Submissions for variant NM_000329.3(RPE65):c.1451G>T (p.Gly484Val)

gnomAD frequency: 0.00001  dbSNP: rs62653015

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Leber Congenital Amaurosis/early Onset Retinal Dystrophy Variant Curation Expert Panel, ClinGen	RCV004527406	SCV005038762	pathogenic	RPE65-related recessive retinopathy	2024-04-22	reviewed by expert panel	curation	NM_000329.3(RPE65):c.1451G>T (p.Gly484Val) is a putative missense variant located in the first nucleotide of exon 14 that is predicted to cause the replacement of glycine with valine at codon 484. The computational predictor REVEL gives a score of 0.991, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.56, which is above the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and predicts a damaging impact on splicing (PP3_Moderate). Another missense variant at the same nucleotide, NM_000329.3(RPE65):c.1451G>A (p.Gly484Asp), has been classified as likely pathogenic for RPE65-related recessive retinopathy by the ClinGen LCA / eoRD VCEP and has a SpliceAI score of 0.23 for acceptor loss, indicating that both variants are predicted to have a damaging impact on splicing (PMID: 30025081, PMID: 34492281, PS1_Moderate). This variant is present in gnomAD v2.1.1 at a GrpMax allele frequency of 0.000002990, with 2 alleles / 111,040 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). This variant has been reported in at least 3 unrelated probands with early-onset severe retinal dystrophy who are homozygous for the variant (1 pt, PMID: 33308271, PMID: 32531858, PMID: 33472769). The 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.272G>A (p.Arg91Gln) variant confirmed in trans (1 pt, PMID: 38002999), which was previously classified pathogenic or likely pathogenic by the ClinGen LCA / eoRD VCEP (2 total pts, PM3_Strong). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 2 similarly affected relatives, with the variant present in the homozygous state (PMID: 33308271, PP1_Moderate). At least one proband harboring this variant exhibits a phenotype including clinical diagnosis of Leber congenital amaurosis (0.5 pts), symptomatic onset at age 3 months (1 pt), extinguished ERG responses from rods (0.5 pts) and cones, optic nerve pallor (0.5 pts), macular atrophy (0.5 pts), decreased peripheral vision (1 pt), abnormal color vision (1 pt), decreased central visual acuity (1 pt), nystagmus (1 pt), which together are specific for RPE65-related recessive retinopathy (total 7 pts, PMID: 33308271, PP4). 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: PS1_moderate, PM2_supporting, PM3_strong, PP1_moderate, PP3, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023).
Molecular Genetics Laboratory, Institute for Ophthalmic Research	RCV001199757	SCV001162647	pathogenic	Leber congenital amaurosis	2020-01-09	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV003769401	SCV004580025	pathogenic	Leber congenital amaurosis 2; Retinitis pigmentosa 20	2023-11-06	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 484 of the RPE65 protein (p.Gly484Val). This variant is present in population databases (rs62653015, gnomAD 0.01%). This missense change has been observed in individuals with RPE65-related conditions (PMID: 32531858, 33308271, 37704110). ClinVar contains an entry for this variant (Variation ID: 813222). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Gly484 amino acid residue in RPE65. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20811047, 29332120, 30653986; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.