Variant: NM_000329.3(RPE65):c.1380G>A (p.Trp460Ter)

CA340742114

870343 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: fcaac434-0096-4c19-9ab9-be5edaec35c1

HGVS expressions

NM_000329.3:c.1380G>A
NM_000329.3(RPE65):c.1380G>A (p.Trp460Ter)
NC_000001.11:g.68431135C>T
CM000663.2:g.68431135C>T
NC_000001.10:g.68896818C>T
CM000663.1:g.68896818C>T
NC_000001.9:g.68669406C>T
NG_008472.1:g.23825G>A
NG_008472.2:g.23825G>A
ENST00000262340.6:c.1380G>A
ENST00000262340.5:c.1380G>A
NM_000329.2:c.1380G>A

Pathogenic

• Met criteria codes: PVS1 PP4 PM3 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.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).

Met criteria codes

• PVS1: The c.1380G>A (p.Trp460Ter) variant in RPE65 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 13/14 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).
• PP4: At least one LCA patient (P25 in PMID: 19117922) with this variant displayed no detectable rod ERGs and only reduced cone ERGs, nystagmus from infancy, Visual Acuity (RE-LE) 20/1600–20/800, vessel attenuation, RPE depigmentation and granularity in the fundus which together are highly specific for RPE65 retinopathy (PP4).
• PM3: Jacobsen et al. (PMID 19117922) reports P25 who is compound heterozygous with c.11+5G>A (classified as Pathogenic by the LCA/eoRD VCEP), trans phase not confirmed (0.5 pt). Gao et al. (PMID 33952291) reports F15-1 who is compound heterozygous for the paternal c.1380G>A (p.Arg460Ter) and maternal c.886del (classified as Pathogenic by the LCA/eoRD VCEP)(1 pt). In summary 1.5 points total meets PM3.
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

Approved on: 2024-02-20

Published on: 2024-02-20