GM1 gangliosidosis type 3

Summary

GM1 gangliosidosis type 3 (MONDO:0009262) is a disease caused by GLB1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GLB1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 167

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		70	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	GM1 gangliosidosis type 3
Mondo ID	MONDO:0009262
OMIM	230650
Orphanet	79257
DOID	DOID:0080489
ICD-11	1331496842
SNOMED CT	238027003
UMLS	C0268273
MedGen	78655
GARD	0002431
Is cancer (heuristic)	no

Also known as: adult GM1 gangliosidosis · adult-onset GM1 gangliosidosis · Beta-galactosidase deficiency type 3 · gangliosidosis generalised GM1 chronic type · gangliosidosis generalized GM1 chronic type · gangliosidosis GM1 type 3 · gangliosidosis, generalised GM1, adult type · gangliosidosis, generalised GM1, chronic type · gangliosidosis, generalised GM1, type 3

Data availability: 167 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › GM1 gangliosidosis › GM1 gangliosidosis type 3

Related subtypes (2): GM1 gangliosidosis type 1, GM1 gangliosidosis type 2

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

167 retrieved; paginated sample, class counts are floors:

56 pathogenic/likely pathogenic, 41 likely pathogenic, 30 pathogenic, 21 uncertain significance, 14 conflicting classifications of pathogenicity, 3 benign, 1 likely benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1063917	NM_000404.4(GLB1):c.107A>G (p.Tyr36Cys)	GLB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069817	NM_000404.4(GLB1):c.1324C>T (p.Arg442Ter)	GLB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071414	NM_000404.4(GLB1):c.994G>A (p.Asp332Asn)	GLB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1301844	NM_000404.4(GLB1):c.998A>G (p.Tyr333Cys)	GLB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1449094	NM_000404.4(GLB1):c.591dup (p.Asp198Ter)	GLB1	Pathogenic	criteria provided, multiple submitters, no conflicts
1454377	NM_000404.4(GLB1):c.1142del (p.Lys381fs)	GLB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1473187	NM_000404.4(GLB1):c.435TCT[1] (p.Leu147del)	GLB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1683247	NM_000404.4(GLB1):c.1598_1601dup (p.His534fs)	GLB1	Pathogenic	criteria provided, multiple submitters, no conflicts
195074	NM_000404.4(GLB1):c.203G>A (p.Arg68Gln)	GLB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
198077	NM_000404.4(GLB1):c.602G>A (p.Arg201His)	GLB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
202191	NM_000404.4(GLB1):c.1577dup (p.Trp527fs)	GLB1	Pathogenic	criteria provided, multiple submitters, no conflicts
2043978	NM_000404.4(GLB1):c.833del (p.Gly278fs)	GLB1	Pathogenic	criteria provided, multiple submitters, no conflicts
2164182	NM_000404.4(GLB1):c.1147A>T (p.Lys383Ter)	GLB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
252985	NM_000404.4(GLB1):c.1733A>G (p.Lys578Arg)	GLB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
264673	NM_000404.4(GLB1):c.276G>A (p.Trp92Ter)	GLB1	Pathogenic	criteria provided, multiple submitters, no conflicts
265179	NM_000404.4(GLB1):c.464T>G (p.Leu155Arg)	GLB1	Pathogenic	criteria provided, multiple submitters, no conflicts
284172	NM_000404.4(GLB1):c.808T>G (p.Tyr270Asp)	GLB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2927179	NM_000404.4(GLB1):c.710A>G (p.Tyr237Cys)	GLB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
344790	NM_000404.4(GLB1):c.1343A>T (p.Asp448Val)	GLB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3589141	NM_000404.4(GLB1):c.275G>A (p.Trp92Ter)	GLB1	Pathogenic	criteria provided, single submitter
417873	NM_000404.4(GLB1):c.245+1G>A	GLB1	Pathogenic	criteria provided, multiple submitters, no conflicts
496895	NM_000404.4(GLB1):c.175C>T (p.Arg59Cys)	GLB1	Pathogenic	criteria provided, multiple submitters, no conflicts
521991	NM_000404.4(GLB1):c.146G>A (p.Arg49His)	GLB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
522884	NM_000404.4(GLB1):c.443G>A (p.Arg148His)	GLB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
528328	NM_000404.4(GLB1):c.1325G>A (p.Arg442Gln)	GLB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
549962	NM_000404.4(GLB1):c.572G>A (p.Ser191Asn)	GLB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
550166	NM_000404.4(GLB1):c.1481G>T (p.Gly494Val)	GLB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
550413	NM_000404.4(GLB1):c.1634dup (p.Asn545fs)	GLB1	Pathogenic	criteria provided, multiple submitters, no conflicts
550513	NM_000404.4(GLB1):c.433_437del (p.Ile145fs)	GLB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
550856	NM_000404.4(GLB1):c.1038G>C (p.Lys346Asn)	GLB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 23 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
GLB1	Definitive	Autosomal recessive	GM1 gangliosidosis	23

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GLB1	Orphanet:309310	Mucopolysaccharidosis type 4B
GLB1	Orphanet:79255	GM1 gangliosidosis type 1
GLB1	Orphanet:79256	GM1 gangliosidosis type 2
GLB1	Orphanet:79257	GM1 gangliosidosis type 3

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GLB1	HGNC:4298	ENSG00000170266	P16278	Beta-galactosidase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GLB1	Beta-galactosidase	Cleaves beta-linked terminal galactosyl residues from gangliosides, glycoproteins, and glycosaminoglycans.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GLB1	Other/Unknown	no		Glycoside_Hdrlase_35, Galactose-bd-like_sf, GH_hydrolase_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
monocyte	1
mononuclear cell	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GLB1	258	ubiquitous	marker	monocyte, mononuclear cell, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GLB1	1,578

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GLB1	P16278	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 30. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
MPS IV - Morquio syndrome B (Keratin metabolism)	1	5710.0×	0.003	GLB1
MPS IV - Morquio syndrome B (CS/DS degradation)	1	5710.0×	0.003	GLB1
Defective NEU1 causes sialidosis	1	2855.0×	0.004	GLB1
Mucopolysaccharidoses	1	1903.3×	0.004	GLB1
Diseases of carbohydrate metabolism	1	815.7×	0.005	GLB1
Keratan sulfate degradation	1	713.8×	0.005	GLB1
Diseases associated with N-glycosylation of proteins	1	634.4×	0.005	GLB1
Heparan sulfate/heparin (HS-GAG) metabolism	1	543.8×	0.005	GLB1
CS/DS degradation	1	543.8×	0.005	GLB1
Keratan sulfate/keratin metabolism	1	496.5×	0.005	GLB1
HS-GAG degradation	1	496.5×	0.005	GLB1
Sialic acid metabolism	1	326.3×	0.007	GLB1
Glycosphingolipid metabolism	1	300.5×	0.007	GLB1
Synthesis of substrates in N-glycan biosythesis	1	292.8×	0.007	GLB1
Glycosphingolipid catabolism	1	292.8×	0.007	GLB1
Glycosaminoglycan metabolism	1	219.6×	0.008	GLB1
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein	1	207.6×	0.008	GLB1
Sphingolipid metabolism	1	167.9×	0.010	GLB1
Diseases of glycosylation	1	131.3×	0.012	GLB1
Metabolism of carbohydrates and carbohydrate derivatives	1	120.2×	0.012	GLB1
Diseases of metabolism	1	80.4×	0.018	GLB1
Asparagine N-linked glycosylation	1	60.1×	0.023	GLB1
Metabolism of lipids	1	31.6×	0.041	GLB1
Innate Immune System	1	25.5×	0.049	GLB1
Neutrophil degranulation	1	23.1×	0.052	GLB1
Post-translational protein modification	1	19.2×	0.060	GLB1
Disease	1	13.1×	0.083	GLB1
Immune System	1	13.0×	0.083	GLB1
Metabolism of proteins	1	12.4×	0.084	GLB1
Metabolism	1	11.6×	0.086	GLB1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to cortisone	1	8426.0×	4e-04	GLB1
keratan sulfate proteoglycan catabolic process	1	5617.3×	4e-04	GLB1
response to Thyroglobulin triiodothyronine	1	5617.3×	4e-04	GLB1
galactose catabolic process	1	2808.7×	6e-04	GLB1
ganglioside catabolic process	1	1872.4×	7e-04	GLB1
glycoprotein catabolic process	1	1053.2×	0.001	GLB1
carbohydrate metabolic process	1	135.9×	0.007	GLB1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
GLB1	MIGALASTAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GLB1	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MIGALASTAT	4	GLB1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
GLB1	124	Binding:123, ADMET:1

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
GLB1	124

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
MIGALASTAT	4	GLB1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GLB1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.