GBE1

Summary

GBE1 (1,4-alpha-glucan branching enzyme 1, HGNC:4180) is a protein-coding gene on chromosome 3p12.2, encoding 1,4-alpha-glucan-branching enzyme (Q04446). Glycogen-branching enzyme participates in the glycogen biosynthetic process along with glycogenin and glycogen synthase.

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).

Source: NCBI Gene 2632 — RefSeq curated summary.

At a glance

• Gene–disease (curated): glycogen storage disease due to glycogen branching enzyme deficiency (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 23
• Clinical variants (ClinVar): 1,177 total — 89 pathogenic, 100 likely-pathogenic
• Phenotypes (HPO): 55
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_000158

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4180
Approved symbol	GBE1
Name	1,4-alpha-glucan branching enzyme 1
Location	3p12.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000114480
Ensembl biotype	protein_coding
OMIM	607839
Entrez	2632

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 9 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000429644, ENST00000477426, ENST00000484687, ENST00000486920, ENST00000489715, ENST00000498468, ENST00000895874, ENST00000895875, ENST00000942738, ENST00000942739, ENST00000942740, ENST00000942741, ENST00000942742

RefSeq mRNA: 1 — MANE Select: NM_000158 NM_000158

CCDS: CCDS54612

Canonical transcript exons

ENST00000429644 — 16 exons

Exon	Start	End
ENSE00000773670	81586092	81586190
ENSE00000773675	81642781	81642990
ENSE00000773678	81649796	81649921
ENSE00000773679	81670838	81670953
ENSE00000773680	81705444	81705613
ENSE00001198060	81591037	81591164
ENSE00001198063	81593908	81594023
ENSE00001227561	81577925	81578096
ENSE00001227574	81581165	81581275
ENSE00001227661	81761375	81761645
ENSE00001597521	81499110	81499227
ENSE00001761050	81489703	81490463
ENSE00001762126	81535195	81535325
ENSE00002428795	81646392	81646482
ENSE00003535017	81648856	81648991
ENSE00003595815	81536911	81537095

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 98.56.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 87.6230 / max 1060.6514, expressed in 1823 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
43236	68.5780	1792
43232	9.9480	1763
43239	2.2861	1352
43238	1.5544	1006
43237	1.4000	876
43233	1.0951	744
43240	0.8945	649
43234	0.7499	443
43231	0.4429	194
43235	0.3485	156

Top tissues by expression

294 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
gluteal muscle	UBERON:0002000	98.56	gold quality
tibialis anterior	UBERON:0001385	98.30	gold quality
biceps brachii	UBERON:0001507	98.01	gold quality
deltoid	UBERON:0001476	97.89	gold quality
choroid plexus epithelium	UBERON:0003911	97.88	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.86	gold quality
left ventricle myocardium	UBERON:0006566	97.81	gold quality
heart right ventricle	UBERON:0002080	97.79	gold quality
tibia	UBERON:0000979	97.68	gold quality
nephron tubule	UBERON:0001231	97.50	gold quality
vastus lateralis	UBERON:0001379	97.37	gold quality
quadriceps femoris	UBERON:0001377	97.33	gold quality
gastrocnemius	UBERON:0001388	97.22	gold quality
skeletal muscle tissue	UBERON:0001134	97.09	gold quality
muscle organ	UBERON:0001630	97.08	gold quality
muscle of leg	UBERON:0001383	97.00	gold quality
myocardium	UBERON:0002349	96.92	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	96.61	gold quality
renal glomerulus	UBERON:0000074	96.47	gold quality
metanephric glomerulus	UBERON:0004736	96.45	gold quality
substantia nigra pars reticulata	UBERON:0001966	96.41	gold quality
muscle tissue	UBERON:0002385	96.39	gold quality
cartilage tissue	UBERON:0002418	96.39	gold quality
decidua	UBERON:0002450	96.33	gold quality
triceps brachii	UBERON:0001509	96.15	gold quality
kidney epithelium	UBERON:0004819	95.81	gold quality
stromal cell of endometrium	CL:0002255	95.72	gold quality
adipose tissue	UBERON:0001013	95.69	gold quality
pericardium	UBERON:0002407	95.64	gold quality
substantia nigra pars compacta	UBERON:0001965	95.51	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-25	yes	8.41
E-GEOD-100618	no	254.05
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HIF1A

miRNA regulators (miRDB)

65 targeting GBE1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-3617-5P	99.75	69.41	1968
HSA-MIR-641	99.75	69.35	1975
HSA-MIR-187-5P	99.74	70.26	1404
HSA-MIR-556-3P	99.74	68.75	1203
HSA-MIR-2116-3P	99.74	64.32	889
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-3177-5P	99.65	70.38	1174
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-892A	99.54	68.16	1141
HSA-MIR-510-3P	99.54	70.06	2965

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 22)

• Nine novel GBE1 mutations were identified, including nonsense, missense, deletion, insertion, and splice-junction mutations. Implications for protein structure and interactions were modeled. (PMID:15452297)
• Mutations in the GBE1 gene, located on chromosome 3, have been identified in phenotypes of glycogenosis 4. (PMID:17915577)
• brain white matter degeneration in APBD may result from tissue damage involving axons and myelin in GBE missense mutation (PMID:17994551)
• A c.1558delC frame shift mutation in exon 12 and a c.1999C>T mutation in exon 14 of the GBE1 gene were observed in a neonate with glycogen storage disease type IV. (PMID:18289670)
• Case Report: report an as yet undefined and different phenotype of glycogen storage disease with diminished branching enzyme activity associated with multisystemic involvement. (PMID:18392749)
• Case Reports: novel missense/deletion mutations in GBE1 in glycogen storage disease type IV. (PMID:20058079)
• GYS1 regulation by HIF plays a central role in the hypoxic accumulation of glycogen, and hypoxia also upregulates the expression of UTP:glucose-1-phosphate urydylyltransferase (UGP2) and 1,4-alpha glucan branching enzyme (GBE1) (PMID:20300197)
• A review of the literature for glycogen storage disease type IV patients with characterized molecular defects and deficient enzyme activity reveals most GBE1 mutations to be missense mutations clustering in the catalytic enzyme domain. (PMID:22305237)
• this is the first epidemiologic study of the mutation frequency of the adult polyglucosan body disease -associated GBE1 mutation c.1076A>C in a large Ashkenazi Jewish cohort. (PMID:22943850)
• APBD with GBE deficiency is a clinically homogenous disorder that should be suspected in patients with adult onset leukodystrophy or spastic paraplegia with early onset of urinary symptoms and spinal atrophy. (PMID:23034915)
• Compound heterozygous mutations in GBE1 were identified as the cause of lethal multiple pterygium syndrome in a family. (PMID:23218673)
• GBE1 mutations can cause an early adult-onset relapsing-remitting form of polyglucosan body disease distinct from adult polyglucosan body disease in several ways, including younger age at onset. (PMID:24248152)
• GBE1 mutation is found in manifesting heterozygous patients with adult polyglucosan body disease (PMID:25665141)
• The crystal structure of GBE1 in complex with oligosaccharides was determined, the structural and molecular bases of Adult Polyglucosan Body Disease-linked missense mutations was investigated. (PMID:26199317)
• The presence of polyglucosan bodies in intramuscular nerve twigs by itself and is not an indication of APBD mutation. (PMID:26670585)
• Case Report: novel heterozygous variant (c.760A>G; p.Thr254Ala) in exon 6 of the GBE1 gene resulting in glycogen storage disease type IV. (PMID:27107456)
• Data show a definitive role of GBE1 in the infiltration of T lymphocytes into lung adenocarcinoma sites. Its depletion can upregulate CCL5 and CXCL10 expression through STING signaling to activate IFN-I pathway, potentiate T cell infiltration, and cause induced expression of PD-L1 on tumor cells simultaneously. (PMID:31221150)
• Hypoxia-induced GBE1 expression promotes tumor progression through metabolic reprogramming in lung adenocarcinoma. (PMID:32439898)
• GBE1-related disorders: Adult polyglucosan body disease and its neuromuscular phenotypes. (PMID:33141444)
• A family study implicates GBE1 in the etiology of autism spectrum disorder. (PMID:34633740)
• Abundant copathologies of polyglucosan bodies, frontotemporal lobar degeneration with TDP-43 inclusions and ageing-related tau astrogliopathy in a family with a GBE1 mutation. (PMID:36456471)
• Severe neuromuscular forms of glycogen storage disease type IV: Histological, clinical, biochemical, and molecular findings in a large French case series. (PMID:38012812)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	gbe1a	ENSDARG00000029051
danio_rerio	gbe1b	ENSDARG00000099524
mus_musculus	Gbe1	ENSMUSG00000022707
rattus_norvegicus	Gbe1	ENSRNOG00000051232
drosophila_melanogaster	AGBE	FBGN0053138
caenorhabditis_elegans		WBGENE00011409

Paralogs (7): SLC3A1 (ENSG00000138079), SLC3A2 (ENSG00000168003), AMY1B (ENSG00000174876), AMY1C (ENSG00000187733), AMY1A (ENSG00000237763), AMY2B (ENSG00000240038), AMY2A (ENSG00000243480)

Protein

Protein identifiers

1,4-alpha-glucan-branching enzyme — Q04446 (reviewed: Q04446)

Alternative names: Brancher enzyme, Glycogen-branching enzyme

All UniProt accessions (2): Q04446, E9PGM4

UniProt curated annotations — full annotation on UniProt →

Function. Glycogen-branching enzyme participates in the glycogen biosynthetic process along with glycogenin and glycogen synthase. Generates alpha-1,6-glucosidic branches from alpha-1,4-linked glucose chains, to increase solubility of the glycogen polymer.

Subunit / interactions. Monomer.

Disease relevance. 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. The disease is caused by variants affecting the gene represented in this entry. 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. 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. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Binds its carbohydrate substrate close to the active site, but also via regions close to the N-terminus; this may result in increased affinity and therefore increased catalytic efficiency.

Pathway. Glycan biosynthesis; glycogen biosynthesis.

Similarity. Belongs to the glycosyl hydrolase 13 family. GlgB subfamily.

RefSeq proteins (1): NP_000149* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004193	Glyco_hydro_13_N	Domain
IPR006047	GH13_cat_dom	Domain
IPR006048	A-amylase/branching_C	Domain
IPR013780	Glyco_hydro_b	Homologous_superfamily
IPR013783	Ig-like_fold	Homologous_superfamily
IPR014756	Ig_E-set	Homologous_superfamily
IPR017853	GH_hydrolase_sf	Homologous_superfamily
IPR037439	Branching_enzy	Family

Pfam: PF00128, PF02806, PF02922

UniProt features (92 total): strand 34, helix 27, sequence variant 12, binding site 6, turn 5, modified residue 2, active site 2, initiator methionine 1, chain 1, site 1, sequence conflict 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
4BZY	X-RAY DIFFRACTION	2.75
5CLT	X-RAY DIFFRACTION	2.79
5CLW	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q04446-F1	96.30	0.94

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (3): 481 (transition state stabilizer); 357 (nucleophile); 412 (proton donor)

Ligand- & substrate-binding residues (6): 62–63; 91–93; 107; 118–121; 143; 333–336

Post-translational modifications (2): 2, 173

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-3322077	Glycogen synthesis
R-HSA-3878781	Glycogen storage disease type IV (GBE1)

MSigDB gene sets: 340 (showing top): MODULE_52, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, MOOTHA_GLYCOGEN_METABOLISM, GOBP_POLYSACCHARIDE_BIOSYNTHETIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_DN, MENSE_HYPOXIA_UP, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, HERNANDEZ_MITOTIC_ARREST_BY_DOCETAXEL_1_DN, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, GROSS_ELK3_TARGETS_DN, GROSS_HYPOXIA_VIA_ELK3_DN, GROSS_HIF1A_TARGETS_DN, GROSS_HYPOXIA_VIA_HIF1A_DN, GROSS_HYPOXIA_VIA_ELK3_AND_HIF1A_UP

GO Biological Process (5): glycogen metabolic process (GO:0005977), glycogen biosynthetic process (GO:0005978), generation of precursor metabolites and energy (GO:0006091), negative regulation of neuron apoptotic process (GO:0043524), carbohydrate metabolic process (GO:0005975)

GO Molecular Function (8): 1,4-alpha-glucan branching enzyme activity (GO:0003844), hydrolase activity, hydrolyzing O-glycosyl compounds (GO:0004553), carbohydrate binding (GO:0030246), cation binding (GO:0043169), catalytic activity (GO:0003824), protein binding (GO:0005515), transferase activity (GO:0016740), glycosyltransferase activity (GO:0016757)

GO Cellular Component (3): cytoplasm (GO:0005737), cytosol (GO:0005829), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Glycogen metabolism	1
Glycogen storage diseases	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
cellular anatomical structure	2
energy reserve metabolic process	1
glucan metabolic process	1
glycogen metabolic process	1
glucan biosynthetic process	1
metabolic process	1
negative regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
primary metabolic process	1
hexosyltransferase activity	1
hydrolase activity, acting on glycosyl bonds	1
ion binding	1
molecular_function	1
catalytic activity	1
transferase activity	1
intracellular anatomical structure	1
cytoplasm	1
extracellular vesicle	1

Protein interactions and networks

STRING

3266 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GBE1	GYS1	P13807	809
GBE1	AGL	P35573	808
GBE1	GYG1	P46976	793
GBE1	PYGL	P06737	763
GBE1	UGP2	Q16851	760
GBE1	PYGM	P11217	758
GBE1	GYS2	P54840	743
GBE1	GYG2	O15488	742
GBE1	PYGB	P11216	721
GBE1	PGM1	P36871	645
GBE1	PRCP	P42785	628
GBE1	NHLRC1	Q6VVB1	610
GBE1	NGB	Q9NPG2	608
GBE1	PHKB	Q93100	588
GBE1	EPM2A	O95278	585

IntAct

30 interactions, top by confidence:

A	B	Type	Score
KIFAP3	KIF3B	psi-mi:“MI:0914”(association)	0.900
RHOC	RAP1GDS1	psi-mi:“MI:0914”(association)	0.730
OAZ1	AZIN1	psi-mi:“MI:0914”(association)	0.640
MMP9	TIMP1	psi-mi:“MI:0914”(association)	0.640
Cdc20	BUB1	psi-mi:“MI:0914”(association)	0.560
rep	GBE1	psi-mi:“MI:0915”(physical association)	0.560
STBD1	MID1	psi-mi:“MI:0914”(association)	0.530
GBE1	GYS1	psi-mi:“MI:0914”(association)	0.530
HMGN2	GBE1	psi-mi:“MI:0914”(association)	0.530
	MYL12B	psi-mi:“MI:0914”(association)	0.460
GBE1	TRDMT1	psi-mi:“MI:0915”(physical association)	0.370
EPHB3	GBE1	psi-mi:“MI:0915”(physical association)	0.370
GBE1	PRMT6	psi-mi:“MI:0915”(physical association)	0.370
Rhoa	CLK2	psi-mi:“MI:0914”(association)	0.350
Kctd5		psi-mi:“MI:0914”(association)	0.350
PRICKLE3	UBL4A	psi-mi:“MI:0914”(association)	0.350
VAPA		psi-mi:“MI:0914”(association)	0.350
SETD4	TADA3	psi-mi:“MI:0914”(association)	0.350
SUN2		psi-mi:“MI:0914”(association)	0.350
HMGN2	MACROH2A1	psi-mi:“MI:0914”(association)	0.350
OR1D4	FZD7	psi-mi:“MI:0914”(association)	0.350
YY1AP1	CEBPZ	psi-mi:“MI:0914”(association)	0.350
SWSAP1	NACA	psi-mi:“MI:2364”(proximity)	0.270
CDH5	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
PGD	GBE1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (106): ACO1 (Co-fractionation), GBE1 (Co-fractionation), GBE1 (Co-fractionation), GBE1 (Co-fractionation), GBE1 (Co-fractionation), GBE1 (Co-fractionation), GBE1 (Co-fractionation), GBE1 (Co-fractionation), GBE1 (Co-fractionation), GBE1 (Co-fractionation), GBE1 (Co-fractionation), MIF (Co-fractionation), GBE1 (Affinity Capture-MS), GBE1 (Affinity Capture-MS), GBE1 (Affinity Capture-MS)

ESM2 similar proteins: A0A6C7EEG6, A0R1Y4, A0ZZH6, A1UJW9, A3Q396, B2URJ0, C6A9K7, D7BAR0, D7BMJ2, D9Q7U8, D9TT09, E4PMA5, J9VGQ7, P0A4Y5, P0CN82, P0CN83, P10249, P28629, P32775, P33910, P72235, P76041, P9WQ24, P9WQ25, Q01401, Q04446, Q08047, Q08295, Q1B568, Q555Q9, Q59495, Q6A8Q7, Q6BXN1, Q6CCT1, Q6CX53, Q6EAS5, Q6FJV0, Q757Q6, Q7UGJ6, Q84HD6

Diamond homologs: D2WL32, J9VGQ7, O22637, O23647, P0CN82, P0CN83, P30924, P32775, Q01401, Q04446, Q08047, Q253M6, Q2YB47, Q41058, Q41059, Q55088, Q555Q9, Q5L6K4, Q6BXN1, Q6CCT1, Q6CX53, Q6EAS5, Q6FJV0, Q6T308, Q757Q6, Q823Y5, Q8NKE1, Q96VA4, Q9D6Y9, Q9LZS3, Q9RX51, Q9Y8H3, B0B998, B0BAX7, O84874, P14899, P21543, P21567, P95867, Q2RR72

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
GBE1	“down-regulates quantity”	α-D-glucosyl-glycogenin	“chemical modification”
GBE1	“up-regulates quantity”	glycogen	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

1177 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	89
Likely pathogenic	100
Uncertain significance	317
Likely benign	500
Benign	37

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1075597	NM_000158.4(GBE1):c.43G>T (p.Glu15Ter)	Pathogenic
1076126	NC_000003.11:g.(?81810516)(81810678_?)del	Pathogenic
1076127	NC_000003.11:g.(?81584336)(81584486_?)del	Pathogenic
1076128	NC_000003.11:g.(?81627056)(81810688_?)del	Pathogenic
1076129	NC_000003.11:g.(?81584336)(81810678_?)del	Pathogenic
1076130	NC_000003.11:g.(?81539548)(81754774_?)del	Pathogenic
1322988	NM_000158.4(GBE1):c.1403del (p.Arg468fs)	Pathogenic
1430861	NM_000158.4(GBE1):c.149del (p.Lys50fs)	Pathogenic
1440801	NM_000158.4(GBE1):c.42C>G (p.Tyr14Ter)	Pathogenic
1440888	NM_000158.4(GBE1):c.1333C>T (p.Gln445Ter)	Pathogenic
1443192	NM_000158.4(GBE1):c.810_811delinsTT (p.Gln270_Glu271delinsHisTer)	Pathogenic
1452840	NM_000158.4(GBE1):c.1861_1875CTT[2]TTCATTTTCTTTTTTTTTTTTTTTTTTTTNNNNNNNNNNTGTTAGCCAGGATGGTCTCGATCTCCTGACCTCGTGATCCGCCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACCGCGCCCGGCCTTCTTTTCATTTTC[1] (p.Asn626delinsPhePhePhePhePhePheXaaXaaXaaXaaCysTer)	Pathogenic
1453753	NM_000158.4(GBE1):c.317del (p.Gly106fs)	Pathogenic
1453763	NC_000003.11:g.(?81584336)(81754774_?)del	Pathogenic
1454397	NM_000158.4(GBE1):c.1032G>A (p.Trp344Ter)	Pathogenic
1454918	NM_000158.4(GBE1):c.1031G>A (p.Trp344Ter)	Pathogenic
1457168	NC_000003.11:g.(?81691922)(81699082_?)del	Pathogenic
1457849	NM_000158.4(GBE1):c.1961_1962del (p.Ala654fs)	Pathogenic
1458725	NC_000003.11:g.(?81627066)(81754774_?)del	Pathogenic
1459653	NC_000003.11:g.(?81695533)(81695643_?)del	Pathogenic
1967945	NM_000158.4(GBE1):c.1538_1563del (p.Ile513fs)	Pathogenic
1977757	NM_000158.4(GBE1):c.2011del (p.Ser671fs)	Pathogenic
2000168	NM_000158.4(GBE1):c.367G>T (p.Glu123Ter)	Pathogenic
2002203	NM_000158.4(GBE1):c.691+1G>T	Pathogenic
2004612	NM_000158.4(GBE1):c.169A>T (p.Lys57Ter)	Pathogenic
2033141	NM_000158.4(GBE1):c.34G>T (p.Glu12Ter)	Pathogenic
2039568	NM_000158.4(GBE1):c.1743del (p.Asn581fs)	Pathogenic
2065260	NM_000158.4(GBE1):c.1854del (p.Ala619fs)	Pathogenic
2112781	NM_000158.4(GBE1):c.1169del (p.Ala389_Leu390insTer)	Pathogenic
2114164	NM_000158.4(GBE1):c.1126_1127insCGGGAGAAGTAGATTGAAGCCAGTTGATTAGGGTGCTTAGC (p.Asp376delinsAlaGlyGluValAspTer)	Pathogenic

SpliceAI

4482 predictions. Top by Δscore:

Variant	Effect	Δscore
3:81535196:T:TA	donor_gain	1.0000
3:81535197:C:A	donor_gain	1.0000
3:81536906:CTTA:C	donor_loss	1.0000
3:81536907:TTAC:T	donor_loss	1.0000
3:81536908:TA:T	donor_loss	1.0000
3:81536909:A:C	donor_loss	1.0000
3:81536910:CCTGT:C	donor_loss	1.0000
3:81537092:TTAC:T	acceptor_gain	1.0000
3:81537092:TTACC:T	acceptor_loss	1.0000
3:81537093:TAC:T	acceptor_gain	1.0000
3:81537093:TACC:T	acceptor_loss	1.0000
3:81537094:ACCTG:A	acceptor_loss	1.0000
3:81537096:C:CG	acceptor_loss	1.0000
3:81537097:T:A	acceptor_loss	1.0000
3:81577918:CA:C	donor_gain	1.0000
3:81577920:CTTA:C	donor_loss	1.0000
3:81577922:TA:T	donor_loss	1.0000
3:81577923:A:AC	donor_gain	1.0000
3:81577923:AC:A	donor_gain	1.0000
3:81577923:ACC:A	donor_gain	1.0000
3:81577924:C:CC	donor_gain	1.0000
3:81577924:C:CG	donor_loss	1.0000
3:81577924:CC:C	donor_gain	1.0000
3:81577924:CCC:C	donor_gain	1.0000
3:81578093:ATGC:A	acceptor_gain	1.0000
3:81578097:C:CC	acceptor_gain	1.0000
3:81578098:T:A	acceptor_loss	1.0000
3:81581161:TTA:T	donor_loss	1.0000
3:81581162:TA:T	donor_loss	1.0000
3:81581163:A:AT	donor_loss	1.0000

AlphaMissense

4658 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:81537072:A:G	W548R	0.999
3:81537072:A:T	W548R	0.999
3:81581169:T:A	D481V	0.999
3:81581169:T:G	D481A	0.999
3:81581173:G:C	H480D	0.999
3:81581174:G:C	S479R	0.999
3:81581174:G:T	S479R	0.999
3:81581176:T:G	S479R	0.999
3:81586100:A:G	W443R	0.999
3:81586100:A:T	W443R	0.999
3:81646430:G:C	S248R	0.999
3:81646430:G:T	S248R	0.999
3:81646432:T:G	S248R	0.999
3:81577929:G:C	F538L	0.998
3:81577929:G:T	F538L	0.998
3:81577931:A:G	F538L	0.998
3:81581168:A:C	D481E	0.998
3:81581168:A:T	D481E	0.998
3:81581171:A:C	H480Q	0.998
3:81581171:A:T	H480Q	0.998
3:81642809:A:G	W322R	0.998
3:81642809:A:T	W322R	0.998
3:81646427:A:C	F249L	0.998
3:81646427:A:T	F249L	0.998
3:81646429:A:G	F249L	0.998
3:81537061:G:C	F551L	0.997
3:81537061:G:T	F551L	0.997
3:81537063:A:G	F551L	0.997
3:81537070:C:A	W548C	0.997
3:81537070:C:G	W548C	0.997

dbSNP variants (sampled 300 via entrez): RS1000003269 (3:81543138 A>T), RS1000009858 (3:81655652 G>A), RS1000044585 (3:81718637 GTTTTGTTTTGTTT>G), RS1000058420 (3:81750784 G>A), RS1000060951 (3:81699246 C>T), RS1000071466 (3:81562650 A>G), RS1000072188 (3:81726587 T>C), RS1000074752 (3:81611116 T>A,C), RS1000086813 (3:81524963 T>C), RS1000098203 (3:81501273 A>G), RS1000098816 (3:81587447 A>G), RS1000099609 (3:81667699 A>G), RS1000107143 (3:81630550 T>C), RS1000136044 (3:81673196 A>T), RS1000147034 (3:81719728 A>C,G)

Disease associations

OMIM: gene MIM:607839 | disease phenotypes: MIM:232500, MIM:263570, MIM:614437, MIM:615220, MIM:232200, MIM:617468, MIM:208150

GenCC curated gene-disease

Disease	Classification	Inheritance
glycogen storage disease due to glycogen branching enzyme deficiency	Definitive	Autosomal recessive
adult polyglucosan body disease	Moderate	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
glycogen storage disease due to glycogen branching enzyme deficiency	Definitive	AR

Mondo (13): glycogen storage disease due to glycogen branching enzyme deficiency (MONDO:0009292), adult polyglucosan body disease (MONDO:0009897), cutis laxa, autosomal recessive, type 1B (MONDO:0013754), osteogenesis imperfecta type 15 (MONDO:0014086), arthrogryposis syndrome (MONDO:0015225), polyneuropathy (MONDO:0001824), glycogen storage disease due to glycogen branching enzyme deficiency, congenital neuromuscular form (MONDO:0017698), dementia (MONDO:0001627), disorder of glycogen metabolism (MONDO:0002412), glycogen storage disease due to glycogen branching enzyme deficiency, childhood neuromuscular form (MONDO:0017700), glycogen storage disease due to glycogen branching enzyme deficiency, fatal perinatal neuromuscular form (MONDO:0017697), arthrogryposis multiplex congenita (MONDO:0015168), fetal akinesia deformation sequence 1 (MONDO:0100101)

Orphanet (11): Glycogen storage disease due to glycogen branching enzyme deficiency (Orphanet:367), Adult polyglucosan body disease (Orphanet:206583), Autosomal recessive cutis laxa type 1 (Orphanet:90349), Osteogenesis imperfecta (Orphanet:666), Arthrogryposis syndrome (Orphanet:109007), Glycogen storage disease due to glycogen branching enzyme deficiency, congenital neuromuscular form (Orphanet:308670), Glycogen storage disease (Orphanet:79201), Glycogen storage disease due to glycogen branching enzyme deficiency, childhood neuromuscular form (Orphanet:308698), Glycogen storage disease due to glycogen branching enzyme deficiency, fatal perinatal neuromuscular form (Orphanet:308655), Arthrogryposis multiplex congenita (Orphanet:1037), Fetal akinesia deformation sequence (Orphanet:994)

HPO phenotypes

55 total (30 of 55 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000011	Neurogenic bladder
HP:0000020	Urinary incontinence
HP:0000708	Atypical behavior
HP:0000726	Dementia
HP:0000969	Edema
HP:0001249	Intellectual disability
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001258	Spastic paraplegia
HP:0001265	Hyporeflexia
HP:0001269	Hemiparesis
HP:0001278	Orthostatic hypotension
HP:0001288	Gait disturbance
HP:0001315	Reduced tendon reflexes
HP:0001324	Muscle weakness
HP:0001371	Flexion contracture
HP:0001376	Limitation of joint mobility
HP:0001394	Cirrhosis
HP:0001399	Hepatic failure
HP:0001409	Portal hypertension
HP:0001433	Hepatosplenomegaly
HP:0001508	Failure to thrive
HP:0001541	Ascites
HP:0001558	Decreased fetal movement
HP:0001561	Polyhydramnios
HP:0001638	Cardiomyopathy
HP:0001662	Bradycardia
HP:0001762	Talipes equinovarus

GWAS associations

23 associations (top):

Study	Trait	p-value
GCST002783_200	Body mass index	3.000000e-08
GCST002783_355	Body mass index	2.000000e-08
GCST002783_594	Body mass index	2.000000e-07
GCST002831_5	Lead levels in blood	1.000000e-06
GCST002936_11	Cadmium levels	8.000000e-06
GCST004015_1	Extraversion	1.000000e-09
GCST004065_87	Waist circumference	2.000000e-08
GCST005830_58	Hand grip strength	1.000000e-08
GCST006923_8	Loneliness	2.000000e-08
GCST006924_8	Loneliness (MTAG)	3.000000e-09
GCST007323_93	Risk-taking tendency (4-domain principal component model)	1.000000e-09
GCST007576_3	Chronotype	1.000000e-10
GCST007576_381	Chronotype	2.000000e-08
GCST007576_382	Chronotype	4.000000e-10
GCST007687_2	Photic sneeze reflex	6.000000e-14
GCST009413_3	Intraocular pressure	5.000000e-07
GCST009415_4	Intraocular pressure and central corneal thickness (multi-trait analysis)	8.000000e-08
GCST010132_12	Processed meat consumption	5.000000e-09
GCST010143_36	Meat-related diet	1.000000e-08
GCST010988_102	Adult body size	3.000000e-10
GCST011494_85	Daytime nap	3.000000e-14
GCST012490_2	Femur bone mineral density x serum urate levels interaction	8.000000e-16
GCST012490_364	Femur bone mineral density x serum urate levels interaction	3.000000e-12

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004317	extraversion
EFO:0006941	grip strength measurement
EFO:0007865	loneliness measurement
EFO:0008579	risk-taking behaviour
EFO:0008328	chronotype measurement
EFO:0007887	autosomal dominant compelling helio-ophthalmic outburst syndrome
EFO:0004695	intraocular pressure measurement
EFO:0005213	central corneal thickness
EFO:0008111	diet measurement
EFO:0007828	daytime rest measurement
EFO:0004531	urate measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D003704	Dementia	C10.228.140.380; F03.615.400
D006008	Glycogen Storage Disease	C16.320.565.202.449; C18.452.648.202.449
D011115	Polyneuropathies	C10.668.829.800
C564878	Polyglucosan Body Disease, Adult Form (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

96 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression, decreases methylation, increases expression	5
cobaltous chloride	increases expression, decreases reaction	3
Cisplatin	decreases expression, increases expression	3
Oxygen	increases expression	3
Valproic Acid	affects expression, decreases expression	3
Cyclosporine	decreases expression, increases expression	3
sodium arsenite	affects cotreatment, increases abundance, increases expression	2
manganese chloride	increases abundance, increases expression, decreases expression, increases methylation, affects cotreatment	2
cadmium sulfate	increases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, decreases expression	2
Benzo(a)pyrene	increases expression, increases methylation	2
Estradiol	affects cotreatment, increases expression, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Cadmium Chloride	increases abundance, increases expression	2
aristolochic acid I	decreases expression, increases expression	1
bisphenol F	increases expression	1
dicrotophos	decreases expression	1
tungsten carbide	affects cotreatment, increases expression	1
chloroacetaldehyde	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
sodium arsenate	increases expression	1
pyrogallol 1,3-dimethyl ether	decreases expression, increases expression, affects cotreatment, affects localization	1
decabromobiphenyl ether	decreases expression	1
ethyl-p-hydroxybenzoate	increases expression	1
beta-lapachone	increases expression	1
afimoxifene	increases expression	1
zinc chloride	decreases reaction, increases expression	1
butyraldehyde	decreases expression	1
nickel chloride	increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_SP70	HAP1 GBE1 (-) 1	Cancer cell line	Male
CVCL_XP08	HAP1 GBE1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00162968	PHASE4	COMPLETED	Escitalopram as a Treatment for Pain in Polyneuropathy
NCT00832572	PHASE4	TERMINATED	Study of Ranexa in Patients With Coronary Artery Disease and Painful Polyneuropathy
NCT01047488	PHASE4	UNKNOWN	Imipramine and Pregabalin Combination in Painful Polyneuropathy
NCT01076478	PHASE4	COMPLETED	Asian Study on Cilostazol Effectivity in Neuropathies of Diabetes Mellitus Type 2-A Pilot Study in the Philippines
NCT01302275	PHASE4	COMPLETED	Oxcarbazepine for the Treatment of Chronic Peripheral Neuropathic Pain
NCT02033057	PHASE4	UNKNOWN	Muscular Electrostimulation of the Sedated and Mechanically Ventilated Critically Ill Patient. Analysis of the Effect on Acquired Muscular Weakness and Its Clinical Consequences.
NCT00043849	PHASE4	COMPLETED	Treatment of Agitation/Psychosis in Dementia/Parkinsonism (TAP/DAP)
NCT00127114	PHASE4	WITHDRAWN	Amantadine for the Treatment of Behavioral Disturbance in Frontotemporal Dementia (FTD)
NCT00164970	PHASE4	COMPLETED	Can Oral Vitamin B12 and Folate Supplementation Preserve Cognitive Function of Patients With Early Dementia?
NCT00177671	PHASE4	COMPLETED	Antidepressant Medication Plus Donepezil for Treating Late-life Depression
NCT00208819	PHASE4	COMPLETED	A Comparison of Two Standard Therapies in the Management of Dementia With Agitation
NCT00245206	PHASE4	COMPLETED	Side Effects of Newer Antipsychotics in Older Adults
NCT00254033	PHASE4	COMPLETED	Apathy Associated With Alzheimer’s Disease
NCT00371059	PHASE4	COMPLETED	Memantine for Agitation in Dementia
NCT00375557	PHASE4	WITHDRAWN	Safety and Efficacy of Divalproex and Quetiapine in Elderly Alzheimer’s Dementia Patients
NCT00385684	PHASE4	COMPLETED	Low-Dose Opiate Therapy for Discomfort in Dementia (L-DOT)
NCT00433121	PHASE4	COMPLETED	Discontinuation of Antipsychotics and Antidepressants Among Patients With BPSD
NCT00450047	PHASE4	COMPLETED	Study on the Efficacy of Speed-Feedback Therapy for Elderly People With Dementia
NCT00495820	PHASE4	COMPLETED	Methylphenidate for Apathy in Alzheimer’s Dementia: A Controlled Study
NCT00594269	PHASE4	COMPLETED	Dementia Antipsychotics And Antidepressants Discontinuation Study
NCT00626613	PHASE4	UNKNOWN	The Relationship Between Risperdal Treatment and Quality of Life in Patients With Alzheimer’s Disease and Behavioural and Psychological Symptoms of Dementia (BPSD)
NCT00768261	PHASE4	COMPLETED	Corticolimbic Degeneration and Treatment of Dementia
NCT00792662	PHASE4	WITHDRAWN	Improving Function, Quality of Life, Glycemia in Diabetics With Dementia
NCT00814658	PHASE4	COMPLETED	The Use of Galantamine (Reminyl ER) in Patients With MIXed Dementia: Effects on Cognition and Quality of Life
NCT00914095	PHASE4	COMPLETED	Study of Methylphenidate to Treat Gait Disorders And Attention Deficit In Parkinson’s Disease (PARKGAIT-II)
NCT01012830	PHASE4	UNKNOWN	Huperzine-A to Help With Mental Problems and the Inability to Care for Onself in Patients With Schizophrenia
NCT01109836	PHASE4	COMPLETED	Austrian Polyintervention Study to Prevent Cognitive Decline After Ischemic Stroke
NCT01340950	PHASE4	COMPLETED	Clinical Trial of Brain-Penetrating HIV Drugs to Prevent Cognitive Impairment in China
NCT01453127	PHASE4	ENROLLING_BY_INVITATION	DaTSCAN Imaging in Aging and Neurodegenerative Disease
NCT01799941	PHASE4	COMPLETED	Safety, Tolerability and Effectiveness of Nuedexta in the Treatment of Pseudobulbar Affect (PBA)
NCT01825577	PHASE4	TERMINATED	Exploring the Use of Transdermal Methylphenidate to Reduce Fall Risk in Patients With Dementia.
NCT01849042	PHASE4	UNKNOWN	Effect of Memantine Oral Pump on Language in Patients With Probable Alzheimer’s Disease
NCT02267057	PHASE4	COMPLETED	Efficacy of Pain Treatment on Depression in Patients With Dementia
NCT02782429	PHASE4	UNKNOWN	The Role of Ketamine in Preventing Cognitive Dysfunctions in Postoperative Period of Cardiac Surgery
NCT03061006	PHASE4	COMPLETED	Impact of Anticoagulation Therapy on the Cognitive Decline and Dementia in Patients With Non-Valvular Atrial Fibrillation
NCT03066518	PHASE4	COMPLETED	Effect of Melatonin on Sleep Quality in Patients Dementia
NCT03221751	PHASE4	TERMINATED	Prazosin and Cerebrospinal Fluid (CSF) Biomarkers in Mild Traumatic Brain Injury (mTBI)
NCT03817931	PHASE4	COMPLETED	Higher Neural Changes Following Anticholinergic, Beta 3 Agonist, or Placebo in Patients With Overactive Bladder
NCT04117178	PHASE4	COMPLETED	Monitoring Anti-Dementia Drugs by Serum Levels
NCT04262206	PHASE4	RECRUITING	Pragmatic Evaluation of Events And Benefits of Lipid-lowering in Older Adults