Variant: NM_000329.3(RPE65):c.1205G>A (p.Trp402Ter)

CA902254

660359 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: d1675ab6-2cdb-429d-9089-08505c1d2a7e

HGVS expressions

NM_000329.3:c.1205G>A
NM_000329.3(RPE65):c.1205G>A (p.Trp402Ter)
NC_000001.11:g.68431509C>T
CM000663.2:g.68431509C>T
NC_000001.10:g.68897192C>T
CM000663.1:g.68897192C>T
NC_000001.9:g.68669780C>T
NG_008472.1:g.23451G>A
NG_008472.2:g.23451G>A
ENST00000262340.6:c.1205G>A
ENST00000262340.5:c.1205G>A
NM_000329.2:c.1205G>A

Pathogenic

• Met criteria codes: PVS1 PP4_Moderate PM3_Supporting PM2_Supporting

• Not Met criteria codes: BA1 BS1

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 nonsense 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). At least one patient was analyzed on a 100+ retinal dystrophy gene panel testing that did not provide an alternative explanation for visual impairment (2 pts), displayed non-detectable ERG responses from rods (0.5 pts) and cones (1 pt), visual acuity 20/400 (1 pt), visual field of central island only (1 pt), nystagmus (1 pt), nyctalopia (0.5 pts), and no pigment in peripheral retina (0.5 pts), which together are specific for RPE65 retinopathy (7.5 pts total, PMID: 23847139, PP4). This variant has also been reported in at least 8 probands, one of whom exhibited LCA and was compound heterozygous with the p.Leu341Ser suspected in trans, which was previously classified pathogenic by the ClinGen LCA / eoRD VCEP (0.5 total points, PMID: 23847139, PM3_Supporting). This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00008316, with 9 alleles / 24960 total alleles in the African / African-American 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, PP4_Moderate, PM3_Supporting, and PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/23/2023).

Met criteria codes

• PVS1: The c.1205G>A (p.Trp402Ter) variant in exon 11 of RPE65 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 11/14 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).
• PP4_Moderate: At least one patient (analyzed on a 100+ retinal dystrophy gene panel testing in PMID: 23847139) with this variant displayed a non-detectable rod ERG (required, 1 pt), non-detectable cone ERG (1 pt), visual acuity 20/400 OD and OS (1 pt), visual field of central island only (1 pt), nystagmus (1 pt), nyctalopia (required, 1 pt), and no pigment in peripheral retina, which is highly specific for RPE65 retinopathy (PP4_Moderate).
• PM3_Supporting: At least 8 patients have been observed with this variant, only 1 of which had sufficient phenotypic information available to be included in this criteria. LCA patient 3784 is compound heterozygous for Trp402Ter and L341S (classified Pathogenic by the LCA/eoRD VCEP; ClinVar 13118). Confirmation of trans phase was not reported.
• PM2_Supporting: The Popmax Filtering AF in gnomAD v2.1.1 is 0.00008316, which is lower than the ClinGen LCA/eoRP VCEP threshold (>0.0002) for this criterion.

Not Met criteria codes

• BA1: The Popmax Filtering AF in gnomAD v2.1.1 is 0.00008316, which is lower than the ClinGen LCA/eoRP VCEP threshold (>0.00816) for this criterion.
• BS1: The Popmax Filtering AF in gnomAD v2.1.1 is 0.00008316, which is lower than the ClinGen LCA/eoRP VCEP threshold (>0.000816) for this criterion.

Approved on: 2023-12-22

Published on: 2023-12-22