glutaric acidemia IIc

Summary

glutaric acidemia IIc (MONDO:0700076) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 10

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	glutaric acidemia IIc
Mondo ID	MONDO:0700076
UMLS	C3278156
MedGen	479786
GARD	0026348
Is cancer (heuristic)	no

Also known as: ETFDH deficiency · GA2C · glutaric acidemia 2C · multiple acyl-CoA dehydrogenase deficiency caused by mutation in ETFDH

Data availability: 10 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › glutaric aciduria › multiple acyl-CoA dehydrogenase deficiency › glutaric acidemia IIc

Related subtypes (4): multiple acyl-CoA dehydrogenase deficiency, severe neonatal type, multiple acyl-CoA dehydrogenase deficiency, mild type, glutaric acidemia IIa, glutaric acidemia IIb

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

10 retrieved; paginated sample, class counts are floors:

5 pathogenic/likely pathogenic, 3 pathogenic, 2 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
12026	NM_004453.4(ETFDH):c.2T>C (p.Met1Thr)	ETFDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12027	NM_004453.4(ETFDH):c.36del (p.Tyr13fs)	ETFDH	Pathogenic	criteria provided, single submitter
12028	NM_004453.4(ETFDH):c.250G>A (p.Ala84Thr)	ETFDH	Pathogenic	criteria provided, multiple submitters, no conflicts
12029	NM_004453.4(ETFDH):c.524G>T (p.Arg175Leu)	ETFDH	Pathogenic	criteria provided, multiple submitters, no conflicts
12030	NM_004453.4(ETFDH):c.380T>A (p.Leu127His)	ETFDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31576	NM_004453.4(ETFDH):c.524G>A (p.Arg175His)	ETFDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
459963	NM_004453.4(ETFDH):c.1414G>A (p.Gly472Arg)	ETFDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
802100	NM_004453.4(ETFDH):c.295C>T (p.Arg99Cys)	ETFDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1030500	NM_001985.3(ETFB):c.274C>T (p.Pro92Ser)	ETFB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
565800	NM_004453.4(ETFDH):c.807A>C (p.Gln269His)	ETFDH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

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

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ETFB	Orphanet:394529	Multiple acyl-CoA dehydrogenase deficiency, severe neonatal type
ETFB	Orphanet:394532	Multiple acyl-CoA dehydrogenase deficiency, mild type
ETFDH	Orphanet:394529	Multiple acyl-CoA dehydrogenase deficiency, severe neonatal type
ETFDH	Orphanet:394532	Multiple acyl-CoA dehydrogenase deficiency, mild type

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ETFB	HGNC:3482	ENSG00000105379	P38117	Electron transfer flavoprotein subunit beta	clinvar
ETFDH	HGNC:3483	ENSG00000171503	Q16134	Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ETFB	Electron transfer flavoprotein subunit beta	Heterodimeric electron transfer flavoprotein that accepts electrons from several mitochondrial dehydrogenases, including acyl-CoA dehydrogenases, glutaryl-CoA and sarcosine dehydrogenase.
ETFDH	Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial	Accepts electrons from ETF and reduces ubiquinone.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ETFB	Other/Unknown	no		ET-Flavoprotein_bsu_CS, ETF_b, Rossmann-like_a/b/a_fold
ETFDH	Enzyme (other)	yes	1.5.5.1	ETF-QO/FixX_C, 4Fe4S_Fe-S-bd, FAD/NAD-bd_sf

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	2
heart left ventricle	2
right lobe of liver	1
hindlimb stylopod muscle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ETFB	290	ubiquitous	marker	apex of heart, right lobe of liver, heart left ventricle
ETFDH	285	ubiquitous	marker	apex of heart, heart left ventricle, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ETFB	2,599
ETFDH	2,031

Intra-cohort edges

A	B	Sources
ETFB	ETFDH	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ETFB	P38117	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ETFDH	Q16134	93.60

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 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
Respiratory electron transport	2	95.2×	2e-04	ETFB, ETFDH
Protein methylation	1	335.9×	0.003	ETFB

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
fatty acid beta-oxidation using acyl-CoA dehydrogenase	2	1404.3×	2e-06	ETFB, ETFDH
respiratory electron transport chain	2	842.6×	3e-06	ETFB, ETFDH
amino acid catabolic process	1	1404.3×	0.001	ETFB
electron transport chain	1	766.0×	0.002	ETFDH
response to oxidative stress	1	65.3×	0.015	ETFDH

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ETFB	1	3
ETFDH	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CRENOLANIB	3	ETFB

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ETFB	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ETFDH	1.5.5.1	electron-transferring-flavoprotein dehydrogenase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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)
CRENOLANIB	3	ETFB

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	1	ETFB
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	ETFDH
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ETFDH	0	ETFB

Clinical trials & evidence

Clinical trials

Clinical trials: 0.