# NM_000321.3(RB1):c.2139dup (p.Val714fs)

https://sugi.bio/variant/rb1-p-val714fs

## Summary

**RB1 p.Val714fs (c.2139dup)** is classified **Pathogenic** in RB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-17). Associated with hereditary retinoblastoma.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the RB1 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to hereditary retinoblastoma.

*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, Not applicable |
| Age of onset (of this condition) | Antenatal, Childhood, Infancy |
| Prevalence | <1 / 1 000 000 (Europe) |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | RB1 is a diagnostic-grade gene on 7 Genomics England panels |

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

- Retinoblastoma — Obligate (100%)
- Strabismus — Frequent (79-30%)
- Glaucoma — Frequent (79-30%)
- Proptosis — Frequent (79-30%)
- Leukocoria — Frequent (79-30%)
- Hypopyon — Frequent (79-30%)
- Uveitis — Occasional (29-5%)
- Heterochromia iridis — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017544/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [RB1](https://sugi.bio/atlas/gene/RB1/) |
| Protein change (HGVS p.) | p.Val714fs |
| Coding change (HGVS c.) | c.2139dup |
| MANE Select transcript | [NM_000321](https://www.ncbi.nlm.nih.gov/nuccore/NM_000321) |
| Variant type | Duplication |
| Location | chr13:48463760-48463761 (GRCh38) |
| ClinVar | [VCV4759394](https://www.ncbi.nlm.nih.gov/clinvar/variation/4759394/) |

**All HGVS expressions:** `LRG_517:g.165017dup`, `LRG_517t1:c.2139dup`, `NC_000013.10:g.49037899dup`, `NC_000013.11:g.48463763dup`, `NG_009009.1:g.165017dup`, `NM_000321.3:c.2139dup`, `NM_001407165.1:c.2139dup`

## 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 1.394, GERP 0.979, phastCons 1 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.239, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 21 of 27**, 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.

*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}

**RB1** population constraint: LOEUF 0.239, pLI 1, missense-Z 2.32; ClinGen dosage — haploinsufficiency 3, 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):

- **retinoblastoma** — Definitive (AD)

## Protein context {#protein}

Residue **714** lies in an α-helix; the 'pocket; binds t and e1a' region; the 'domain b' region.

AlphaFold model confidence (whole protein): pLDDT 77.03, 53% of residues very-high.

**19 experimental structure(s)** (PDB): [1AD6](https://www.rcsb.org/structure/1AD6), [1GH6](https://www.rcsb.org/structure/1GH6), [1GUX](https://www.rcsb.org/structure/1GUX), [1H25](https://www.rcsb.org/structure/1H25), [1N4M](https://www.rcsb.org/structure/1N4M), [1O9K](https://www.rcsb.org/structure/1O9K).

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

*Describes the biological roles of RB1 (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:** RB1's established molecular role includes kinase binding. p.Val714fs falls in the pocket; binds t and e1a region. In Reactome, RB1 is annotated in disease pathway(s) including **Aberrant regulation of mitotic exit in cancer due to RB1 defects**, **Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)**.

**Disease mechanism (Reactome):** RB1 loss or alteration is curated in [Aberrant regulation of mitotic exit in cancer due to RB1 defects](https://reactome.org/content/detail/R-HSA-9687136), [Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)](https://reactome.org/content/detail/R-HSA-9661069), [Defective translocation of RB1 mutants to the nucleus](https://reactome.org/content/detail/R-HSA-9661070).

### Pathways affected {#pathways}

RB1 participates in **18 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Aberrant regulation of mitotic exit in cancer due to RB1 defects](https://reactome.org/content/detail/R-HSA-9687136) | curated |
| ⚕ [Defective binding of RB1 mutants to E2F1,(E2F2, E2F3)](https://reactome.org/content/detail/R-HSA-9661069) | curated |
| ⚕ [Defective translocation of RB1 mutants to the nucleus](https://reactome.org/content/detail/R-HSA-9661070) | curated |
| ⚕ [Nuclear events stimulated by ALK signaling in cancer](https://reactome.org/content/detail/R-HSA-9725371) | curated |
| ⚕ [Replication of the SARS-CoV-1 genome](https://reactome.org/content/detail/R-HSA-9682706) | curated |
| ⚕ [Replication of the SARS-CoV-2 genome](https://reactome.org/content/detail/R-HSA-9694686) | electronic |
| [APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1](https://reactome.org/content/detail/R-HSA-174178) | curated |
| [Condensation of Prophase Chromosomes](https://reactome.org/content/detail/R-HSA-2299718) | curated |
| [Cyclin A:Cdk2-associated events at S phase entry](https://reactome.org/content/detail/R-HSA-69656) | curated |
| [Cyclin D associated events in G1](https://reactome.org/content/detail/R-HSA-69231) | curated |
| [Cyclin E associated events during G1/S transition ](https://reactome.org/content/detail/R-HSA-69202) | curated |
| [Formation of Senescence-Associated Heterochromatin Foci (SAHF)](https://reactome.org/content/detail/R-HSA-2559584) | curated |
| [MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis](https://reactome.org/content/detail/R-HSA-9841922) | curated |
| [Oncogene Induced Senescence](https://reactome.org/content/detail/R-HSA-2559585) | curated |
| [Phosphorylation of proteins involved in G1/S transition by active Cyclin E:Cdk2 complexes](https://reactome.org/content/detail/R-HSA-69200) | curated |
| [Positive Regulation of CDH1 Gene Transcription](https://reactome.org/content/detail/R-HSA-9764790) | curated |
| [Inhibition of replication initiation of damaged DNA by RB1/E2F1](https://reactome.org/content/detail/R-HSA-113501) | electronic |
| [RUNX2 regulates osteoblast differentiation](https://reactome.org/content/detail/R-HSA-8940973) | electronic |

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

**Molecular function:** kinase binding, ubiquitin protein ligase binding, identical protein binding, phosphoprotein binding, molecular adaptor activity, importin-alpha family protein binding.

**Biological process:** regulation of DNA-templated transcription, negative regulation of protein kinase activity, Ras protein signal transduction, regulation of mitotic cell cycle, negative regulation of gene expression, sister chromatid biorientation.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-09-17.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ramesar Group, Division of Human Genetics, Institute of Infectious Diseases and Molecular Medicine, UCT/MRC Genomic and Precision Medicine Research Unit, University of Cape Town | Pathogenic | criteria provided, single submitter | research | 2025-09-17 |

## Associated conditions {#conditions}

[hereditary retinoblastoma](https://sugi.bio/atlas/disease/hereditary-retinoblastoma/).

**Reported phenotype names (ClinVar):** Hereditary retinoblastoma.

## Similar variants {#similar}

Related RB1 variant pages (same residue, condition, or type): [RB1 p.Leu506fs](/variant/rb1-p-leu506fs), [RB1 p.Lys122fs](/variant/rb1-p-lys122fs), [RB1 p.Ser807fs](/variant/rb1-p-ser807fs), [RB1 c.1421+26dup](/variant/rb1-c-1421-plus-26dup), [RB1 c.1128-1G>A](/variant/rb1-c-1128-minus-1g-a), [RB1 c.1215+1G>A](/variant/rb1-c-1215-plus-1g-a), [RB1 c.1960+1G>T](/variant/rb1-c-1960-plus-1g-t), [RB1 c.2211+2T>C](/variant/rb1-c-2211-plus-2t-c).

### 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 4759394). 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.*