# NM_201253.3(CRB1):c.3708_3709dup (p.Ser1237fs)

https://sugi.bio/variant/crb1-p-ser1237fs

## Summary

**CRB1 p.Ser1237fs (c.3708_3709dup)** is classified **Pathogenic** in CRB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-25). No gnomAD frequency available for this variant; Associated with Leber congenital amaurosis 8.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2528205271 · 1 submitter · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CRB1 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Leber congenital amaurosis 8.

*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) |
| Diagnostic panels | CRB1 is a diagnostic-grade gene on 3 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/0010881/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CRB1](https://sugi.bio/atlas/gene/CRB1/) |
| Protein change (HGVS p.) | p.Ser1237fs |
| Coding change (HGVS c.) | c.3708_3709dup |
| MANE Select transcript | [NM_201253](https://www.ncbi.nlm.nih.gov/nuccore/NM_201253) |
| dbSNP | [rs2528205271](https://www.ncbi.nlm.nih.gov/snp/rs2528205271/) |
| Variant type | Duplication |
| Location | chr1:197435570-197435571 (GRCh38) |
| ClinVar | [VCV2060368](https://www.ncbi.nlm.nih.gov/clinvar/variation/2060368/) |

**All HGVS expressions:** `NC_000001.10:g.197404701_197404702dup`, `NC_000001.11:g.197435571_197435572dup`, `NG_008483.2:g.239110_239111dup`, `NG_008483.3:g.239069_239070dup`, `NM_001193640.2:c.3372_3373dup`, `NM_001257965.2:c.3636_3637dup`, `NM_001257966.2:c.2129-29_2129-28dup`, `NM_201253.3:c.3708_3709dup`, `NR_047563.2:n.3661_3662dup`, `NR_047564.2:n.3869_3870dup`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **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 1.619, GERP -2.67, phastCons 0.272 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.776, pLI 9.3619e-17. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 9 of 12**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication 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}

**CRB1** population constraint: LOEUF 0.776, pLI 9.3619e-17, missense-Z 0.63626. *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):

- **inherited retinal dystrophy** — Definitive (AR)

## Protein context {#protein}

Residue **1237** lies in a UniProt-annotated variant site (in lca8); the egf-like 17 domain.

AlphaFold model confidence (whole protein): pLDDT 75.19, 14% of residues very-high.

**1 experimental structure(s)** (PDB): [4UU5](https://www.rcsb.org/structure/4UU5).

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-12-25.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2021-12-25 |

## Associated conditions {#conditions}

[Leber congenital amaurosis 8](https://sugi.bio/atlas/disease/leber-congenital-amaurosis-8/), [retinitis pigmentosa 12](https://sugi.bio/atlas/disease/retinitis-pigmentosa-12/).

**Reported phenotype names (ClinVar):** Leber congenital amaurosis 8, Retinitis pigmentosa 12, RP WITH OR WITHOUT PPRPE, RP WITH OR WITHOUT PRESERVED PARAARTERIOLE RETINAL PIGMENT EPITHELIUM, RETINITIS PIGMENTOSA WITH OR WITHOUT PARAARTERIOLAR PRESERVATION OF RETINAL PIGMENT EPITHELIUM.

## Similar variants {#similar}

Related CRB1 variant pages (same residue, condition, or type): [CRB1 c.3878+2dup](/variant/crb1-c-3878-plus-2dup), [CRB1 p.Cys1240fs](/variant/crb1-p-cys1240fs), [CRB1 p.Ile20fs](/variant/crb1-p-ile20fs), [CRB1 p.Ile211fs](/variant/crb1-p-ile211fs), [CRB1 p.Ile384fs](/variant/crb1-p-ile384fs), [CRB1 p.Ser345fs](/variant/crb1-p-ser345fs), [CRB1 p.Ser586fs](/variant/crb1-p-ser586fs), [CRB1 p.Leu613_Gly614insVal](/variant/crb1-p-leu613-gly614insval).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2026-10-14); 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 2060368). 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.*