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.2414T>C (p.Leu805Pro)

CA6712335

866922 (ClinVar)

Gene: CEP290 (HGNC:80184)

Condition: CEP290-related ciliopathy (MONDO:0100451)

Inheritance Mode: Autosomal recessive inheritance

UUID: 8853a8cb-6125-497d-bafa-adfccd503e4d

Approved on: 2026-07-20

Published on: 2026-07-20

HGVS expressions

NM_025114.4:c.2414T>C

NM_025114.4(CEP290):c.2414T>C (p.Leu805Pro)

NC_000012.12:g.88109135A>G

CM000674.2:g.88109135A>G

NC_000012.11:g.88502912A>G

CM000674.1:g.88502912A>G

NC_000012.10:g.87027043A>G

NG_008417.1:g.38082T>C

NG_008417.2:g.38082T>C

ENST00000309041.12:c.2414T>C

ENST00000552810.6:c.2414T>C

ENST00000672414.2:c.*585T>C

ENST00000673058.2:c.2414T>C

ENST00000674971.1:c.2414T>C

ENST00000675230.1:c.2393T>C

ENST00000675408.1:c.2414T>C

ENST00000675476.1:c.3275T>C

ENST00000675628.1:n.2641T>C

ENST00000675794.1:c.*585T>C

ENST00000675833.1:c.3182T>C

ENST00000676074.1:c.2414T>C

ENST00000676363.1:n.4477T>C

ENST00000676448.1:c.*327T>C

ENST00000309041.11:c.2420T>C

ENST00000397838.7:c.2418T>C

ENST00000552810.5:c.2414T>C

ENST00000604024.5:c.1673T>C

NM_025114.3:c.2414T>C

Likely Pathogenic

PM2_Supporting PP4 PP1 PP3 PM3_Strong

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.2414T>C (p.Leu805Pro) is a missense variant that replaces the leucine with proline at amino acid 805. This variant is present in gnomAD v4.1.1 at a total allele frequency of 0.0000143, with 21 alleles / 1,464,678 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0006 (PM2_Supporting). 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). This variant has been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_025114.4(CEP290):c.1666del (p.Ile556fs) variant or the NM_025114.4(CEP290):c.4452_4455del (p.Lys1484AsnfsTer4) variant confirmed in trans, which were previously classified pathogenic by the ClinGen LCA/eoRD VCEP (2 total points, PM3_Strong). At least one proband harboring this variant exhibits a phenotype including diagnosis of cone-rod dystrophy (0.5 pts) with onset at birth (0.5 pts), frequent rubbing of the eyes (0.5 pts), glare sensitivity (0.5 pts), poor visual acuity (0.5 pts), visual field constriction (0.5 pts), normal scotopic but absent photopic electroretinogram responses, and a color vision disorder, with genotyping by whole genome sequencing and inherited retinal disease gene panel that did not identify an alternative basis for retinal disease (4 pts), which together are specific for CEP290-related ciliopathy (total 7 points, PMID: 37642804, PP4). The variant has also 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: 28559085, PP1). In summary, this variant meets the criteria to be classified as Likely Pathogenic for CEP290-related ciliopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: PM2_Supporting, PP3, PM3_Strong, PP4, and PP1. (LCA/eoRD VCEP Specifications for CEP290 Version 1.0.0)

PM2_Supporting

This variant is present in gnomAD v4.1.0 at a total allele frequency of 0.0000143, with 21 alleles / 1,464,678 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 cone-rod dystrophy (0.5 pts) with onset at birth (0.5 pts), frequent rubbing of the eyes (0.5 pts), glare sensitivity (0.5 pts), poor visual acuity (0.5 pts), visual field constriction (0.5 pts), normal scotopic but absent photopic electroretinogram responses, and a color vision disorder, with genotyping by whole genome sequencing and inherited retinal disease gene panel that did not identify an alternative basis for retinal disease (4 pts), which together are specific for RPE65-related recessive retinopathy (total 7 points, PMID: 37642804, PP4).

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: 28559085, 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).

PM3_Strong

This variant has been reported in at least 2 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_025114.4(CEP290):c.1666del (p.Ile556fs) variant or the NM_025114.4(CEP290):c.4452_4455del (p.Lys1484AsnfsTer4) variant confirmed in trans, which were previously classified pathogenic by the ClinGen LCA/eoRD VCEP (2 total points, PM3_Strong). This variant has been reported in 3 additional affected patients with either the c.5493del, p.Ala1832Profs*19, c.1065+1G>A, or c.4962_4963del, p.(Glu1656Asnfs*3) variant suspected in trans (VCEP member-provided data). These have not been included in PM3 pending confirmation of necessary phenotype details.

Curation History

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