Variant: NM_000329.3(RPE65):c.102C>A (p.Ile34=)

CA902595

770050 (ClinVar)

Gene: RPE65

Condition: RPE65-related recessive retinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: f3ab6638-bf66-49ae-a21a-a0e63704ac9d

Approved on: 2025-06-30

Published on: 2025-06-30

HGVS expressions

NM_000329.3:c.102C>A
NM_000329.3(RPE65):c.102C>A (p.Ile34=)
NC_000001.11:g.68446853G>T
CM000663.2:g.68446853G>T
NC_000001.10:g.68912536G>T
CM000663.1:g.68912536G>T
NC_000001.9:g.68685124G>T
NG_008472.1:g.8107C>A
NG_008472.2:g.8107C>A
ENST00000262340.6:c.102C>A
ENST00000262340.5:c.102C>A
NM_000329.2:c.102C>A

Likely Benign

• Met criteria codes: BP4 BP7

• Not Met criteria codes: BS1 PM2

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.102C>A is a synonymous variant encoding isoleucine at position p.34, and is located at the 8th nucleotide from the start of exon 3, outside of the first 3 nucleotides considered to be important for splicing. The splicing impact predictor SpliceAI gives a delta score of 0.0, which is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4, BP7). This variant is present in gnomAD v.4.1.0 with a GrpMax allele frequency of 0.0005837, with 733 alleles / 1,180,046 total alleles in the European (non-Finnish) population, which is higher than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 but lower than the BS1 threshold of >0.0008 and fails to meet either criterion. This variant has been reported in at least 1 proband with adult-onset retinal dystrophy who harbored the variant in the compound heterozygous state (PMID 35569774). However, the proband was not counted for PM3 because of the age of onset and because the NM_000329.3(RPE65):c.1237C>T (p.Arg413Cys) variant in trans has not yet been classified by the LCA / eoRD VCEP. 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: BP4 and BP7. (VCEP specifications version 1.0.0; date of approval 09/21/2023).

Met criteria codes

• BP4: NM_000329.3(RPE65):c.102C>A (p.Ile34=) is a synonymous (silent) exonic variant located 8th nucleotide from the start of exon 3, outside the splice region (first and the last 3 bases of the exon). SpliceAi reports a delta score 0.0. This is below the ClinGen LCA / eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4).
• BP7: NM_000329.3(RPE65):c.102C>A (p.Ile34=) is a synonymous (silent) exonic variant located 8th nucleotide from the start of exon 3, outside the splice region (first and the last 3 bases of the exon). (BP7).

Not Met criteria codes

• BS1: This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 0.0005837, with 733 alleles/1180046 total alleles in the European (non-Finnish) population, which is less than the ClinGen LCA/eoRD VCEP BS1 threshold of >0.0008.
• PM2: This variant is present in gnomAD v.4.1.0 at a Grpmax allele frequency of 0.0005837, with 733 alleles/1180046 total alleles in the European (non-Finnish) population , which is greater than the ClinGen LCA/eoRD VCEP PM2 threshold of <0.0002.