Variant: NM_000329.3(RPE65):c.190C>T (p.Gln64Ter)

CA340749039

973954 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: 66188110-7a70-4f75-8d24-a9ca483ccd5b

Approved on: 2025-03-27

Published on: 2025-03-27

HGVS expressions

NM_000329.3:c.190C>T
NM_000329.3(RPE65):c.190C>T (p.Gln64Ter)
NC_000001.11:g.68446765G>A
CM000663.2:g.68446765G>A
NC_000001.10:g.68912448G>A
CM000663.1:g.68912448G>A
NC_000001.9:g.68685036G>A
NG_008472.1:g.8195C>T
NG_008472.2:g.8195C>T
ENST00000262340.6:c.190C>T
ENST00000262340.5:c.190C>T
NM_000329.2:c.190C>T

Pathogenic

• Met criteria codes: PP4_Moderate PM3_Supporting PVS1 PM2_Supporting

Expert Panel

Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP

Criteria Specification Information

Criteria Specification: ClinGen Leber Congenital Amaurosis/early onset Retinal Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPE65 Version 1.0.0

Evidence submitted by expert panel

Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP

NM_000329.3(RPE65):c.190C>T (p.Gln64Ter) is a nonsense variant that introduces a premature stop codon into exon 3 of 14, and is predicted to lead to nonsense-mediated decay in a gene (RPE65) in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting) but has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 points, PMID: 10090910, PM3_Supporting). At least one proband harboring this variant exhibits a phenotype including a clinical diagnosis of Leber congenital amaurosis (0.5 pts) with symptomatic onset between birth and age five years (1 pt). Additional phenotype features included nystagmus (1 pt), inability to follow light or objects, initially normal fundus, which gradually displayed a salt-and-pepper appearance (2 pts) with a reduction in blood-vessel diameter and often the typical appearance of retinitis pigmentosa (0.5 pts). Rod and cone ERG response were totally extinguished (1.5 pts). Proband also exhibited night blindness (0.5 pts), reduced visual acuity and decreased peripheral vision (1 pt). Together these are highly specific for RPE65-related recessive retinopathy (total 8 points, PMID:10090910, PP4_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: PVS1, PP4_Moderate, PM3_Supporting, PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023).

Met criteria codes

• PP4_Moderate: At least one proband harboring this variant exhibits a phenotype including a clinical diagnosis of Leber congenital amaurosis (0.5 pts) with symptomatic onset between birth and age five years (1 pt). Additional phenotype features included nystagmus (1 pt); inability to follow light or objects, initially normal fundus, which gradually displayed a salt-and-pepper appearance (2 pts) with a reduction in blood-vessel diameter and often the typical appearance of retinitis pigmentosa (0.5 pts). Rod and cone ERG response were totally extinguished (1.5 pts). Proband also exhibited night blindness (0.5 pts), reduced visual acuity and decreased peripheral vision (1 pt). Together these are highly specific for RPE65-related recessive retinopathy (total 8 points, PMID: 10090910, PP4_Moderate).
• PM3_Supporting: 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, PMID: 10090910, PM3_Supporting).
• PVS1: This is a nonsense variant that introduces a premature stop codon into exon 3 of 14, and is predicted to lead to nonsense-mediated decay in a gene (RPE65) in which loss-of-function is an established mechanism of disease.
• PM2_Supporting: This variant is absent from gnomAD v4.1.0 (PM2_Supporting).