Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV004527424 | SCV005038774 | pathogenic | RPE65-related recessive retinopathy | 2024-04-22 | reviewed by expert panel | curation | The NM_000329.3(RPE65):c.545A>G (p.His182Arg) variant in RPE65 is a missense variant resulting in a substitution of histidine by arginine at codon 182 . This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in at least 2 probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMIDs: 19117922, 27102010). This variant has also been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) variant confirmed in trans (1 point, PMID: 31273949), which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2 total points, PM3_Strong). This variant is a missense substitution at p.His182, which is located within the active site, a well-characterized functional domain required for enzymatic activity (PM1, PMID: 34492281). The computational predictor REVEL gives a score of 0.900, which is above the ClinGen LCA / eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). Another missense variant in the same codon (NM_000329.3(RPE65):c.544C>T (p.His182Tyr) has been classified as Pathogenic for RPE65-related recessive retinopathy by the ClinGen LCA / eoRD VCEP (PM5, ClinVar Variation ID: 98875). Splicing prediction using SpliceAI did not strongly predict an effect on splicing due to either of these variants. 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: PM2_Supporting, PM3_Strong, PM1, PP3_Moderate, PM5. (VCEP specifications version 1.0.0; date of approval 09/21/2023). |
| Labcorp Genetics |
RCV001388256 | SCV001589176 | pathogenic | Leber congenital amaurosis 2; Retinitis pigmentosa 20 | 2022-02-20 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.His182 amino acid residue in RPE65. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9501220, 16150724, 27874104). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1074826). This missense change has been observed in individual(s) with retinitis pigementosa or Leber congenital amaurosis (PMID: 18722466, 20079931, 31273949). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 182 of the RPE65 protein (p.His182Arg). |
| Baylor Genetics | RCV003469740 | SCV004209261 | pathogenic | Leber congenital amaurosis 2 | 2023-06-29 | criteria provided, single submitter | clinical testing |