GBE1
protein-coding1,4-alpha-glucan branching enzyme 1
Gene summary
The protein encoded by this gene is a glycogen branching enzyme that catalyzes the transfer of alpha-1,4-linked glucosyl units from the outer end of a glycogen chain to an alpha-1,6 position on the same or a neighboring glycogen chain. Branching of the chains is essential to increase the solubility of the glycogen molecule and, consequently, in reducing the osmotic pressure within cells. Highest level of this enzyme are found in liver and muscle. Mutations in this gene are associated with glycogen storage disease IV (also known as Andersen's disease). [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~271.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009292
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0009897
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0009897
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009292
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0009292
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009292
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0009292
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0009292
Submitter: Laboratory for Molecular Medicine
This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.
Inheritance Pattern: AR
Disease ID:MONDO:0009292
Submitter: ClinGen
Glycogen storage disease type 4 (GSD IV) is a clinically heterogeneous autosomal recessive disease caused by deficiency of the glycogen branching enzyme (GBE) encoded by the GBE1 gene. Abnormally long chains of glycogen known as polyglucosan bodies accumulate in various tissues of the body resulting in hepatic, cardiac and neurological disease. The severity of disease is correlated with residual activity of the GBE enzyme. Severe prenatal presentations can include fetal akinesia deformation sequence, decreased fetal movements, polyhydramnios, and fetal hydrops. Neonates have profound hypotonia, respiratory distress, and dilated cardiomyopathy, with death typically in early infancy. A historical subtype system used to classify patients along the GSD IV spectrum based on severity and age of onset is no longer favored, as all individuals with GBE deficiency have homozygous or compound heterozygous pathogenic variants in the GBE1 gene. OMIM currently lists two separate disease entities for GBE1: #232500 for GSD IV and #263570 for adult polyglucosan body disease. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism or inheritance pattern. Therefore, the following disease entities have been lumped into one disease entity, glycogen storage disease due to glycogen branching enzyme deficiency (MONDO: 0009292) We have curated 26 variants in GBE1 (missense, nonsense, frameshift, large deletion) reported in 17 probands across 7 publications (PMIDs: 8613547, 15452297, 15019703, 17662246, 15520786, 16278887, 12913206). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. The gene-disease association is also supported by experimental evidence showing reduced GBE expression and activity in patient cells, reduced GBE activity in COS-7 cells transfected with specific GBE1 variants, multiple animal models including three separate mouse models that mimic varying disease severities with GBE1 gene alterations, and finally partial rescue of activity using a peptide designed to increase protein stability (PMIDs: 8613547, 9851430, 15452297, 11817063, 17257876, 21075835, 21856731, 26385640, 26199317). In summary, the GBE1 gene is definitively associated with autosomal recessive GBE IV. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Prenatal GCEP on the meeting date August 23, 2023 (SOP Version 9).
Inheritance Pattern: AR
Disease ID:MONDO:0009292
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Cardiovascular; Gastrointestinal; Genitourinary; Musculoskeletal; Neurologic
Intervention: Biochemical; Cardiovascular
Rationale: In some forms of Glycogen storage disease IV, management to decrease morbidity and mortality related to cardiac sequalae may be beneficial; Liver transplant may be beneficial in some individuals with Glycogen storage disease IV; In Polyglucosan body neuropathy, adult form, surveillance for cardiac sequelae such as cardiomyopathy has been recommended
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GBE1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000158.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 13 | 299 | 313 | ||
| missense | 2 | 52 | 273 | 22 | 1 | 350 |
| nonsense | 29 | 30 | 2 | 61 | ||
| start loss | 1 | 1 | ||||
| frameshift | 72 | 46 | 118 | |||
| splice donor/acceptor (+/-2bp) | 5 | 43 | 2 | 50 | ||
| Total | 108 | 172 | 291 | 321 | 1 | 893 |
Highest pathogenic variant AF is 0.0010059425
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000149.4 | 16 | MANE Select | |
| Ensembl | ENSP00000410833.2 | 16 | MANE Select | |
| Ensembl | ENSP00000419638.1 | 16 | Standard | |
| Ensembl | ENSP00000419638.1 | 16 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Starch and sucrose metabolism - Homo sapiens (human)
- Glycogen synthetase deficiency
- Glycogenosis, Type III. Cori disease, Debrancher glycogenosis
- Mucopolysaccharidosis VI. Sly syndrome
- Sucrase-isomaltase deficiency
Biological Process
- carbohydrate metabolic process
- glycogen metabolic process
- glycogen biosynthetic process
- generation of precursor metabolites and energy
Molecular Function
- 1,4-alpha-glucan branching enzyme activity
- hydrolase activity, hydrolyzing O-glycosyl compounds
- protein binding
- cation binding
- 1,4-alpha-glucan branching enzyme activity (using a glucosylated glycogenin as primer for glycogen synthesis)
Cellular Component
- cytosol
- extracellular exosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000429644
- Coding exons
- 16
- Length
- 272463
- Individuals with no LoFs
- 124549
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 109
- Defined
- 124658
- p
- 0.000437
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.0919 | 352 | 357 | 0.986 | 0.0000185 | 4595 |
| Missense (PolyPhen) | 123 | 157.13 | 0.78281 | 2061 | ||
| Synonymous | 0.726 | 117 | 127 | 0.918 | 0.00000678 | 1255 |
| Loss of Function | 1.69 | 24 | 34.7 | 0.691 | 0.00000168 | 473 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00026 | 0.00026 | rare |
| Latino/Admixed American | 0.0018 | 0.0017 | notable |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00024 | 0.00022 | rare |
| Finnish | 0.000094 | 0.000093 | rare |
| European (Non-Finnish) | 0.00029 | 0.00028 | rare |
| South Asian | 0.00015 | 0.00013 | rare |
| Other | 0.0011 | 0.00099 | notable |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Required for normal glycogen accumulation (PubMed:8463281, PubMed:26199317, PubMed:8613547). The alpha 1-6 branches of glycogen play an important role in increasing the solubility of the molecule (Probable). {ECO:0000269|PubMed:26199317, ECO:0000269|PubMed:8463281, ECO:0000269|PubMed:8613547, ECO:0000305}.;
- Disease
- DISEASE: Glycogen storage disease 4 (GSD4) [MIM:232500]: A metabolic disorder characterized by the accumulation of an amylopectin-like polysaccharide. The typical clinical manifestation is liver disease of childhood, progressing to lethal hepatic cirrhosis. Most children with this condition die before two years of age. However, the liver disease is not always progressive. No treatment apart from liver transplantation has been found to prevent progression of the disease. There is also a neuromuscular form of glycogen storage disease type 4 that varies in onset (perinatal, congenital, juvenile, or adult) and severity. {ECO:0000269|PubMed:10545044, ECO:0000269|PubMed:15452297, ECO:0000269|PubMed:8613547}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Neuromuscular perinatal glycogen storage disease type 4 is associated with non-immune hydrops fetalis, a generalized edema of the fetus with fluid accumulation in the body cavities due to non-immune causes. Non-immune hydrops fetalis is not a diagnosis in itself but a symptom, a feature of many genetic disorders, and the end-stage of a wide variety of disorders. {ECO:0000269|PubMed:15452297}.; DISEASE: Polyglucosan body neuropathy, adult form (APBN) [MIM:263570]: A late-onset, slowly progressive disorder affecting the central and peripheral nervous systems. Patients typically present after age 40 years with a variable combination of cognitive impairment, pyramidal tetraparesis, peripheral neuropathy, and neurogenic bladder. Other manifestations include cerebellar dysfunction and extrapyramidal signs. The pathologic hallmark of APBN is the widespread accumulation of round, intracellular polyglucosan bodies throughout the nervous system, which are confined to neuronal and astrocytic processes. {ECO:0000269|PubMed:10762170}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.455
Intolerance Scores
- LoFtool
- 0.116
- RVIS EVS
- 0.62
- RVIS percentile EVS
- 83.53
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.776
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | Medium | Medium | Medium |