Variant: NM_000329.3(RPE65):c.893del (p.Lys298fs)

CA226586

372493 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: 2e6cbe73-5f18-4f64-99a5-01c90bfb9211

Approved on: 2024-02-20

Published on: 2024-02-20

HGVS expressions

NM_000329.3:c.893del
NM_000329.3:c.893delA
NM_000329.3(RPE65):c.893del (p.Lys298fs)
NC_000001.11:g.68439051del
CM000663.2:g.68439051del
NC_000001.10:g.68904734del
CM000663.1:g.68904734del
NC_000001.9:g.68677322del
NG_008472.1:g.15913del
NG_008472.2:g.15913del
ENST00000262340.6:c.893del
ENST00000262340.5:c.893del
NM_000329.2:c.893del

Pathogenic

• Met criteria codes: PP4 PVS1 PM3_Supporting PM2_Supporting

• Not Met criteria codes: BS1 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

NM_000329.3(RPE65):c.893delA (p.Lys298fs) 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 is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00002294, with 7 alleles / 129102 total alleles in the European (non-Finnish) population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). At least two probands harboring this variant exhibit a phenotype including undetectable ERG responses from rods (0.5 pts) and cones (1 pt), nystagmus (1 pt), retinal pigment epithelial mottling (0.5 pts), and reduced visual acuity (1 pt), which together are specific for RPE65-related recessive retinopathy (4 total points, PMID: 35129589, PP4). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 pts, PMID: 35129589, PM3_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_Supporting, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023).

Met criteria codes

• PP4: Two patients described in PMID: 35129589 exhibit undetectable rod ERG (required, 1pt), nystagmus (1pt), retinal pigment epithelial mottling (0.5pt), undetectable cone ERG (1pt), and reduced visual acuity (1pt), meeting the 4 required points for this criterion (PP4). The patients described in PMID: 15837919, PMID: 17848510, and PMID: 20079931 lack sufficient phenotypic detail for inclusion.
• PVS1: This deletion variant in exon 9 of 14 causes a frameshift that introduces a premature stop after 27 codons. This frameshift is predicted to trigger either nonsense mediated decay or disruption of approximately 44% of the protein product. Loss of function is a known mechanism for Leber congenital amaurosis 2 (PVS1).
• PM3_Supporting: Two homozygous cases meet the phenotypic requirement for consideration but are not necessarily unrelated (0.5pt, PMID: 35129589, PM3_Supporting). PM3 scoring from a compound heterozygous case (PMID: 15837919) was not considered to avoid circularity. Relevant evidence from VCEP-provided data was also not counted for PM3 to avoid circularity, as PM3 will be considered for one of the variants in trans.
• PM2_Supporting: The Popmax Filtering AF for this variant in gnomAD v2.1.1 is 0.00001972, which is lower than the ClinGen LCA/eoRD VCEP threshold (<0.0002) for this criterion (PM2_Supporting).

Not Met criteria codes

• BS1: The Popmax Filtering AF for this variant in gnomAD v2.1.1 is 0.00001972, which is lower than the ClinGen LCA/eoRD VCEP threshold (>0.000816) for BS1, failing to meet this criterion.
• BA1: The Popmax Filtering AF for this variant in gnomAD v2.1.1 is 0.00001972, which is lower than the ClinGen LCA/eoRD VCEP threshold (>0.00816) for BA1, failing to meet this criterion.