Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome

Summary

Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome (MONDO:0009268) is a disease caused by GBA1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GBA1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 65
• Phenotypes (HPO): 57

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

57 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0001433	Hepatosplenomegaly	Frequent (30-79%)
HP:0001873	Thrombocytopenia	Frequent (30-79%)
HP:0003656	Decreased beta-glucocerebrosidase level	Frequent (30-79%)
HP:0004380	Aortic valve calcification	Frequent (30-79%)
HP:0004382	Mitral valve calcification	Frequent (30-79%)
HP:0004963	Calcification of the aorta	Frequent (30-79%)
HP:0007957	Corneal opacity	Frequent (30-79%)
HP:6001185	Elevated circulating glucosylsphingosine concentration	Frequent (30-79%)
HP:0000238	Hydrocephalus	Occasional (5-29%)
HP:0000407	Sensorineural hearing impairment	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000602	Ophthalmoplegia	Occasional (5-29%)
HP:0000657	Oculomotor apraxia	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001258	Spastic paraplegia	Occasional (5-29%)
HP:0001265	Hyporeflexia	Occasional (5-29%)
HP:0001288	Gait disturbance	Occasional (5-29%)
HP:0001347	Hyperreflexia	Occasional (5-29%)
HP:0001510	Growth delay	Occasional (5-29%)
HP:0001650	Aortic valve stenosis	Occasional (5-29%)
HP:0001653	Mitral regurgitation	Occasional (5-29%)
HP:0001714	Ventricular hypertrophy	Occasional (5-29%)
HP:0001718	Mitral stenosis	Occasional (5-29%)
HP:0001744	Splenomegaly	Occasional (5-29%)
HP:0001761	Pes cavus	Occasional (5-29%)
HP:0001822	Hallux valgus	Occasional (5-29%)
HP:0001876	Pancytopenia	Occasional (5-29%)
HP:0001903	Anemia	Occasional (5-29%)
HP:0002079	Hypoplasia of the corpus callosum	Occasional (5-29%)
HP:0002119	Ventriculomegaly	Occasional (5-29%)
HP:0002206	Pulmonary fibrosis	Occasional (5-29%)
HP:0002315	Headache	Occasional (5-29%)
HP:0004406	Spontaneous, recurrent epistaxis	Occasional (5-29%)
HP:0007018	Attention deficit hyperactivity disorder	Occasional (5-29%)
HP:0000027	Azoospermia	Very rare (<1-4%)
HP:0000248	Brachycephaly	Very rare (<1-4%)
HP:0000508	Ptosis	Very rare (<1-4%)
HP:0000570	Abnormal saccadic eye movements	Very rare (<1-4%)
HP:0000605	Supranuclear gaze palsy	Very rare (<1-4%)
HP:0000767	Pectus excavatum	Very rare (<1-4%)
HP:0000974	Hyperextensible skin	Very rare (<1-4%)
HP:0001081	Cholelithiasis	Very rare (<1-4%)
HP:0001270	Motor delay	Very rare (<1-4%)
HP:0001276	Hypertonia	Very rare (<1-4%)
HP:0002040	Esophageal varix	Very rare (<1-4%)
HP:0002070	Limb ataxia	Very rare (<1-4%)
HP:0002092	Pulmonary arterial hypertension	Very rare (<1-4%)
HP:0002650	Scoliosis	Very rare (<1-4%)
HP:0005619	Thoracolumbar kyphosis	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome
Mondo ID	MONDO:0009268
MeSH	C565553
OMIM	231005
Orphanet	2072
DOID	DOID:0112250
SNOMED CT	1156813002
UMLS	C1856476
MedGen	341563
GARD	0012504
Is cancer (heuristic)	no

Also known as: cardiovascular Gaucher disease · Gaucher disease - ophthalmoplegia - cardiovascular calcification · Gaucher disease type 3C · Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome · Gaucher-like disease · pseudo Gaucher disease

Data availability: 65 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › Gaucher disease › Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome

Related subtypes (4): Gaucher disease type I, Gaucher disease type II, Gaucher disease type III, Gaucher disease perinatal lethal

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

65 retrieved; paginated sample, class counts are floors:

24 pathogenic/likely pathogenic, 11 uncertain significance, 11 conflicting classifications of pathogenicity, 9 pathogenic, 4 likely pathogenic, 2 likely benign, 1 benign/likely benign, 1 conflicting classifications of pathogenicity; other, 1 conflicting classifications of pathogenicity; risk factor, 1 pathogenic/likely pathogenic; risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
1119997	NM_000157.4(GBA1):c.604C>T (p.Arg202Ter)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1211295	NM_000157.4(GBA1):c.1249T>G (p.Trp417Gly)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
193611	NM_000157.4(GBA1):c.1265_1319del (p.Leu422fs)	GBA1	Pathogenic	criteria provided, multiple submitters, no conflicts
21070	NM_000157.4(GBA1):c.1505G>A (p.Arg502His)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
21072	NM_000157.4(GBA1):c.703T>C (p.Ser235Pro)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4290	NM_000157.4(GBA1):c.1226A>G (p.Asn409Ser)	GBA1	Pathogenic/Likely pathogenic; risk factor	criteria provided, multiple submitters, no conflicts
4291	NM_000157.4(GBA1):c.476G>A (p.Arg159Gln)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4292	NM_000157.4(GBA1):c.1297G>T (p.Val433Leu)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4293	NM_000157.4(GBA1):c.1342G>C (p.Asp448His)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4295	NM_000157.4(GBA1):c.1504C>T (p.Arg502Cys)	GBA1	Pathogenic	criteria provided, multiple submitters, no conflicts
4298	NM_000157.4(GBA1):c.764T>A (p.Phe255Tyr)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4301	NM_000157.4(GBA1):c.754T>A (p.Phe252Ile)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4302	NM_000157.4(GBA1):c.84dup (p.Leu29fs)	GBA1	Pathogenic	criteria provided, multiple submitters, no conflicts
4311	NM_000157.4(GBA1):c.1604G>A (p.Arg535His)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4314	NM_000157.4(GBA1):c.680A>G (p.Asn227Ser)	GBA1	Pathogenic	criteria provided, multiple submitters, no conflicts
4321	NM_000157.4(GBA1):c.259C>T (p.Arg87Trp)	GBA1	Pathogenic	criteria provided, multiple submitters, no conflicts
4326	NM_000157.4(GBA1):c.1192C>T (p.Arg398Ter)	GBA1	Pathogenic	criteria provided, multiple submitters, no conflicts
4327	NM_000157.4(GBA1):c.1246G>A (p.Gly416Ser)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4328	NM_000157.4(GBA1):c.887G>A (p.Arg296Gln)	GBA1	Pathogenic	criteria provided, multiple submitters, no conflicts
632835	NM_000157.4(GBA1):c.595_596del (p.Leu199fs)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
633240	NM_000157.4(GBA1):c.762-1G>C	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
642539	NM_000157.4(GBA1):c.222_224del (p.Thr75del)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
813336	NM_000157.4(GBA1):c.1174C>T (p.Arg392Trp)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
928837	NM_000157.4(GBA1):c.914del (p.Pro305fs)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
932181	NM_000157.4(GBA1):c.661C>A (p.Pro221Thr)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
93445	NM_000157.4(GBA1):c.115+1G>A	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
93446	NM_000157.4(GBA1):c.1171G>C (p.Val391Leu)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
93453	NM_000157.4(GBA1):c.508C>T (p.Arg170Cys)	GBA1	Pathogenic	criteria provided, multiple submitters, no conflicts
93455	NM_000157.4(GBA1):c.625C>T (p.Arg209Cys)	GBA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
93459	NM_000157.4(GBA1):c.721G>A (p.Gly241Arg)	GBA1	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 17 · Orphanet: 6 · 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
GBA1	Definitive	Autosomal recessive	Gaucher disease perinatal lethal	17

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GBA1	Orphanet:2072	Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome
GBA1	Orphanet:411602	Hereditary late-onset Parkinson disease
GBA1	Orphanet:77259	Gaucher disease type 1
GBA1	Orphanet:77260	Gaucher disease type 2
GBA1	Orphanet:77261	Gaucher disease type 3
GBA1	Orphanet:85212	Fetal Gaucher disease

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
GBA1	HGNC:4177	ENSG00000177628	P04062	Lysosomal acid glucosylceramidase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GBA1	Lysosomal acid glucosylceramidase	Glucosylceramidase that catalyzes, within the lysosomal compartment, the hydrolysis of glucosylceramides/GlcCers (such as beta-D-glucosyl-(1<->1’)-N-acylsphing-4-enine) into free ceramides (such as N-acylsphing-4-enine) and glucose.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GBA1	Enzyme (other)	yes	3.2.1.45	Glyco_hydro_30, GH_hydrolase_sf, GH30_C

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
islet of Langerhans	1
placenta	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GBA1	134	ubiquitous	marker	stromal cell of endometrium, islet of Langerhans, placenta

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GBA1	2,568

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GBA1	P04062	58

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Association of TriC/CCT with target proteins during biosynthesis	1	292.8×	0.003	GBA1
Glycosphingolipid catabolism	1	292.8×	0.003	GBA1

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
positive regulation of neuronal action potential	1	16852.0×	0.002	GBA1
cerebellar Purkinje cell layer formation	1	8426.0×	0.002	GBA1
beta-glucoside catabolic process	1	8426.0×	0.002	GBA1
glucosylceramide catabolic process	1	5617.3×	0.002	GBA1
termination of signal transduction	1	5617.3×	0.002	GBA1
regulation of lysosomal protein catabolic process	1	5617.3×	0.002	GBA1
pyramidal neuron differentiation	1	3370.4×	0.002	GBA1
autophagosome organization	1	3370.4×	0.002	GBA1
response to pH	1	2808.7×	0.002	GBA1
lymphocyte migration	1	2407.4×	0.002	GBA1
negative regulation of protein metabolic process	1	2106.5×	0.002	GBA1
response to thyroid hormone	1	2106.5×	0.002	GBA1
microglial cell proliferation	1	1872.4×	0.002	GBA1
microglia differentiation	1	1532.0×	0.002	GBA1
positive regulation of type 2 mitophagy	1	1532.0×	0.002	GBA1
glycolipid biosynthetic process	1	1404.3×	0.002	GBA1
response to dexamethasone	1	1203.7×	0.003	GBA1
sphingosine biosynthetic process	1	1053.2×	0.003	GBA1
lysosomal protein catabolic process	1	1053.2×	0.003	GBA1
regulation of TOR signaling	1	936.2×	0.003	GBA1
respiratory electron transport chain	1	842.6×	0.003	GBA1
brain morphogenesis	1	732.7×	0.003	GBA1
antigen processing and presentation	1	702.2×	0.003	GBA1
homeostasis of number of cells	1	674.1×	0.003	GBA1
hematopoietic stem cell proliferation	1	648.1×	0.003	GBA1
motor behavior	1	561.7×	0.004	GBA1
lipid storage	1	543.6×	0.004	GBA1
neuromuscular process	1	526.6×	0.004	GBA1
response to testosterone	1	468.1×	0.004	GBA1
negative regulation of protein-containing complex assembly	1	455.5×	0.004	GBA1

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
GBA1	MIGALASTAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GBA1	12	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MIGALASTAT	4	GBA1
GLUCONOLACTONE	4	GBA1
MIGLITOL	4	GBA1
MEXILETINE	4	GBA1
GENTIAN VIOLET	4	GBA1
CHLORHEXIDINE	4	GBA1
TAMOXIFEN	4	GBA1
AMBROXOL	3	GBA1
AFEGOSTAT	2	GBA1
AFEGOSTAT TARTRATE	2	GBA1
DUVOGLUSTAT	2	GBA1
NIZUBAGLUSTAT	2	GBA1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
GBA1	436	Binding:403, Functional:33

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GBA1	3.2.1.45	glucosylceramidase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
GBA1	436

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

12 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	GBA1
GLUCONOLACTONE	4	GBA1
MIGLITOL	4	GBA1
MEXILETINE	4	GBA1
GENTIAN VIOLET	4	GBA1
CHLORHEXIDINE	4	GBA1
TAMOXIFEN	4	GBA1
AMBROXOL	3	GBA1
AFEGOSTAT	2	GBA1
AFEGOSTAT TARTRATE	2	GBA1
DUVOGLUSTAT	2	GBA1
NIZUBAGLUSTAT	2	GBA1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GBA1
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.