# NM_000518.5(HBB):c.201del (p.Val68fs)

https://sugi.bio/variant/hbb-p-val68fs

## Summary

**HBB p.Val68fs (c.201del)** is classified **Likely pathogenic** in HBB (ClinVar, Single submitter, 2 submitters; last evaluated 2011-08-18). No gnomAD frequency available for this variant; Associated with dominant beta-thalassemia.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs193922553 · 2 submitters · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the HBB gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to dominant beta-thalassemia.

*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 |
| Age of onset (of this condition) | Childhood |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | HBB is a diagnostic-grade gene on 4 Genomics England panels |

**Commonly reported features of Unstable beta globin chain variant disease** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Persistence of hemoglobin F — Very frequent (99-80%)
- Reduced hemoglobin A — Very frequent (99-80%)
- Pallor — Frequent (79-30%)
- Hypersplenism — Frequent (79-30%)
- Extramedullary hematopoiesis — Frequent (79-30%)
- Hypochromic microcytic anemia — Frequent (79-30%)
- Anisocytosis — Frequent (79-30%)
- Decreased mean corpuscular volume — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017164/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [HBB](https://sugi.bio/atlas/gene/HBB/) |
| Protein change (HGVS p.) | p.Val68fs |
| Coding change (HGVS c.) | c.201del |
| MANE Select transcript | [NM_000518](https://www.ncbi.nlm.nih.gov/nuccore/NM_000518) |
| dbSNP | [rs193922553](https://www.ncbi.nlm.nih.gov/snp/rs193922553/) |
| Variant type | Deletion |
| Location | chr11:5226691-5226691 (GRCh38) |
| ClinVar | [VCV36302](https://www.ncbi.nlm.nih.gov/clinvar/variation/36302/) |

**All HGVS expressions:** `LRG_1232:g.5381del`, `LRG_1232t1:c.201del`, `NC_000011.10:g.5226693del`, `NC_000011.9:g.5247923del`, `NG_000007.3:g.70925del`, `NG_042296.1:g.224del`, `NG_046672.1:g.4628del`, `NG_059281.1:g.5381del`, `NM_000518.5:c.201del`

## 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 4.51, GERP 1.87, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.964, pLI 7.4233e-10. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 3**, 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}

**HBB** population constraint: LOEUF 1.964, pLI 7.4233e-10, missense-Z 0.77937. *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):

- **beta-thalassemia HBB/LCRB** — Definitive (AR)
- **hemoglobin M disease** — Definitive (AD)
- **obsolete sickle cell disease and related diseases** — Definitive (AR)
- **unstable hemoglobin disease** — Definitive (AD)

## Protein context {#protein}

Residue **68** lies in a UniProt-annotated variant site (in sydney; unstable); a UniProt-annotated variant site (in bristol); a UniProt-annotated variant site (in non-spherocytic haemolytic anemia; manukau); a UniProt-annotated variant site (in alesha; unstable); an α-helix; the globin domain.

AlphaFold model confidence (whole protein): pLDDT 97.09, 97% of residues very-high.

**350 experimental structure(s)** (PDB): [1A00](https://www.rcsb.org/structure/1A00), [1A01](https://www.rcsb.org/structure/1A01), [1A0U](https://www.rcsb.org/structure/1A0U), [1A0Z](https://www.rcsb.org/structure/1A0Z), [1A3N](https://www.rcsb.org/structure/1A3N), [1A3O](https://www.rcsb.org/structure/1A3O) — incl. mutant structure 1A00.

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

*Describes the biological roles of HBB (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:** HBB's established molecular role includes oxygen binding. p.Val68fs falls in the globin domain. In Reactome, HBB is annotated in disease pathway(s) including **Heme assimilation**.

**Disease mechanism (Reactome):** HBB loss or alteration is curated in [Heme assimilation](https://reactome.org/content/detail/R-HSA-9927020).

### Pathways affected {#pathways}

HBB participates in **10 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Heme assimilation](https://reactome.org/content/detail/R-HSA-9927020) | curated |
| [Cytoprotection by HMOX1](https://reactome.org/content/detail/R-HSA-9707564) | curated |
| [Erythrocytes take up carbon dioxide and release oxygen](https://reactome.org/content/detail/R-HSA-1237044) | curated |
| [Erythrocytes take up oxygen and release carbon dioxide](https://reactome.org/content/detail/R-HSA-1247673) | curated |
| [Factors involved in megakaryocyte development and platelet production](https://reactome.org/content/detail/R-HSA-983231) | curated |
| [Heme signaling](https://reactome.org/content/detail/R-HSA-9707616) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [Scavenging of heme from plasma](https://reactome.org/content/detail/R-HSA-2168880) | curated |
| [Chaperone Mediated Autophagy](https://reactome.org/content/detail/R-HSA-9613829) | electronic |
| [Late endosomal microautophagy](https://reactome.org/content/detail/R-HSA-9615710) | electronic |

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

**Molecular function:** oxygen binding, hemoglobin binding.

**Biological process:** inflammatory response, oxygen transport, nitric oxide transport, response to hydrogen peroxide, hydrogen peroxide catabolic process, renal absorption.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2011-08-18.

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

**Submission history:** 2 submissions (2011–2019); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| The ITHANET community portal, The Cyprus Institute of Neurology and Genetics | Pathogenic | no assertion criteria provided | curation | 2019-11-25 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely pathogenic | criteria provided, single submitter | curation | 2011-08-18 |

## Associated conditions {#conditions}

[dominant beta-thalassemia](https://sugi.bio/atlas/disease/dominant-beta-thalassemia/), [beta thalassemia](https://sugi.bio/atlas/disease/beta-thalassemia/).

**Reported phenotype names (ClinVar):** Dominant beta-thalassemia, beta Thalassemia, Beta-thalassemia, dominant inclusion body type, Cooley's anemia, Erythroblastic anemia, Mediterranean anemia.

## Same-residue context {#hotspot}

Residue **68** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [HBB p.Val68Met](/variant/hbb-p-val68met). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related HBB variant pages (same residue, condition, or type): [HBB c.315+2del](/variant/hbb-c-315-plus-2del), [HBB c.93-22_95del](/variant/hbb-c-93-minus-22-95del), [HBB c.*110_*111del](/variant/hbb-c-star-110-star-111del), [HBB c.*110_*114del](/variant/hbb-c-star-110-star-114del), [HBB p.Glu23fs](/variant/hbb-p-glu23fs), [HBB p.Glu7fs](/variant/hbb-p-glu7fs), [HBB p.Gly70fs](/variant/hbb-p-gly70fs), [HBB p.Gly84fs](/variant/hbb-p-gly84fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 36302). 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.*