Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003768029 | SCV004697411 | likely pathogenic | RPE65-related recessive retinopathy | 2024-02-20 | reviewed by expert panel | curation | The NM_000329.3(RPE65):c.433G>C (p.Ala145Pro) is a predicted missense variant that changes the alanine at position 145 to proline. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.94, which is above the ClinGen LCA/eoRD VCEP threshold of >=0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). The variant exhibited approximately 0% enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is lower than the ClinGen LCA/eoRD PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PS3_Supporting, unpublished data from VCEP member). At least one proband harboring this variant exhibits a phenotype including diagnosis of severe early onset retinal dystrophy or retinitis pigmentosa with onset during the first decade of life, genotyping by hereditary retinal dystrophy panel showing no alternative explanation for disease (2 pts), reduced visual acuity (1 pt), peripheral visual field constriction (1 pt), and macular atrophy (0.5 pts), which together are specific for RPE65-related recessive retinopathy (4.5 points, PMID: 36017377, PP4). The reported proband was homozygous for the variant (PMID: 36017377, PM3_Supporting). Two other missense variants at the same codon have been reported in similarly affected individuals (NM_000329.3(RPE65):c.434C>A (p.Ala145Asp) in PMIDs: 31273949 and 23661369, and NM_000329.3(RPE65):c.433G>A (p.Ala145Thr) in PMID: 26906952). The p.Ala145Asp variant has been classified as likely pathogenic for RPE65-related recessive retinopathy by the ClinGen LCA/eoRD VCEP (PM5_Supporting). 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: PS3_Supporting, PM2_Supporting, PM3_Supporting, PM5_Supporting, PP3_Moderate, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000678616 | SCV000804704 | uncertain significance | Cone-rod dystrophy | 2016-09-01 | no assertion criteria provided | clinical testing |