Variant: NM_000329.3(RPE65):c.615_616del (p.Ile206fs)

CA226567

98880 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: 8ed7c094-b7ce-4bf5-9869-7768089704a9

Approved on: 2023-12-22

Published on: 2023-12-22

HGVS expressions

NM_000329.3:c.615_616del
NM_000329.3(RPE65):c.615_616del (p.Ile206fs)
NC_000001.11:g.68440881_68440882del
CM000663.2:g.68440881_68440882del
NC_000001.10:g.68906564_68906565del
CM000663.1:g.68906564_68906565del
NC_000001.9:g.68679152_68679153del
NG_008472.1:g.14079_14080del
NG_008472.2:g.14079_14080del
ENST00000262340.6:c.615_616del
ENST00000262340.5:c.615_616del
NM_000329.2:c.615_616del

Pathogenic

• Met criteria codes: PM2_Supporting PP4 PVS1

• Not Met criteria codes: BS1 PM3 BA1

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 RPE65 c.615_616del (p.Ile206fs) variant, previously known as 669delCA, is a frameshift variant that introduces a premature stop codon into exon 6 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). At least 1 patient with this variant exhibited nonrecordable ERG responses from rods (0.5 pts) and cones (1 pt), congenital night blindness (0.5 pts), onset between birth and five years (1 pt), decreased peripheral vision (1 pt), decreased central visual acuity (1 pt), and nystagmus (1 pt), which together are specific for RPE65-related recessive retinopathy (6 pts total, PMID: 11095629, PP4). This variant is absent from gnomAD v2.1.1 (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, PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023).

Met criteria codes

• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
• PP4: At least 2 patients with this variant (PMID: 11095629) displayed nonrecordable ERG and congenital night blindness, as well as laboratory phenotypes that scored 4 and 5 additional points, respectively. These included onset between birth and five years (1 point), decreased peripheral vision (1 point), evidence of cone involvement on ERG (1 point), decreased central vision acuity (1 point), and nystagmus (1 point). None of the 3 specific RPE65 phenotype findings were reported for either patient, however, this criterion has been met (PP4). An additional case from VCEP-provided data did not have sufficient phenotypic detail.
• PVS1: This deletion variant in exon 6 of 14 causes a frameshift that would introduce a premature stop after 27 codons. This frameshift is predicted to trigger either nonsense mediated decay or disruption of approximately 62% of the protein product. The affected exon 6 is present in both NCBI-reported transcripts.

Not Met criteria codes

• BS1: This variant is absent from gnomAD v2.1.1.
• PM3: This variant has been detected in at least 2 individuals with Leber congenital amaurosis, both of whom were compound heterozygous and found to harbor a second variant in trans. The variants in trans were NM_000329.3(RPE65):c.11+5G>A (ClinVar: 98825) and NM_000329.3(RPE65):c.1583G>T (p.Gly528Val) (ClinVar: 801494), respectively. Parental testing is likely to have been performed to confirm the presence of these variants in trans, but has not been explicitly described for these particular patients. A third, unpublished adult patient was reported through VCEP-provided data, with a diagnosis of Leber congenital amaurosis and no family history of the disease. The patient harbors this variant in trans with the NM_000329.3(RPE65):c.709C>T (p.Pro237Ser) variant (CA340745938). Since PM3 evidence may be applied in the opposite direction to evaluate the pathogenicity of these other variants, PM3 has not been considered in this curation to avoid circularity.
• BA1: This variant is absent from gnomAD v2.1.1.