The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene label mismatch: RPE65 vs undefined
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!


Variant: NM_000329.3(RPE65):c.310G>C (p.Gly104Arg)

CA340748268

978980 (ClinVar)

Gene: RPE65
Condition: RPE65-related recessive retinopathy
Inheritance Mode: Autosomal recessive inheritance
UUID: f5e96d1a-ab07-4c47-9160-a283113e88dd
Approved on: 2025-06-11
Published on: 2025-06-11

HGVS expressions

NM_000329.3:c.310G>C
NM_000329.3(RPE65):c.310G>C (p.Gly104Arg)
NC_000001.11:g.68444819C>G
CM000663.2:g.68444819C>G
NC_000001.10:g.68910502C>G
CM000663.1:g.68910502C>G
NC_000001.9:g.68683090C>G
NG_008472.1:g.10141G>C
NG_008472.2:g.10141G>C
ENST00000262340.6:c.310G>C
ENST00000262340.5:c.310G>C
NM_000329.2:c.310G>C
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Likely Pathogenic

Met criteria codes 4
PM2_Supporting PM3 PP3_Moderate PM5_Supporting
Not Met criteria codes 1
PP1

Evidence Links 0

Expert Panel

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

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP
NM_000329.3(RPE65):c.310G>C (p.Gly104Arg) is a missense variant that replaces glycine with arginine at amino acid 104. Another missense variant in the same codon, NM_000329.3(RPE65):c.311G>A (p.Gly104Asp), has been classified as likely pathogenic for RPE65-related recessive retinopathy by the ClinGen LCA/eoRD VCEP (PM5_Supporting). Splicing prediction using SpliceAI did not strongly predict an effect on splicing due to either of these variants. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 2 unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 point, PMID: 26355662, PMID: 23105016). The variant has been reported to segregate with RP through the proband plus at least 3 similarly affected relatives, with the variant present in the homozygous state (potential PP1_Strong; PMID: 23105016). However, the details on the phenotype was not included and unable for VCEP to confirm if phenotypically in keeping with LCA / eoRP. The computational predictor REVEL gives a score of 0.97, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate). In summary, this variant meets the criteria to be classified as likely pathogenic for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PM3, PM5_Supporting, and PP3_Moderate. (VCEP specifications version 1.0.0; date of approval 09/21/2023).
Met criteria codes
PM2_Supporting
This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
PM3
This variant has been reported in at least 1 unrelated probands with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 point, PMIDs: 26355662). This variant has been reported in at least 1 unrelated probands with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 point, PMIDs: 23105016).
PP3_Moderate
The computational predictor REVEL gives a score of 0.97, which is above the ClinGen LCA / eoRD VCEP threshold of ≥0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate).
PM5_Supporting
Another missense variant in the same codon (p.Gly104Asp) has been classified as likely pathogenic for RPE65-related recessive retinopathy by the ClinGen LCA/eoRD VCEP (PM5_Supporting). Splicing prediction using SpliceAI did not strongly predict an effect on splicing due to either of these variants.
Not Met criteria codes
PP1
The variant has been reported to segregate with RP through the proband plus at least 3 similarly affected relatives, with the variant present in the homozygous state (potential PP1_Strong; PMID: 23105016). However, the details on the phenotype was not included and unable for VCEP to confirm if phenotypically in keeping with LCA/eoRP.
Curation History
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