Variant: NM_000329.3(RPE65):c.353+7G>A

CA902539

1117757 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: f90dd243-1bbd-4e2c-93d4-febbf9760216

Approved on: 2024-02-20

Published on: 2024-02-20

HGVS expressions

NM_000329.3:c.353+7G>A
NM_000329.3(RPE65):c.353+7G>A
NC_000001.11:g.68444769C>T
CM000663.2:g.68444769C>T
NC_000001.10:g.68910452C>T
CM000663.1:g.68910452C>T
NC_000001.9:g.68683040C>T
NG_008472.1:g.10191G>A
NG_008472.2:g.10191G>A
ENST00000262340.6:c.353+7G>A
ENST00000262340.5:c.353+7G>A
NM_000329.2:c.353+7G>A

Uncertain Significance

• Met criteria codes: PM2_Supporting

• Not Met criteria codes: BP4 PP3

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.353+7G>A is a non-coding variant in intron 4 near the junction with exon 4. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.0001415, with 6 alleles / 18394 total alleles in the East Asian population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting). The splicing impact predictor SpliceAI gives a score of 0.14 for acceptor gain, which is below the ClinGen LCA / eoRD VCEP recommended PP3 threshold of ≥0.2 and higher than the BP4 threshold of <0.1 and does not strongly predict an impact on splicing, so neither in silico predictor code is met. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: PM2_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023).

Met criteria codes

• PM2_Supporting: This variant has a frequency in gnomAD of 0.0001415 (East Asian population), which is lower than the VCEP's threshold of <0.0002 for PM2_Supporting.

Not Met criteria codes

• BP4: BP4 is not met because the SpliceAI score of 0.14 for acceptor gain is higher than the BP4 threshold of <0.1.
• PP3: PP3 is not met because the SpliceAI score of 0.14 for acceptor gain is lower than the PP3 threshold of >0.2.