Variant: NM_000329.3(RPE65):c.962dup (p.Asn321fs)

CA226596

98902 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: 7f1ef1c4-0d84-41bd-84a9-da8ecb7a6b69

Approved on: 2024-04-22

Published on: 2024-04-22

HGVS expressions

NM_000329.3:c.962dup
NM_000329.3(RPE65):c.962dup (p.Asn321fs)
NC_000001.11:g.68438979dup
CM000663.2:g.68438979dup
NC_000001.10:g.68904662dup
CM000663.1:g.68904662dup
NC_000001.9:g.68677250dup
NG_008472.1:g.15982dup
NG_008472.2:g.15982dup
ENST00000262340.6:c.962dup
ENST00000262340.5:c.962dup
NM_000329.2:c.962dup

Pathogenic

• Met criteria codes: PM2_Supporting PVS1 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

This is a frameshift variant that introduces a premature stop codon into exon 9 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 been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the p.Arg124Ter variant confirmed in trans (1 point, PMID: 9501220), which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (1 total point, PM3).This variant has an allele frequency of 0.0001148 (1/8712) in the African/African-American population in gnomAD v2.1.1 (with no homozygotes). This allele frequency is lower than the ClinGen LCA/eoRD VCEP threshold (<0.0002) for this criterion (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, PM3, and PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023).

Met criteria codes

• PM2_Supporting: This variant has an allele frequency of 0.0001148 (1/8712) in the African / African-American population in gnomAD v2.1.1 (with no homozygotes). This allele frequency is lower than the ClinGen LCA/eoRD VCEP threshold (<0.0002) for this criterion (PM2_Supporting).
• PVS1: This is a frameshift variant that introduces a premature stop codon into exon 9 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).
• PM3: This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the p.Arg124Ter variant confirmed in trans (1 point) PMIDs: 9501220), which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (1 total points, PM3).