Leber congenital amaurosis, and retinal dystrophy (PMID: 11035546, 15512997, 30268864). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 98863). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
Institute of Medical Genetics and Applied Genomics, |
RCV000085192 | SCV001446903 | pathogenic | not provided | 2020-10-23 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000085192 | SCV001803594 | pathogenic | not provided | 2022-04-26 | criteria provided, single submitter | clinical testing | Nonsense 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: 15512997, 25525159, 32531858, 31589614, 11035546, 30268864) |
Baylor Genetics | RCV003467000 | SCV004209245 | pathogenic | Leber congenital amaurosis 2 | 2023-08-13 | criteria provided, single submitter | clinical testing | |
Retina International | RCV000085192 | SCV000117329 | not provided | not provided | no assertion provided | not provided | ||
Genome |
RCV001249229 | SCV001423163 | not provided | RPE65-Related Disorders | no assertion provided | phenotyping only | Variant interpretted as Pathogenic and reported on 02-05-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. | |
Natera, |
RCV001275333 | SCV001460407 | pathogenic | Leber congenital amaurosis | 2020-09-16 | no assertion criteria provided | clinical testing |