Variant: NM_000329.3(RPE65):c.441A>G (p.Thr147=)

CA902507

716567 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: ad6cdaf9-6645-4a76-8fb6-68346a72c8aa

Approved on: 2024-04-22

Published on: 2024-04-22

HGVS expressions

NM_000329.3:c.441A>G
NM_000329.3(RPE65):c.441A>G (p.Thr147=)
NC_000001.11:g.68444585T>C
CM000663.2:g.68444585T>C
NC_000001.10:g.68910268T>C
CM000663.1:g.68910268T>C
NC_000001.9:g.68682856T>C
NG_008472.1:g.10375A>G
NG_008472.2:g.10375A>G
ENST00000262340.6:c.441A>G
ENST00000262340.5:c.441A>G
NM_000329.2:c.441A>G

Likely Benign

• Met criteria codes: BS1 BP7 BP4

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.441A>C (p.Thr147=) is a synonymous variant located in exon 5. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.006282, with 142 alleles/19954 total alleles in the East Asian 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 0.05 for donor gain, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4, 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, BP4, and BP7. (VCEP specifications version 1.0.0; date of approval 09/21/2023).

Met criteria codes

• BS1: This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.006282, with 142 alleles/19954 total alleles in the East Asian population, which is higher than the ClinGen LCA/eoRD VCEP BS1 threshold of >0.0008. Additionally, there is 1 homozygote in this population (BS1).
• BP7: The splicing impact predictor SpliceAI gives a delta score of 0.05, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP7).
• BP4: There is no REVEL data for this variant. The splicing impact predictor SpliceAI gives a delta score of 0.05, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4).