Variant: NM_000329.3(RPE65):c.89dup (p.Thr31fs)

CA226588

98898 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: 0a22e08a-0d93-4ef4-8e46-166ede59e369

Approved on: 2024-02-20

Published on: 2024-02-20

HGVS expressions

NM_000329.3:c.89dup
NM_000329.3(RPE65):c.89dup (p.Thr31fs)
NC_000001.11:g.68448629dup
CM000663.2:g.68448629dup
NC_000001.10:g.68914312dup
CM000663.1:g.68914312dup
NC_000001.9:g.68686900dup
NG_008472.1:g.6331dup
NG_008472.2:g.6331dup
ENST00000262340.6:c.89dup
ENST00000262340.5:c.89dup
NM_000329.2:c.89dup

Pathogenic

• Met criteria codes: PP4 PVS1 PM2_Supporting

• Not Met criteria codes: PM3

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.89dup (p.Thr31fs) is a frameshift variant that introduces a premature stop codon into exon 2 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). At least one proband harboring this variant exhibits a phenotype including diagnosis of cone-rod dystrophy, nyctalopia, RPE mottling (0.5 pts), abnormal color vision (1 pt), absence of fundus autofluorescence (2 pts), and infantile onset (1 pt), which together are specific for RPE65-related recessive retinopathy (4.5 total pts, PMID: 17525851, PMID: 15288992, 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 and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023).

Met criteria codes

• PP4: At least one published patient (described in both PMID: 17525851 and PMID: 15288992) has the required phenotype of nyctalopia (1 pt) as well as infantile onset (1 pt), RPE mottling (0.5 pt), absence of autofluorescence (2 pt) and abnormal color vision (1 pt), meeting the phenotype score required (PP4).
• PVS1: This variant causes a frameshift in exon 2 of 14 and is predicted to trigger nonsense-mediated decay (PVS1).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

Not Met criteria codes

• PM3: At least one proband (PMID: 17525851, PMID: 15288992) harbors this variant in the compound heterozygous state with the c.11+5G>A variant but has not been considered in order to avoid circularity.