Variant: NM_000329.3:c.1205_1206insCCTG

CA2497030194

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: 8b760b00-df46-4ba6-a3a2-4492ee13bcaa

Approved on: 2024-02-20

Published on: 2024-02-20

HGVS expressions

NM_000329.3:c.1205_1206insCCTG
NC_000001.11:g.68431511_68431512insGCAG
CM000663.2:g.68431511_68431512insGCAG
NC_000001.10:g.68897194_68897195insGCAG
CM000663.1:g.68897194_68897195insGCAG
NC_000001.9:g.68669782_68669783insGCAG
NG_008472.1:g.23451_23452insCCTG
NG_008472.2:g.23451_23452insCCTG
ENST00000262340.6:c.1205_1206insCCTG
ENST00000262340.5:c.1205_1206insCCTG
NM_000329.2:c.1205_1206insCCTG

Pathogenic

• Met criteria codes: PM2_Supporting PVS1 PP1_Strong

• Not Met criteria codes: PP4 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.1205_1206insCCTG (p.Trp402CysfsTer6) 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). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus at least 3 similarly affected relatives, with the variant present in the compound heterozygous state with the p.Leu341Ser variant in trans (PP1_strong; PMID: 9501220). At least 1 proband with early-onset severe retinal dystrophy harbored the variant in the compound heterozygous state with the p.Leu341Ser variant confirmed in trans (PMID: 9501220), however, the PM3 code was not considered to avoid circularity. 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, PP1_Strong. (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).
• 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).
• PP1_Strong: The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus at least 3 similarly affected relatives, with the variant present in the compound heterozygous state with the p.Leu341Ser variant in trans (PP1_strong; PMID: 9501220).

Not Met criteria codes

• PP4: At least one proband harboring this variant exhibits a phenotype including reduced or nondetectable rod (0.5 pts) and cone (1 pt) electroretinogram responses, which are not sufficiently specific for RPE65-related recessive retinopathy (1.5 points, PMID: 9501220), so the PP4 code is not met.
• PM3: This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who harbored the variant in the compound heterozygous state with the p.Leu341Ser variant confirmed in trans (PMID: 9501220). However, the PM3 code was not considered to avoid circularity.