Variant: NM_000329.3(RPE65):c.1129-14A>G

CA902275

811223 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: ce12e5ac-edc8-4977-b646-46c3d6b79fe3

Approved on: 2024-07-23

Published on: 2024-07-23

HGVS expressions

NM_000329.3:c.1129-14A>G
NM_000329.3(RPE65):c.1129-14A>G
NC_000001.11:g.68431599T>C
CM000663.2:g.68431599T>C
NC_000001.10:g.68897282T>C
CM000663.1:g.68897282T>C
NC_000001.9:g.68669870T>C
NG_008472.1:g.23361A>G
NG_008472.2:g.23361A>G
ENST00000262340.6:c.1129-14A>G
ENST00000262340.5:c.1129-14A>G
NM_000329.2:c.1129-14A>G

Likely Benign

• Met criteria codes: BS1 BP4

• Not Met criteria codes: BP7

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.1129-14A>G is a non-coding variant located in intron 10. This variant is present in gnomAD v.4.1.1 at a GrpMax allele frequency of 0.003418, with 254 alleles / 74804 total alleles in the African / African American population, which is higher than the ClinGen LCA / eoRD VCEP BS1 threshold of >0.0008 (BS1). The splicing impact predictor SpliceAI gives a delta score of 0.01 for acceptor loss and donor loss, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4). This intronic variant is located between -1 and -21 relative to exon 11, and so is not considered eligible for BP7. In summary, this variant meets the criteria to be classified as likely benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: BS1 and BP4. (VCEP specifications version 1.0.0; date of approval 09/21/2023).

Met criteria codes

• BS1: This variant is present in gnomAD v.4.1.1 at a GrpMax allele frequency of 0.003418, with 254 alleles / 74804 total alleles in the African/African American population, which is higher than the ClinGen LCA / eoRD VCEP BS1 threshold of >0.0008 (BS1).
• BP4: There is no REVEL data for this variant. The splicing impact predictor SpliceAI gives a delta score of 0.01 for acceptor loss and donor loss, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4).

Not Met criteria codes

• BP7: This intronic variant c.1129-14A>G have an impact at splicing sites according to SpliceAI, which predicts a delta score of 0.01 for acceptor loss and donor loss, this intronic sites is between +7 and -21, which are not considered as eligible for this BP7 in ClinGen LCA / eoRD VCEP.