# NM_000158.4:c.(?_314)_(992_?)del

https://sugi.bio/variant/gbe1-c-314

## Summary

**GBE1 c.(?_314** is classified **Pathogenic** in GBE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-27). Associated with glycogen storage disease due to glycogen branching enzyme deficiency.

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

## For patients & families {#patients}

This is a change in the GBE1 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to glycogen storage disease due to glycogen branching enzyme deficiency.

*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 |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-9 / 1 000 000 (Worldwide) |
| Clinical trials | 4 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | GBE1 is a diagnostic-grade gene on 23 Genomics England panels |

**Commonly reported features of Glycogen storage disease due to glycogen branching enzyme deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Decreased liver function — Very frequent (99-80%)
- Hepatomegaly — Very frequent (99-80%)
- Generalized abnormality of skin — Very frequent (99-80%)
- Abnormal muscle glycogen content — Very frequent (99-80%)
- Abnormal cardiomyocyte morphology — Very frequent (99-80%)
- Abnormal neuron branching — Very frequent (99-80%)
- Motor delay — Frequent (79-30%)
- Generalized hypotonia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002520/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [GBE1](https://sugi.bio/atlas/gene/GBE1/) |
| Coding change (HGVS c.) | c.(?_314 |
| MANE Select transcript | [NM_000158](https://www.ncbi.nlm.nih.gov/nuccore/NM_000158) |
| Variant type | Deletion |
| ClinVar | [VCV4528904](https://www.ncbi.nlm.nih.gov/clinvar/variation/4528904/) |

**All HGVS expressions:** `NM_000158.4:c.(?_314)_(992_?)del`

## Gene constraint & dosage {#gene-context}

**GBE1** population constraint: LOEUF 1.211, pLI 1.475e-08, missense-Z -0.075477. *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):

- **glycogen storage disease due to glycogen branching enzyme deficiency** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 96.30, 94% of residues very-high.

**3 experimental structure(s)** (PDB): [4BZY](https://www.rcsb.org/structure/4BZY), [5CLT](https://www.rcsb.org/structure/5CLT), [5CLW](https://www.rcsb.org/structure/5CLW).

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

*Describes the biological roles of GBE1 (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:** GBE1's established molecular role includes 1,4-alpha-glucan branching enzyme activity. In Reactome, GBE1 is annotated in disease pathway(s) including **Glycogen storage disease type IV (GBE1)**.

**Disease mechanism (Reactome):** GBE1 loss or alteration is curated in [Glycogen storage disease type IV (GBE1)](https://reactome.org/content/detail/R-HSA-3878781).

### Pathways affected {#pathways}

GBE1 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Glycogen storage disease type IV (GBE1)](https://reactome.org/content/detail/R-HSA-3878781) | curated |
| [Glycogen synthesis](https://reactome.org/content/detail/R-HSA-3322077) | curated |

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

**Molecular function:** 1,4-alpha-glucan branching enzyme activity.

**Biological process:** glycogen biosynthetic process.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-10-27.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Medical Genetic Diagnosis and Therapy Center, Fujian Medical University | Pathogenic | criteria provided, single submitter | clinical testing | 2025-10-27 |

## Associated conditions {#conditions}

[glycogen storage disease due to glycogen branching enzyme deficiency](https://sugi.bio/atlas/disease/glycogen-storage-disease-due-to-glycogen-branching-enzyme-deficiency/).

**Reported phenotype names (ClinVar):** Glycogen storage disease, type IV, AMYLOPECTINOSIS, ANDERSEN DISEASE, BRANCHER DEFICIENCY, CIRRHOSIS, FAMILIAL, WITH DEPOSITION OF ABNORMAL GLYCOGEN, GBE1 DEFICIENCY, GLYCOGEN BRANCHING ENZYME DEFICIENCY, GLYCOGENOSIS IV, GSD IV, Glycogen storage disease due to glycogen branching enzyme deficiency.

## Similar variants {#similar}

Related GBE1 variant pages (same residue, condition, or type): [GBE1 c.1799_1803+8del](/variant/gbe1-c-1799-1803-plus-8del), [GBE1 p.Ala16fs](/variant/gbe1-p-ala16fs), [GBE1 p.Ala9fs](/variant/gbe1-p-ala9fs), [GBE1 p.Arg156fs](/variant/gbe1-p-arg156fs), [GBE1 p.Arg468fs](/variant/gbe1-p-arg468fs), [GBE1 p.Asp169fs](/variant/gbe1-p-asp169fs), [GBE1 p.Asp24fs](/variant/gbe1-p-asp24fs), [GBE1 p.Asp413fs](/variant/gbe1-p-asp413fs).

### 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 4528904). 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.*