3-methylglutaconic aciduria, type VIIB

Summary

3-methylglutaconic aciduria, type VIIB (MONDO:0014561) is a disease caused by CLPB (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CLPB (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 723
• Phenotypes (HPO): 38

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		22	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

38 HPO clinical features (Orphanet curated; top 38 by frequency):

HPO ID	Term	Frequency
HP:0000107	Renal cyst	Very frequent (80-99%)
HP:0000121	Nephrocalcinosis	Very frequent (80-99%)
HP:0000518	Cataract	Very frequent (80-99%)
HP:0001875	Decreased total neutrophil count	Very frequent (80-99%)
HP:0003535	3-Methylglutaconic aciduria	Very frequent (80-99%)
HP:0011451	Congenital microcephaly	Very frequent (80-99%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001266	Choreoathetosis	Frequent (30-79%)
HP:0001272	Cerebellar atrophy	Frequent (30-79%)
HP:0001298	Encephalopathy	Frequent (30-79%)
HP:0001336	Myoclonus	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0002059	Cerebral atrophy	Frequent (30-79%)
HP:0002071	Abnormality of extrapyramidal motor function	Frequent (30-79%)
HP:0002134	Abnormality of the basal ganglia	Frequent (30-79%)
HP:0002151	Increased circulating lactate concentration	Frequent (30-79%)
HP:0002179	Opisthotonus	Frequent (30-79%)
HP:0002194	Delayed gross motor development	Frequent (30-79%)
HP:0002376	Developmental regression	Frequent (30-79%)
HP:0005528	Bone marrow hypocellularity	Frequent (30-79%)
HP:0007153	Progressive extrapyramidal movement disorder	Frequent (30-79%)
HP:0007256	Abnormal pyramidal sign	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0410256	Infection associated neutropenia	Frequent (30-79%)
HP:0000083	Renal insufficiency	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000821	Hypothyroidism	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001276	Hypertonia	Occasional (5-29%)
HP:0001397	Hepatic steatosis	Occasional (5-29%)
HP:0001638	Cardiomyopathy	Occasional (5-29%)
HP:0001998	Neonatal hypoglycemia	Occasional (5-29%)
HP:0002878	Respiratory failure	Occasional (5-29%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Occasional (5-29%)
HP:0002107	Pneumothorax	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	3-methylglutaconic aciduria, type VIIB
Mondo ID	MONDO:0014561
OMIM	616271
Orphanet	445038
DOID	DOID:0081134, DOID:0110003
SNOMED CT	764860006
UMLS	C5676893
MedGen	1810214
GARD	0017767
Is cancer (heuristic)	no

Also known as: 3-methylglutaconic aciduria type 7 · 3-METHYLGLUTACONIC aciduria with cataracts, neurologic involvement, and neutropenia · 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia · 3-methylglutaconic aciduria-cataract-neurologic involvement-neutropenia syndrome · CLPB 3-methylglutaconic aciduria · MEGCANN · MGA7 · MGCA7

Data availability: 723 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › inborn organic aciduria › classic organic aciduria › 3-methylglutaconic aciduria › 3-methylglutaconic aciduria, type VIIB

Related subtypes (9): 3-methylglutaconic aciduria type 1, 3-methylglutaconic aciduria type 4, 3-methylglutaconic aciduria type 3, Barth syndrome, 3-methylglutaconic aciduria type 5, 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome, 3-methylglutaconic aciduria type 8, 3-methylglutaconic aciduria type 9, 3-methylglutaconic aciduria, type VIIA

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

600 retrieved; paginated sample, class counts are floors:

314 uncertain significance, 216 likely benign, 25 pathogenic, 14 conflicting classifications of pathogenicity, 11 likely pathogenic, 10 benign/likely benign, 4 benign, 3 pathogenic/likely pathogenic, 3 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1074465	NM_001258392.3(CLPB):c.1293dup (p.Asp432fs)	CLPB	Pathogenic	criteria provided, single submitter
1322097	NM_030813.6(CLPB):c.654dup (p.Gln219fs)	CLPB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1427364	NC_000011.9:g.(?72145096)(72145518_?)del	CLPB	Pathogenic	criteria provided, single submitter
1452426	NM_001258392.3(CLPB):c.532C>T (p.Arg178Ter)	CLPB	Pathogenic	criteria provided, multiple submitters, no conflicts
1676587	NM_001258392.3(CLPB):c.1190C>T (p.Pro397Leu)	CLPB	Pathogenic	no assertion criteria provided
1676588	NM_001258392.3(CLPB):c.1588G>A (p.Gly530Arg)	CLPB	Pathogenic	criteria provided, multiple submitters, no conflicts
1700633	NM_001258392.3(CLPB):c.1813_1814delinsAA (p.Ala605Lys)	CLPB	Pathogenic	no assertion criteria provided
187780	NM_001258392.3(CLPB):c.1215_1217inv (p.Glu405_Gly406delinsAspPro)	CLPB	Pathogenic	no assertion criteria provided
187781	NM_001258392.3(CLPB):c.1847G>T (p.Gly616Val)	CLPB	Pathogenic	no assertion criteria provided
187782	NM_001258392.3(CLPB):c.1682C>T (p.Ala561Val)	CLPB	Pathogenic	no assertion criteria provided
187784	NM_001258392.3(CLPB):c.1760A>G (p.Tyr587Cys)	CLPB	Pathogenic	no assertion criteria provided
187786	NM_001258392.3(CLPB):c.1159C>T (p.Arg387Ter)	CLPB	Pathogenic	criteria provided, multiple submitters, no conflicts
187788	NM_001258392.3(CLPB):c.871A>T (p.Lys291Ter)	CLPB	Pathogenic	no assertion criteria provided
192392	NM_001258392.3(CLPB):c.1595del (p.Ile532fs)	CLPB	Pathogenic	no assertion criteria provided
2042071	NM_001258392.3(CLPB):c.278dup (p.Pro94fs)	CLPB	Pathogenic	criteria provided, single submitter
2136144	NM_001258392.3(CLPB):c.790C>T (p.Gln264Ter)	CLPB	Pathogenic	criteria provided, multiple submitters, no conflicts
2151624	NM_001258392.3(CLPB):c.1017C>G (p.Tyr339Ter)	CLPB	Pathogenic	criteria provided, single submitter
2426947	NC_000011.9:g.(?72004411)(72006712_?)del	CLPB	Pathogenic	criteria provided, single submitter
2426950	NC_000011.9:g.(?72145398)(72145517_?)del	CLPB	Pathogenic	criteria provided, single submitter
2426951	NC_000011.9:g.(?72145398)(72150823_?)del	CLPB	Pathogenic	criteria provided, single submitter
279604	NM_001258392.3(CLPB):c.658C>T (p.Arg220Ter)	CLPB	Pathogenic	criteria provided, single submitter
2809209	NM_001258392.3(CLPB):c.1341_1344del (p.Asp448fs)	CLPB	Pathogenic	criteria provided, single submitter
3638533	NM_001258392.3(CLPB):c.787del (p.Leu263fs)	CLPB	Pathogenic	criteria provided, single submitter
449301	NM_001258392.3(CLPB):c.873+1G>A	CLPB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4721970	NM_001258392.3(CLPB):c.319del (p.Val107fs)	CLPB	Pathogenic	criteria provided, single submitter
4731503	NM_001258392.3(CLPB):c.788del (p.Leu263fs)	CLPB	Pathogenic	criteria provided, single submitter
4848692	NM_001258392.3(CLPB):c.1492_1493insATTTG (p.Val498fs)	CLPB	Pathogenic	criteria provided, single submitter
187785	NM_001258392.3(CLPB):c.1132A>G (p.Arg378Gly)	LOC126861258	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1172515	NM_001258392.3(CLPB):c.221dup (p.Gly76fs)	CLPB	Likely pathogenic	criteria provided, single submitter
1300024	NM_001258392.3(CLPB):c.455+1G>A	CLPB	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · 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
CLPB	Definitive	Autosomal recessive	3-methylglutaconic aciduria, type VIIB	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CLPB	Orphanet:445038	3-methylglutaconic aciduria-neonatal cataract-neurologic involvement-congenital neutropenia syndrome
CLPB	Orphanet:486	Autosomal dominant severe congenital neutropenia

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CLPB	HGNC:30664	ENSG00000162129	Q9H078	Mitochondrial disaggregase	gencc,clinvar
ANAPC15	HGNC:24531	ENSG00000110200	P60006	Anaphase-promoting complex subunit 15	clinvar
ARV1	HGNC:29561	ENSG00000173409	Q9H2C2	Protein ARV1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CLPB	Mitochondrial disaggregase	Functions as a regulatory ATPase and participates in secretion/protein trafficking process.
ANAPC15	Anaphase-promoting complex subunit 15	Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle.
ARV1	Protein ARV1	Plays a role as a mediator in the endoplasmic reticulum (ER) cholesterol and bile acid homeostasis.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · 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
Scaffold/PPI	1	5.8×	0.327
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CLPB	Scaffold/PPI	no		ClpA/B, Ankyrin_rpt, AAA+_ATPase
ANAPC15	Other/Unknown	no		ANAPC15
ARV1	Other/Unknown	no		Arv1

Expression context

Cohort genes with no expression data: 0.

3 cohort genes 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left testis	2
right testis	2
sperm	1
apex of heart	1
cardiac muscle of right atrium	1
left ventricle myocardium	1
myocardium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CLPB	205	ubiquitous	marker	sperm, left testis, right testis
ANAPC15	276	ubiquitous	marker	apex of heart, right testis, left testis
ARV1	258	ubiquitous	marker	cardiac muscle of right atrium, myocardium, left ventricle myocardium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CLPB	5,095
ANAPC15	937
ARV1	476

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ANAPC15	P60006	18
CLPB	Q9H078	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ARV1	Q9H2C2	82.17

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 47. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Cholesterol biosynthesis	1	571.0×	0.016	ARV1
Inhibition of the proteolytic activity of APC/C required for the onset of anaphase by mitotic spindle checkpoint components	1	317.2×	0.016	ANAPC15
Phosphorylation of the APC/C	1	271.9×	0.016	ANAPC15
Inactivation of APC/C via direct inhibition of the APC/C complex	1	259.6×	0.016	ANAPC15
Conversion from APC/C:Cdc20 to APC/C:Cdh1 in late anaphase	1	259.6×	0.016	ANAPC15
Aberrant regulation of mitotic exit in cancer due to RB1 defects	1	259.6×	0.016	ANAPC15
APC/C:Cdc20 mediated degradation of Cyclin B	1	228.4×	0.016	ANAPC15
APC-Cdc20 mediated degradation of Nek2A	1	211.5×	0.016	ANAPC15
APC:Cdc20 mediated degradation of cell cycle proteins prior to satisfation of the cell cycle checkpoint	1	211.5×	0.016	ANAPC15
Activation of APC/C and APC/C:Cdc20 mediated degradation of mitotic proteins	1	203.9×	0.016	ANAPC15
Aberrant regulation of mitotic cell cycle due to RB1 defects	1	203.9×	0.016	ANAPC15
Diseases of mitotic cell cycle	1	196.9×	0.016	ANAPC15
APC/C:Cdc20 mediated degradation of mitotic proteins	1	178.4×	0.016	ANAPC15
APC/C-mediated degradation of cell cycle proteins	1	167.9×	0.016	ANAPC15
Regulation of mitotic cell cycle	1	167.9×	0.016	ANAPC15
DNA Replication Pre-Initiation	1	158.6×	0.016	ANAPC15
Regulation of APC/C activators between G1/S and early anaphase	1	154.3×	0.016	ANAPC15
Switching of origins to a post-replicative state	1	150.3×	0.016	ANAPC15
Synthesis of DNA	1	150.3×	0.016	ANAPC15
Transcriptional Regulation by VENTX	1	132.8×	0.018	ANAPC15
DNA Replication	1	119.0×	0.019	ANAPC15
Autodegradation of Cdh1 by Cdh1:APC/C	1	95.2×	0.020	ANAPC15
APC/C:Cdc20 mediated degradation of Securin	1	95.2×	0.020	ANAPC15
S Phase	1	90.6×	0.020	ANAPC15
Cdc20:Phospho-APC/C mediated degradation of Cyclin A	1	86.5×	0.020	ANAPC15
APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1	1	85.2×	0.020	ANAPC15
CDK-mediated phosphorylation and removal of Cdc6	1	85.2×	0.020	ANAPC15
Mitotic Spindle Checkpoint	1	79.3×	0.021	ANAPC15
Assembly of the pre-replicative complex	1	69.6×	0.022	ANAPC15
Cellular Senescence	1	68.8×	0.022	ANAPC15

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of plasma membrane sterol distribution	1	5617.3×	0.004	ARV1
regulation of intracellular cholesterol transport	1	1404.3×	0.006	ARV1
intracellular sterol transport	1	1123.5×	0.006	ARV1
RIG-I signaling pathway	1	802.5×	0.006	CLPB
regulation of mitotic cell cycle spindle assembly checkpoint	1	702.2×	0.006	ANAPC15
granulocyte differentiation	1	401.2×	0.006	CLPB
regulation of cholesterol metabolic process	1	374.5×	0.006	ARV1
sphingolipid metabolic process	1	330.4×	0.006	ARV1
bile acid metabolic process	1	330.4×	0.006	ARV1
sterol metabolic process	1	280.9×	0.006	ARV1
protein branched polyubiquitination	1	280.9×	0.006	ANAPC15
regulation of meiotic cell cycle	1	255.3×	0.006	ANAPC15
cholesterol transport	1	244.2×	0.006	ARV1
anaphase-promoting complex-dependent catabolic process	1	234.1×	0.006	ANAPC15
cholesterol biosynthetic process	1	140.4×	0.010	ARV1
protein K11-linked ubiquitination	1	130.6×	0.010	ANAPC15
cellular response to heat	1	114.6×	0.011	CLPB
regulation of mitotic cell cycle	1	80.2×	0.014	ANAPC15
antiviral innate immune response	1	75.9×	0.014	CLPB
protein K48-linked ubiquitination	1	56.2×	0.019	ANAPC15
cell division	1	15.4×	0.064	ANAPC15

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CLPB	0	0
ANAPC15	0	0
ARV1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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	3	CLPB, ANAPC15, ARV1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CLPB	0	—
ANAPC15	0	—
ARV1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.