Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003771239 | SCV004697379 | pathogenic | RPE65-related recessive retinopathy | 2024-02-18 | reviewed by expert panel | curation | NM_000329.3(RPE65):c.1399C>G is a missense variant causing substitution of proline by alanine at position 467. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00001898, with 2 alleles / 18384 total alleles in the East Asian population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). This variant has been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with the NM_000329.3(RPE65):c.998+1G>A or NM_000329.3(RPE65):c.130C>T (p.Arg44Ter) variants confirmed in trans (PMID: 31273949, PMID: 30996589), which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2 total points, PM3_Strong). At least one proband harboring this variant exhibits a phenotype including grey-white fundus albipunctatus‐like changes (2 pts), genotyping by exome sequencing that did not provide an alternative explanation for visual impairment (2 pts), night blindness with onset before age 5 years (1 pt), extinguished rod ERG responses (0.5 pts), and severely reduced cone ERG responses (1 pt), which together are specific for RPE65-related recessive retinopathy (6.5 total points, PMID: 31273949, PP4). Two other probands also meet the PP4 criteria including extinguished ERG, night blindness with onset in early childhood as well as additional consistent features such as white dot deposits in the mid-peripheral retina, and reduced visual acuity (PP4; PMID: 31273949). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative in 2 different families, with the variant present in the compound heterozygous state (PP1; PMID: 31273949). The computational predictor REVEL gives a score of 0.891, 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 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, PMID: 31580392). 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: PS3_Supporting, PM2_Supporting, PM3_Strong, PP1, PP3_Moderate, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). |
| Labcorp Genetics |
RCV001381888 | SCV001580462 | pathogenic | Leber congenital amaurosis 2; Retinitis pigmentosa 20 | 2023-11-27 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 467 of the RPE65 protein (p.Pro467Ala). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with RPE65-related conditions (PMID: 30996589, 31273949). 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. ClinVar contains an entry for this variant (Variation ID: 1069898). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RPE65 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. |
| Baylor Genetics | RCV003469666 | SCV004209210 | pathogenic | Leber congenital amaurosis 2 | 2024-01-27 | criteria provided, single submitter | clinical testing |