CEP290 p.Leu1155fs
c.3462dup · rs2037140260 · VCV813157
ClinGen expert panel — Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP
Likely Pathogenic for CEP290-related ciliopathy. Applied ACMG criteria (verbatim):
PVS1 PM2_Supporting
Curation rationale (ClinGen, verbatim)
NM_025114.4(CEP290):c.3461dup (p.Leu1155ThrfsTer6) is a frameshift variant that introduces a premature stop codon into exon 30 of 54 and is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 1 proband with early-onset severe retinal dystrophy who harbored the variant in the compound heterozygous state with the NM_025114.4(CEP290):c.2T>A (p.Met1Lys) variant suspected in trans (PMID: 32531858). However, the proband was not counted for PM3 in order to avoid circularity. There is an additional report of the variant in an inherited retinal disease cohort (PMID: 36460718) but no additional details were available. 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: PVS1 and PM2_Supporting. (LCA/eoRD VCEP Specifications for CEP290 Version 1.0.0)
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Consequence | frameshift | predicted loss-of-function; NMD-escape possible for C-terminal truncations |
|---|---|---|
| Splicing | ||
| SpliceAI | — | not assessed · substitutions only |
| Constraint at this position | ||
| Conservation | phyloP 7.7 | phastCons 1 |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Population frequency
No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.
Variant & gene context
- Gene
- CEP290
- Protein
- p.Leu1155fs
- Coding
- c.3462dup
- MANE Select
- NM_025114
- dbSNP
- rs2037140260
- Type
- Duplication
- Location
- chr12:88092680 (GRCh38)
- Gene constraint
- LOEUF 1.094 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
- Structure
- AlphaFold pLDDT 60.90
- Residue 1155
- a UniProt-annotated variant site (in lca10; also found in a patient with night blindness and hearing loss); a UniProt-annotated variant site (in lca10)
Similar variants
- CEP290 p.Asn1775fs Pathogenic ★★★ same condition
- CEP290 p.Asn85fs Likely pathogenic ★★★ same condition
- CEP290 p.Asp450fs Likely pathogenic ★★★ same condition
- CEP290 p.Lys1042Ter Pathogenic ★★★ same condition
- CEP290 p.Thr973_Ala974insThr Likely pathogenic ★★★ same condition
- CEP290 p.Phe2466fs Uncertain significance ★★★ same condition
- CEP290 p.Arg1237fs Pathogenic/Likely pathogenic ★★ same condition
- CEP290 p.Leu1884fs Pathogenic ★★ same condition
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cep290-p-leu1155fs (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown