Variant: NM_000329.3(RPE65):c.432C>T (p.Tyr144=)

CA226551

98869 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: 8e911e71-3693-4daf-b9ae-6cb15e45c36a

Approved on: 2024-04-22

Published on: 2024-04-22

HGVS expressions

NM_000329.3:c.432C>T
NM_000329.3(RPE65):c.432C>T (p.Tyr144=)
NC_000001.11:g.68444594G>A
CM000663.2:g.68444594G>A
NC_000001.10:g.68910277G>A
CM000663.1:g.68910277G>A
NC_000001.9:g.68682865G>A
NG_008472.1:g.10366C>T
NG_008472.2:g.10366C>T
ENST00000262340.6:c.432C>T
ENST00000262340.5:c.432C>T
NM_000329.2:c.432C>T

Benign

• Met criteria codes: BA1

• Not Met criteria codes: 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.432C>T (p.Tyr144=) is a synonymous variant located in exon 5. This variant is present in gnomAD v.4.0.0 at a GrpMax allele frequency of 0.01115, with 852 alleles/75,028 total alleles in the African/African-American population, which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). Additionally, there are 5 homozygotes in this population in gnomAD. The splicing impact predictor SpliceAI gives a delta score of 0.15 for acceptor gain, which is above the ClinGen LCA / eoRD VCEP threshold of <0.1, so BP4 and BP7 are not met. In summary, this variant meets the criteria to be classified as benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA / eoRD VCEP: BA1. (VCEP specifications version 1.0.0; date of approval 09/21/2023).

Met criteria codes

• BA1: This variant is present in gnomAD v.4.0.0 at a GrpMax allele frequency of 0.01115, with 852 alleles/75,028 total alleles in the African/African American population, which is higher than the ClinGen LCA/eoRD VCEP BA1 threshold of >0.008. Additionally, there are 5 homozygotes in this population in gnomAD (BA1).

Not Met criteria codes

• BP7: The splicing impact predictor SpliceAI gives a delta score of 0.15 at 78bp, which is above the ClinGen LCA / eoRD VCEP threshold of <0.1 (BP7 not met).
• BP4: There is no REVEL data for this variant. The splicing impact predictor SpliceAI gives a delta score of 0.15 at 78bp, which is above the ClinGen LCA/eoRD VCEP threshold of <0.1 (BP4 not met).