# NM_025114.4(CEP290):c.272_276del (p.Val91fs)

https://sugi.bio/variant/cep290-p-val91fs

## Summary

**CEP290 p.Val91fs (c.272_276del)** is classified **Pathogenic/Likely pathogenic** in CEP290 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-04-15). No gnomAD frequency available for this variant; Associated with Leber congenital amaurosis.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs2040498071 · 3 submitters · 5 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CEP290 gene that is considered likely disease-causing, submitted by 3 submitters, and is linked to Leber congenital amaurosis.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Prevalence | 1-9 / 100 000 (Europe) |
| Clinical trials | 23 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CEP290 is a diagnostic-grade gene on 15 Genomics England panels |

**Commonly reported features of Leber congenital amaurosis** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Severely reduced visual acuity — Very frequent (99-80%)
- Abnormality of retinal pigmentation — Very frequent (99-80%)
- Abnormality of the optic disc — Very frequent (99-80%)
- Abnormal electroretinogram — Frequent (79-30%)
- Cataract — Frequent (79-30%)
- Hypermetropia — Frequent (79-30%)
- Keratoconus — Frequent (79-30%)
- Photophobia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000634/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CEP290](https://sugi.bio/atlas/gene/CEP290/) |
| Protein change (HGVS p.) | p.Val91fs |
| Coding change (HGVS c.) | c.272_276del |
| MANE Select transcript | [NM_025114](https://www.ncbi.nlm.nih.gov/nuccore/NM_025114) |
| dbSNP | [rs2040498071](https://www.ncbi.nlm.nih.gov/snp/rs2040498071/) |
| Variant type | Deletion |
| Location | chr12:88139166-88139170 (GRCh38) |
| ClinVar | [VCV1457067](https://www.ncbi.nlm.nih.gov/clinvar/variation/1457067/) |

**All HGVS expressions:** `LRG_694:g.8047_8051del`, `LRG_694t1:c.272_276del`, `NC_000012.11:g.88532944_88532948del`, `NC_000012.12:g.88139167_88139171del`, `NG_008417.2:g.8047_8051del`, `NG_021187.1:g.1872_1876del`, `NM_025114.3:c.272_276delTAATG`, `NM_025114.4:c.272_276del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 6.134, GERP 1.03, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.094, pLI 1.2493e-48. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 5 of 54**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**CEP290** population constraint: LOEUF 1.094, pLI 1.2493e-48, missense-Z 0.17962; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **CEP290-related ciliopathy** — Definitive (AR)

## Protein context {#protein}

Residue **91** lies in the 'self-association (with itself or c-terminus)' region.

AlphaFold model confidence (whole protein): pLDDT 60.90, 0% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of CEP290 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** CEP290's established molecular role includes identical protein binding. p.Val91fs falls in the self-association (with itself or c-terminus) region.


### Pathways affected {#pathways}

CEP290 participates in **8 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [AURKA Activation by TPX2](https://reactome.org/content/detail/R-HSA-8854518) | curated |
| [Anchoring of the basal body to the plasma membrane](https://reactome.org/content/detail/R-HSA-5620912) | curated |
| [Loss of Nlp from mitotic centrosomes](https://reactome.org/content/detail/R-HSA-380259) | curated |
| [Loss of proteins required for interphase microtubule organization from the centrosome](https://reactome.org/content/detail/R-HSA-380284) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [Recruitment of NuMA to mitotic centrosomes](https://reactome.org/content/detail/R-HSA-380320) | curated |
| [Recruitment of mitotic centrosome proteins and complexes](https://reactome.org/content/detail/R-HSA-380270) | curated |
| [Regulation of PLK1 Activity at G2/M Transition](https://reactome.org/content/detail/R-HSA-2565942) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** identical protein binding.

**Biological process:** positive regulation of DNA-templated transcription, cilium assembly, regulation of establishment of protein localization, positive regulation of intracellular protein transport.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-04-15.

**Submitter consensus:** conflicting (2 Likely pathogenic, 1 Pathogenic).

**Submission history:** 3 submissions (2020–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-11-04 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2020-11-15 |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-04-15 |

## Associated conditions {#conditions}

[Leber congenital amaurosis](https://sugi.bio/atlas/disease/leber-congenital-amaurosis/), [Bardet-Biedl syndrome 14](https://sugi.bio/atlas/disease/bardet-biedl-syndrome-14/), [Joubert syndrome](https://sugi.bio/atlas/disease/joubert-syndrome/), [Meckel syndrome](https://sugi.bio/atlas/disease/meckel-syndrome/), [nephronophthisis](https://sugi.bio/atlas/disease/nephronophthisis/).

**Reported phenotype names (ClinVar):** Leber congenital amaurosis, Joubert syndrome, Meckel-Gruber syndrome, Nephronophthisis, Bardet-Biedl syndrome 14, Leber's amaurosis, Juvenile Nephronophthisis, DYSENCEPHALIA SPLANCHNOCYSTICA, GRUBER SYNDROME, Dysencephalia splachnocystica.

## Similar variants {#similar}

Related CEP290 variant pages (same residue, condition, or type): [CEP290 p.Val91=](/variant/cep290-p-val91), [CEP290 c.4438-3del](/variant/cep290-c-4438-minus-3del), [CEP290 p.Asn737_Leu738insTer](/variant/cep290-p-asn737-leu738inster), [CEP290 p.Ile556fs](/variant/cep290-p-ile556fs), [CEP290 p.Lys1343fs](/variant/cep290-p-lys1343fs), [CEP290 p.Lys484fs](/variant/cep290-p-lys484fs), [CEP290 p.Phe1950fs](/variant/cep290-p-phe1950fs), [CEP290 p.Ser319fs](/variant/cep290-p-ser319fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1457067). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*