Variant: NM_000329.3(RPE65):c.700C>T (p.Arg234Ter)

CA226577

13114 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: c719d99d-e1a0-4363-b926-20e780fdf91c

HGVS expressions

NM_000329.3:c.700C>T
NM_000329.3(RPE65):c.700C>T (p.Arg234Ter)
NC_000001.11:g.68439586G>A
CM000663.2:g.68439586G>A
NC_000001.10:g.68905269G>A
CM000663.1:g.68905269G>A
NC_000001.9:g.68677857G>A
NG_008472.1:g.15374C>T
NG_008472.2:g.15374C>T
ENST00000262340.6:c.700C>T
ENST00000262340.5:c.700C>T
NM_000329.2:c.700C>T

Pathogenic

• Met criteria codes: PM2_Supporting PP4_Moderate PVS1 PP1

• Not Met criteria codes: BS1 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.700C>T (p.Arg234Ter) is a nonsense variant that introduces a premature stop codon in exon 7 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 6 probands have been reported with this variant, one of whom displayed nystagmus (1 pt), night blindness (0.5 pts), reduced visual acuity (1 pt), narrowing of retinal vessels (0.5 pts), moderate pallor of the optic discs (0.5 pts), difficulty discriminating any color (1 pt), unrecordable ERG (0.5 pts), absent autofluorescence (2 pts), and onset at birth (1 pt), which together are highly specific for RPE65-related recessive retinopathy (8 total pts, PMIDs: 9326927, PMID: 11264131 PMID: 15288992, PP4_moderate). Additionally, the variant has been reported to segregate with the phenotype (confirmed by absent ERG) in the proband plus one similarly affected sibling harboring the variant in the compound heterozygous state (PP1; PMID: 9326927). PM3 was not considered to avoid circularity, despite the presence of compound heterozygous cases harboring this variant as well as the p.Asn356fs, c.991_993dup (p.Trp331dup), or p.Arg124Ter variant. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.00002299, with 3 alleles / 34580 total alleles in the Admixed 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, PM2_Supporting, and PP1. (VCEP specifications version 1.0.0; date of approval 09/21/2023)

Met criteria codes

• PM2_Supporting: The Popmax Filtering AF for this variant in gnomAD v2.1.1 is 0.00002299, which is lower than the ClinGen LCA/eoRD VCEP threshold (<0.0002) for this criterion (PM2_Supporting).
• PP4_Moderate: At least one patient (Patient CG in PMIDs: 9326927,11264131 and 15288992) with this variant displayed nystagmus, low contrasted spots in the fundus, night blindness, 4/200 and 2/200 in right and left eyes, narrowing of retinal vessels, moderate pallor of the optic discs, could not discriminate any color, ERG unrecordable and absent autofluorescence, with onset at birth, which is highly specific for RPE65 retinopathy (PP4_moderate).
• PVS1: This nonsense variant in exon 7 of RPE65 is predicted to cause a premature stop codon in biologically-relevant-exon 7/14 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).
• PP1: The variant has been reported to segregate with RPE65 retinopathy (confirmed by absent ERG) in the proband plus one similarly affected sibling, both with the compound heterozygous variants Arg234Ter and c.1067del. (PP1; PMID: 9326927).

Not Met criteria codes

• BS1: The Popmax Filtering AF for this variant in gnomAD v2.1.1 is 0.00002299, which is lower than the ClinGen LCA/eoRD VCEP threshold (>0.000816) for this criterion.
• PM3: A patient with LCA (PMID: 9326927) harbors this variant in trans with the c.1067dup (p.Asn356fs) variant. Patient LCA-45a (PMID: 20683928) harbors this variant and the VCEP-classified VUS c.991_993dup (p.Trp331dup), without confirmation in trans. Both patients have met the required phenotype of severely reduced or extinguished ERG, but were not considered to avoid circularity. Patient arRP114 (PMID: 11095629) harbors this variant in trans with the p.Arg124Ter variant, which was not considered to avoid circularity, although the patient has met the required phenotype of congenital night blindness.

Approved on: 2023-12-22

Published on: 2023-12-22