Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_025114.4(CEP290):c.1466T>C (p.Leu489Pro)

CA385979889

2932624 (ClinVar)

Gene: CEP290 (HGNC:80184)

Condition: CEP290-related ciliopathy (MONDO:0100451)

Inheritance Mode: Autosomal recessive inheritance

UUID: 57abb096-4a3b-4e54-b774-0e897a8bd09d

Approved on: 2026-07-20

Published on: 2026-07-20

HGVS expressions

NM_025114.4(CEP290):c.1466T>C (p.Leu489Pro)

NM_025114.4:c.1466T>C

NC_000012.12:g.88120170A>G

CM000674.2:g.88120170A>G

NC_000012.11:g.88513947A>G

CM000674.1:g.88513947A>G

NC_000012.10:g.87038078A>G

NG_008417.1:g.27047T>C

NG_008417.2:g.27047T>C

ENST00000309041.12:c.1466T>C

ENST00000397838.8:c.1412T>C

ENST00000547926.7:c.1466T>C

ENST00000552810.6:c.1466T>C

ENST00000671822.2:n.1693T>C

ENST00000672414.2:c.1466T>C

ENST00000673058.2:c.1466T>C

ENST00000674971.1:c.1466T>C

ENST00000675230.1:c.1445T>C

ENST00000675408.1:c.1466T>C

ENST00000675476.1:c.1466T>C

ENST00000675559.1:c.1466T>C

ENST00000675628.1:n.1693T>C

ENST00000675794.1:c.1466T>C

ENST00000675833.1:c.1466T>C

ENST00000676074.1:c.1466T>C

ENST00000676351.1:c.*979T>C

ENST00000676363.1:n.3529T>C

ENST00000676418.1:c.1466T>C

ENST00000676448.1:c.1466T>C

ENST00000309041.11:c.1466T>C

ENST00000397838.7:c.1466T>C

ENST00000547926.6:c.1364T>C

ENST00000552810.5:c.1466T>C

ENST00000604024.5:c.632T>C

NM_025114.3:c.1466T>C

Uncertain Significance

PP1 PP3 PM3 PM2_Supporting

PP4

Evidence Links 0

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 CEP290 Version 1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP

NM_025114.4(CEP290):c.1466T>C (p.Leu489Pro) is a missense variant that replaces leucine with proline at amino acid 489. This variant is present in gnomAD v4.1.1 at a total allele frequency of 0.0000006505, with 1 allele / 1,537,272 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0006 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_025114.4(CEP290):c.1666del (p.Ile556fs) variant confirmed in trans, which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (1 total point, PMID: 34196655, PM3). The proband exhibits a phenotype including diagnosis of either Leber congenital amaurosis, early onset severe retinal dystrophy, or retinitis pigmentosa (0.5 pts), which is not sufficiently specific for CEP290-related ciliopathy to meet the PP4 code (0.5 total points, PMID: 34196655). The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PMID: 34196655, PP1). The computational predictor CADD gives a score of 26.5, which is above the ClinGen LCA/eoRD VCEP threshold of ≥25.3 and predicts a damaging effect on CEP290 protein function (PP3). Additionally, the splicing impact predictor SpliceAI gives a score of 0.01 for donor loss, which is below the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing. In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for CEP290-related ciliopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PM3, PP3, and PP1. (LCA/eoRD VCEP Specifications for CEP290 Version 1.0.0)

PP1

The variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 1 similarly affected relative, with the variant present in the compound heterozygous state (PMID: 34196655, PP1).

PP3

The computational predictor CADD gives a score of 26.5, which is above the ClinGen LCA/eoRD VCEP threshold of ≥25.3 and predicts a damaging effect on CEP290 protein function (PP3). Additionally, the splicing impact predictor SpliceAI gives a score of 0.01 for donor loss, which is below the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing.

PM3

This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who was compound heterozygous with the NM_025114.4(CEP290):c.1666del (p.Ile556fs) variant confirmed in trans, which was previously classified pathogenic by the ClinGen LCA/eoRD VCEP (1 total point, PMID: 34196655, PM3).

PM2_Supporting

This variant is present in gnomAD v4.1.0 at a total allele frequency of 0.0000006505, with 1 allele / 1,537,272 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0006 (PM2_Supporting).

PP4

At least one proband harboring this variant exhibits a phenotype including diagnosis of either Leber congenital amaurosis, early onset severe retinal dystrophy, or retinitis pigmentosa (0.5 pts), which is not sufficiently specific for CEP290-related ciliopathy to meet the PP4 code (0.5 total points, PMID: 34196655).

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.