# NM_152384.3(BBS5):c.204dup (p.Val69fs)

https://sugi.bio/variant/bbs5-p-val69fs

## Summary

**BBS5 p.Val69fs (c.204dup)** is classified **Pathogenic** in BBS5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-18). Associated with Bardet-Biedl syndrome.

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

## For patients & families {#patients}

This is a change in the BBS5 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Bardet-Biedl syndrome.

*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 recessive, Oligogenic |
| Age of onset (of this condition) | Antenatal, Childhood, Infancy, Neonatal |
| Prevalence | 1-9 / 100 000 (Specific population) |
| Clinical trials | 18 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | BBS5 is a diagnostic-grade gene on 17 Genomics England panels |

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

- Retinal dystrophy — Obligate (100%)
- Cone/cone-rod dystrophy — Very frequent (99-80%)
- Obesity — Very frequent (99-80%)
- Childhood-onset truncal obesity — Very frequent (99-80%)
- Neurodevelopmental delay — Very frequent (99-80%)
- Abnormality of the genitourinary system — Frequent (79-30%)
- Hypogonadism — Frequent (79-30%)
- Abnormal oral cavity morphology — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006866/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BBS5](https://sugi.bio/atlas/gene/BBS5/) |
| Protein change (HGVS p.) | p.Val69fs |
| Coding change (HGVS c.) | c.204dup |
| MANE Select transcript | [NM_152384](https://www.ncbi.nlm.nih.gov/nuccore/NM_152384) |
| Variant type | Duplication |
| Location | chr2:169487129-169487130 (GRCh38) |
| ClinVar | [VCV3727601](https://www.ncbi.nlm.nih.gov/clinvar/variation/3727601/) |

**All HGVS expressions:** `NC_000002.11:g.170343640dup`, `NC_000002.12:g.169487130dup`, `NG_011567.1:g.12635dup`, `NM_152384.3:c.204dup`

## 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 11.058, GERP 1.57, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.884, pLI 0.00025273. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 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.

*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}

**BBS5** population constraint: LOEUF 0.884, pLI 0.00025273, missense-Z 1.0111; 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):

- **BBS5-related ciliopathy** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 88.87, 73% of residues very-high.

**1 experimental structure(s)** (PDB): [6XTB](https://www.rcsb.org/structure/6XTB).

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

*Describes the biological roles of BBS5 (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:** BBS5's established molecular role includes phosphatidylinositol-3-phosphate binding.


### Pathways affected {#pathways}

BBS5 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [BBSome-mediated cargo-targeting to cilium](https://reactome.org/content/detail/R-HSA-5620922) | curated |

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

**Molecular function:** phosphatidylinositol-3-phosphate binding, RNA polymerase II-specific DNA-binding transcription factor binding.

**Biological process:** cilium assembly.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-12-18.

**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 | 2024-12-18 |

## Associated conditions {#conditions}

[Bardet-Biedl syndrome](https://sugi.bio/atlas/disease/bardet-biedl-syndrome/).

**Reported phenotype names (ClinVar):** Bardet-Biedl syndrome.

## Similar variants {#similar}

Related BBS5 variant pages (same residue, condition, or type): [BBS5 p.Ala19fs](/variant/bbs5-p-ala19fs), [BBS5 p.Asn102Ter](/variant/bbs5-p-asn102ter), [BBS5 p.Asn184_Val185insAsn](/variant/bbs5-p-asn184-val185insasn), [BBS5 p.Leu4fs](/variant/bbs5-p-leu4fs), [BBS5 p.Val188fs](/variant/bbs5-p-val188fs), [BBS5 c.142+3_142+10dup](/variant/bbs5-c-142-plus-3-142-plus-10dup), [BBS5 c.258+14dup](/variant/bbs5-c-258-plus-14dup), [BBS5 c.259-10_259-6dup](/variant/bbs5-c-259-minus-10-259-minus-6dup).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 3727601). 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.*