Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003768526 | SCV004697381 | likely pathogenic | RPE65-related recessive retinopathy | 2024-02-18 | reviewed by expert panel | curation | NM_000329.3(RPE65):c.991_993dup is an in-frame insertion variant encoding a duplication of tryptophan 331. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to cause a change in the length of the protein due to an in-frame insertion encoding 1 amino acid in a non-repeat region, with at least one of the neighboring base pairs highly conserved with a PhyloP conservation score of 7.47347 (PM4_Supporting). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts), visual loss (1 pt) before the age of 5 years (1 pt), nystagmus (1 pt), undetectable or significantly reduced electroretinogram responses from rods (0.5 pts) and cones (1 pt), optic disc pallor (0.5 pt), and retinal pigment epithelium mottling (0.5 pts), which together are specific for RPE65-related recessive retinopathy (6 total pts, PMID: 20683928, 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: 20683928). This variant has also been reported in at least 3 probands with early-onset severe retinal dystrophy who were compound heterozygous with the NM_000329.3(RPE65):c.11+5G>A variant (suspected in trans, VCEP member-provided data), the NM_000329.3(RPE65):c.1102T>C (p.Tyr368His) variant (suspected in trans, PMID: 32032261), or the NM_000329.3(RPE65):c.700C>T (p.Arg234Ter) variant (confirmed in trans, PMID: 20683928), which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2.5 total points, PM3_Strong). 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 in one family member and in the compound heterozygous state in the other (PP1; PMID: 20683928). In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_Supporting, PM3_Strong, PM4_Supporting, PP1, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). |
| Invitae | RCV000815733 | SCV000956202 | pathogenic | Leber congenital amaurosis 2; Retinitis pigmentosa 20 | 2022-06-04 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 658837). This variant has been observed in individual(s) with Leber congenital amaurosis and/or retinitis pigmentosa (PMID: 20683928; Invitae). 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 not present in population databases (gnomAD no frequency). This variant, c.991_993dup, results in the insertion of 1 amino acid(s) of the RPE65 protein (p.Trp331dup), but otherwise preserves the integrity of the reading frame. |