# NM_000518.5(HBB):c.217dup (p.Ser73fs)

https://sugi.bio/variant/hbb-p-ser73fs

## Summary

**HBB p.Ser73fs (c.217dup)** is classified **Pathogenic/Likely pathogenic** in HBB (ClinVar, Multiple submitters, 13 submitters; last evaluated 2025-09-29). Very rare (popmax 0.00446%, eas); Associated with beta-thalassemia HBB/LCRB.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs33969853 · 13 submitters · 8 linked conditions · very rare (popmax 0.00446%, eas)

## For patients & families {#patients}

This is a change in the HBB gene that is considered likely disease-causing, submitted by 13 submitters, and is linked to beta-thalassemia HBB/LCRB.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 9 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024933/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.Ser73fs |
| Coding change (HGVS c.) | c.217dup |
| MANE Select transcript | [NM_000518](https://www.ncbi.nlm.nih.gov/nuccore/NM_000518) |
| dbSNP | [rs33969853](https://www.ncbi.nlm.nih.gov/snp/rs33969853/) |
| Variant type | Duplication |
| Location | chr11:5226674-5226675 (GRCh38) |
| ClinVar | [VCV15419](https://www.ncbi.nlm.nih.gov/clinvar/variation/15419/) |

**All HGVS expressions:** `LRG_1232:g.5397dup`, `LRG_1232t1:c.217dup`, `NC_000011.10:g.5226675dup`, `NC_000011.9:g.5247905dup`, `NG_000007.3:g.70940_70941insA`, `NG_000007.3:g.70941dup`, `NG_042296.1:g.206dup`, `NG_046672.1:g.4610dup`, `NG_053049.1:g.2996dup`, `NG_059281.1:g.5397dup`, `NM_000518.4:c.217dupA`, `NM_000518.5:c.216_217insA`, `NM_000518.5:c.217dup`, `NM_000518.5:c.217dupA`

## 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 -0.072, GERP 1.03 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- 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 duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00446%** (eas) · FAF95 0.000739% · FAF99 0.000276% · 2/44,866 in the highest group · 2/1,614,140 alleles overall — very rare (popmax 0.00446%, eas).

*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 **73** lies in a functional site ((microbial infection) cleavage; by n.americanus apr-2); 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.Ser73fs 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}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-09-29.

**Submitter consensus:** conflicting (11 Pathogenic, 1 pathogenic, 1 Likely pathogenic).

**Submission history:** 13 submissions (1984–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2016-08-15 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | pathogenic | criteria provided, single submitter | clinical testing | 2025-03-26 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 1984-05-01 |
| The ITHANET community portal, The Cyprus Institute of Neurology and Genetics | Pathogenic | no assertion criteria provided | curation | 2019-11-25 |
| Myriad Genetics, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2019-12-20 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Pathogenic | criteria provided, single submitter | clinical testing | 2024-07-02 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-01-04 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2016-09-02 |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-04-03 |
| Juno Genomics, Hangzhou Juno Genomics, Inc | Pathogenic | criteria provided, single submitter | clinical testing |  |
| Precision Medicine Lab Center, Yangjiang People's Hospital | Pathogenic | no assertion criteria provided | clinical testing | 2024-03-04 |
| Natera, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2025-09-29 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2023-11-30 |

## Associated conditions {#conditions}

[beta-thalassemia HBB/LCRB](https://sugi.bio/atlas/disease/beta-thalassemia-hbb-lcrb/), [Heinz body anemia](https://sugi.bio/atlas/disease/heinz-body-anemia/), [dominant beta-thalassemia](https://sugi.bio/atlas/disease/dominant-beta-thalassemia/), [sickle cell disease](https://sugi.bio/atlas/disease/sickle-cell-disease/), [beta thalassemia](https://sugi.bio/atlas/disease/beta-thalassemia/), [hereditary persistence of fetal hemoglobin](https://sugi.bio/atlas/disease/hereditary-persistence-of-fetal-hemoglobin/), [malaria, susceptibility to](https://sugi.bio/atlas/disease/malaria-susceptibility-to/), [erythrocytosis, familial, 6](https://sugi.bio/atlas/disease/erythrocytosis-familial-6/).

**Reported phenotype names (ClinVar):** Beta-thalassemia HBB/LCRB, Beta zero thalassemia, not provided, beta Thalassemia, Inborn genetic diseases, Dominant beta-thalassemia, Erythrocytosis, familial, 6, Hb SS disease, Heinz body anemia, Hereditary persistence of fetal hemoglobin.

## Same-residue context {#hotspot}

Residue **73** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [HBB p.Ser73Ter](/variant/hbb-p-ser73ter), [HBB p.Ser73_Asp74delinsArgTyr](/variant/hbb-p-ser73-asp74delinsargtyr). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related HBB variant pages (same residue, condition, or type): [HBB p.Ser73Ter](/variant/hbb-p-ser73ter), [HBB p.Ser73_Asp74delinsArgTyr](/variant/hbb-p-ser73-asp74delinsargtyr), [HBB p.Ala11fs](/variant/hbb-p-ala11fs), [HBB p.Asn109fs](/variant/hbb-p-asn109fs), [HBB p.Asp22fs](/variant/hbb-p-asp22fs), [HBB p.Asp48fs](/variant/hbb-p-asp48fs), [HBB p.Glu44Ter](/variant/hbb-p-glu44ter), [HBB p.Leu29fs](/variant/hbb-p-leu29fs).

### 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 15419). 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.*