Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV004527431 | SCV005038761 | pathogenic | RPE65-related recessive retinopathy | 2024-04-22 | reviewed by expert panel | curation | NM_000329.3(RPE65):c.1451-1G>A is a canonical splice variant in intron 13 of RPE65 and is predicted to lead to the skipping of a critical exon in which missense variants have previously been established as a mechanism of disease (PVS1). This variant is present in gnomAD v.2.1.1 at an allele frequency of 0.000004024, with 1 allele / 6096 total alleles in the "Remaining Individuals" 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 clinical diagnosis of Leber congenital amaurosis (0.5 pts), symptomatic onset between birth and age five years (1 pt), poor pupillary light response (0.5 pts), RPE mottling (0.5 pts), macular atrophy (0.5 pts), decreased central visual acuity (1 pt), pigmentary retinopathy with attenuated vessels (0.5 pts), and nystagmus (1 pt), which together are specific for RPE65-related recessive retinopathy (total 5.5 points, PMID: 31957135, PP4). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through at least 2 affected meioses from 1 family, with the variant present in the homozygous state (PP1_Moderate; PMID: 31957135). 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, PP1_Moderate, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). |
| Pars Genome Lab | RCV001775532 | SCV002014041 | pathogenic | Retinitis pigmentosa 20 | 2021-11-01 | criteria provided, single submitter | clinical testing | We found this variant in a 9-year-old patient with RP. |
| 3billion | RCV001775532 | SCV002058708 | likely pathogenic | Retinitis pigmentosa 20 | 2022-01-03 | criteria provided, single submitter | clinical testing | Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_S). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M).Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. |
| Invitae | RCV003120686 | SCV003786327 | pathogenic | Leber congenital amaurosis 2; Retinitis pigmentosa 20 | 2022-07-15 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1321180). Disruption of this splice site has been observed in individual(s) with autosomal recessive Leber congenital amaurosis (PMID: 31273949, 31957135). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change affects an acceptor splice site in intron 13 of the RPE65 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. |
| Baylor Genetics | RCV003470896 | SCV004209265 | pathogenic | Leber congenital amaurosis 2 | 2023-06-12 | criteria provided, single submitter | clinical testing |