Variant: NM_000329.3(RPE65):c.1207_1210dup (p.Glu404fs)

CA226492

98831 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: 8d940309-15f6-4411-b246-418af4646f73

Approved on: 2025-03-31

Published on: 2025-03-31

HGVS expressions

NM_000329.3:c.1207_1210dup
NM_000329.3(RPE65):c.1207_1210dup (p.Glu404fs)
NC_000001.11:g.68431508_68431511dup
CM000663.2:g.68431508_68431511dup
NC_000001.10:g.68897191_68897194dup
CM000663.1:g.68897191_68897194dup
NC_000001.9:g.68669779_68669782dup
NG_008472.1:g.23453_23456dup
NG_008472.2:g.23453_23456dup
ENST00000262340.6:c.1207_1210dup
ENST00000262340.5:c.1207_1210dup
NM_000329.2:c.1207_1210dup

Pathogenic

• Met criteria codes: PM2_Supporting PP4 PP1 PM3 PVS1

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

The NM_000329.3(RPE65):c.1207_1210dup (p.Glu404AlafsTer4) frameshift variant introduces a premature stop codon into exon 11 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 has also been reported in 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.2 c.1338+1 G>A variant confirmed in trans (1 point, PMID 32367544), which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (PM3). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state. (PP1; PMID: 32367544). At least one proband harboring this variant was tested by exome sequencing (2.0 pts) and exhibits a phenotype including optic disc pallor (0.5 pts), pigmentary retinopathy with attenuated vessels (0.5 pts), poor pupillary light response (0.5 pts), RPE mottling (0.5 pts), macular atrophy (0.5 pts), and decreased peripheral (1.0 pt) and central vision (1.0 pt) which together are specific for RPE65-related recessive retinopathy (6.5) points, (PMID: 32367544, PP4). This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 2.800e-7 with 3/1613960 alleles in the European (non-Finnish) population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_supporting). 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, PP1 and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023).

Met criteria codes

• PM2_Supporting: This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 2.800e-7 with 2/1613960 in the European (non-Finish) population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting).
• PP4: At least one proband harboring this variant was tested by exome sequencing (2.0) and exhibits a phenotype including optic disc pallor (0.5), pigmentary retinopathy with attenuated vessels (0.5), poor pupillary light response (0.5), RPE mottling (0.5), macular atrophy (0.5), and decreased peripheral (1.0) and central vision (1.0) which together are specific for RPE65-related recessive retinopathy (6.5) points, (PMID: 32367544, PP4).
• PP1: The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PP1; PMID: 32367544)
• PM3: This variant has also been reported in 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_000329.2 c.1338+1 G>A variant confirmed in trans (1 point, PMID 32367544), which was previously classified pathogenic or likely pathogenic by the ClinGen LCA / eoRD VCEP (PM3).
• PVS1: This is a frameshift variant that introduces a premature stop codon into exon 11 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).