ClinVar Genomic variation as it relates to human health

NM_000329.3(RPE65):c.1380G>A (p.Trp460Ter) is a nonsense variant that introduces a premature stop codon into exon 13 of 14, and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in at least 2 unrelated probands with early-onset severe retinal dystrophy who were compound heterozygous with either the c.11+5G>A variant suspected in trans (0.5 points, PMID: 19117922) or the c.886del (p.Arg296fs) variant confirmed in trans (1 point, PMID: 33952291), both of which were previously classified pathogenic by the ClinGen LCA / eoRD VCEP (1.5 total points, PM3). At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts), infantile onset (1 pt), nystagmus (1 pt), no detectable rod ERG responses (0.5 pts), reduced cone ERG responses (1 pt), reduced visual acuity (1 pt), and pigmentary retinopathy with attenuated vessels (0.5 pts), which together are specific for RPE65-related recessive retinopathy (5.5 total points, PMID: 19117922, 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: PVS1, PM2_Supporting, PM3, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023).

This variant is interpreted as likely pathogenic for Leber congenital amaurosis 2, autosomal recessive. The following ACMG Tag(s) were applied: PM2, PVS1-Strong.

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in RPE65 are known to be pathogenic (PMID: 9326941, 9501220, 18632300). This variant has been observed in an individual affected with Leber congenital amaurosis (PMID: 17964524). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Trp460*) in the RPE65 gene. It is expected to result in an absent or disrupted protein product.

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 17964524, 20079931)