Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV004595858 | SCV005088573 | pathogenic | RPE65-related recessive retinopathy | 2024-07-23 | reviewed by expert panel | curation | NM_000329.3(RPE65):c.329A>G (p.Asp110Gly) is a missense variant predicted to replace aspartic acid with glycine at position 110. This variant is a located within the membrane-interacting region between amino acids 107 and 125, which is a well-characterized functional domain required for proper localization to the ER membrane (PM1, PMID: 36265895). This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 0.0000007 with 4 alleles / 1180028 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). At least one proband harboring this variant exhibits a phenotype including a diagnosis of Leber congenital amaurosis (0.5 pts), onset by age 2 years (1 pt), extinguished electroretinogram responses from both rods (0.5 pts) and cones (1 pt), nystagmus (1 pt), attenuated retinal vessels with bone spicule pigmentation (0.5 pts), and optic nerve atrophy (0.5 pts), which together are specific for RPE65-related recessive retinopathy (5 total points, PMID: 26626312, PP4). This variant has been reported in at least 2 apparently unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMID: 26626312). This variant has also been reported in at least 2 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 (0.5+0.5 points, PMID: 26626312), which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (2 total points, PM3_Strong). The computational predictor REVEL gives a score of 0.945, which is above the ClinGen LCA/eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). 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: PM1, PM2_Supporting, PM3_Strong, PP3_Moderate, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023). |
| Labcorp Genetics |
RCV002535759 | SCV003523284 | likely pathogenic | Leber congenital amaurosis 2; Retinitis pigmentosa 20 | 2022-06-04 | criteria provided, single submitter | clinical testing | 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 636202). This missense change has been observed in individuals with autosomal recessive inherited retinal dystrophy (PMID: 26306921, 26626312, 30268864, 30718709). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 110 of the RPE65 protein (p.Asp110Gly). |
| Department of Clinical Genetics, |
RCV000787882 | SCV000926898 | uncertain significance | Retinitis pigmentosa | 2018-04-01 | no assertion criteria provided | research |