Variant: NM_000329.3(RPE65):c.998+1G>A

CA340744551

1468758 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: 152f540a-5895-4486-b972-ddf7a4d2f7a0

HGVS expressions

NM_000329.3:c.998+1G>A
NM_000329.3(RPE65):c.998+1G>A
NC_000001.11:g.68438941C>T
CM000663.2:g.68438941C>T
NC_000001.10:g.68904624C>T
CM000663.1:g.68904624C>T
NC_000001.9:g.68677212C>T
NG_008472.1:g.16019G>A
NG_008472.2:g.16019G>A
ENST00000262340.6:c.998+1G>A
ENST00000262340.5:c.998+1G>A
NM_000329.2:c.998+1G>A

Pathogenic

• Met criteria codes: PVS1 PP4 PM2_Supporting

• Not Met criteria codes: BS1 BA1 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.998+1G>A is a non-coding variant that disrupts a canonical splice donor site in intron 9 at the junction with exon 9 and is predicted to lead to skipping of a critical exon in which missense variants have previously been established as a mechanism of disease (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one proband harboring this variant exhibits a phenotype including onset at before the age of 5 years (1 pt), night blindness, reduced visual acuity (1 pt), and extinguished ERG responses from rods (0.5 pts) and cones (1 pt), with exome sequencing-based genotyping that did not provide an alternative explanation for visual impairment (2 pts), which together are specific for RPE65-related recessive retinopathy (4.5 total pts, PMID: 31273949, PP4). 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, and PP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023).

Met criteria codes

• PVS1: This canonical splice variant disrupts a splicing donor site in intron 9. Abnormal splicing to exclude exon 9 (of 14 exons total) would be predicted to disrupt reading frame and trigger nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).
• PP4: Proband F14 II:1 meets the PP4 criteria with 5 total phenotype points given for trio exome sequencing (specific 2pt), onset at 2.5 years (consistent 1pt), myopia, night blindness (required, 1pt), reduced visual acuity (consistent 1pt), tapetoretinal degeneration, rod ERG extinguished (1pt, required), cone ERG extinguished (consistent 1pt), (PP4; PMID: 31273949). Proband F3-1 from PMID: 33952291 also meets PP4, but it is not clear whether he is distinct from or unrelated to Proband F14 II:1.
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

Not Met criteria codes

• BS1: This variant is absent from gnomAD v2.1.1.
• BA1: This variant is absent from gnomAD v2.1.1.
• PM3: Patient F14-II:1 from PMID: 31273949 meets the required phenotype criteria for consideration and is compound heterozygous for the paternal Pro467Ala and maternal c.998+1G>A variants, but has not been considered for this criterion in order to avoid circularity. Patient 3-1 from PMID: 33952291 has the same genotype as the aforementioned Patient F14-II:1 and may not be distinct or unrelated.

Approved on: 2024-02-20

Published on: 2024-02-20