Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV004527444 | SCV005038784 | pathogenic | RPE65-related recessive retinopathy | 2024-04-22 | reviewed by expert panel | curation | The NM_000329.3(RPE65):c.938A>G (p.His313Arg) variant is a missense substitution at His313, 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 0.964 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 VCEP PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PS3_Supporting, PMID: 24849605). At least one proband harboring this variant exhibits a phenotype including diagnosis of LCA (0.5 points), absent ERG (0.5 points), nystagmus (0.5 points) and decreased visual acuity (1 point). This patient showed significant improvement in several measures of dark-adapted vision after gene therapy treatment (8 points). Together these are highly specific for RPE65-related recessive retinopathy (10.5 points, PMID: 19854499, PP4_Moderate). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 points, PMIDs: 35129589). This variant has also been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the c.292_311del(p.Ile98Hisfs*26) variant suspected in trans (0.5 points) and at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the p.Tyr386 variant suspected in trans (0.5 points) (PMID: 35129589), which were both previously classified pathogenic by the ClinGen LCA/eoRD VCEP. (1.5 total points, PM3).This variant is present in gnomAD v.4.0.0 at a GrpMax allele frequency of 0.000002280, with 4 alleles/418086 total alleles in the European (Non-Finnish) population, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0002 (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: PP3_Moderate, PP4_Moderate, PM1, PM3, PM2_Supporting, PS3_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023) |
| Institute of Human Genetics, |
RCV002226568 | SCV002505527 | pathogenic | Leber congenital amaurosis 2 | 2022-04-21 | criteria provided, single submitter | clinical testing | This variant was identified as compound heterozygous with NM_000329.3:c.859G>T._x000D_ Criteria applied: PS3, PM3, PM5, PM1_SUP, PM2_SUP, PP3 |
| Labcorp Genetics |
RCV003101291 | SCV003523304 | likely pathogenic | Leber congenital amaurosis 2; Retinitis pigmentosa 20 | 2024-02-02 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 313 of the RPE65 protein (p.His313Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with early-onset severe retinal dystrophy, inherited retinal disease, and/or Leber congenital amaurosis (PMID: 17724218, 35129589, 36460718). ClinVar contains an entry for this variant (Variation ID: 1679125). 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 expected to disrupt RPE65 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects RPE65 function (PMID: 24849605). This variant disrupts the p.His313 amino acid residue in RPE65. Other variant(s) that disrupt this residue have been observed in individuals with RPE65-related conditions (PMID: 17724218, 24066033), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Baylor Genetics | RCV002226568 | SCV004209295 | pathogenic | Leber congenital amaurosis 2 | 2023-12-23 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003987987 | SCV004803442 | pathogenic | Leber congenital amaurosis | 2024-01-16 | criteria provided, single submitter | clinical testing | Variant summary: RPE65 c.938A>G (p.His313Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251390 control chromosomes (gnomAD). c.938A>G has been reported in the literature in multiple individuals affected with inherited retinal degeneration including Leber Congenital Amaurosis (e.g. Simonelli_2007, Testa_2022). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding no retinoid isomerase activity from the variant protein (Li_2014). The following publications have been ascertained in the context of this evaluation (PMID: 17724218, 24849605, 36271235). ClinVar contains an entry for this variant (Variation ID: 1679125). Based on the evidence outlined above, the variant was classified as pathogenic. |