Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003460769 | SCV004190227 | pathogenic | RPE65-related recessive retinopathy | 2023-12-22 | reviewed by expert panel | curation | The NM_000329.3(RPE65): c.495+1dup variant disrupts a canonical splice site in intron 5 and is predicted to lead to skipping of a critical exon in which missense variants have previously been established as a mechanism of disease (PVS1). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 point, PMID: 26656277). This variant has also been reported in at least 2 probands with early-onset severe retinal dystrophy, one of whom was compound heterozygous with the c.130C>T p.Arg44Ter variant confirmed in trans (1 pt, PMID: 26626312) which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (1.5 total points, PM3). This variant is absent from gnomAD v2.1.1 (PM2_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, PM3_strong, PM2_supporting (VCEP specifications version 1.0.0; date of approval 09/21/2023). |
| Labcorp Genetics |
RCV001857420 | SCV002247398 | pathogenic | Leber congenital amaurosis 2; Retinitis pigmentosa 20 | 2024-02-24 | criteria provided, single submitter | clinical testing | This sequence change affects a splice site in intron 5 of the RPE65 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RPE65 are known to be pathogenic (PMID: 9326941, 9501220, 9843205, 18632300). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Leber congenital amaurosis (PMID: 16123401, 26626312, 30268864). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS5+1_+2insG and c.495_495+1insG. ClinVar contains an entry for this variant (Variation ID: 98872). 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. |
| Gene |
RCV000085202 | SCV005327168 | pathogenic | not provided | 2024-03-19 | criteria provided, single submitter | clinical testing | Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16123401, 30268864, 26626312) |
| Retina International | RCV000085202 | SCV000117339 | not provided | not provided | no assertion provided | not provided |