ETFDH

Summary

ETFDH (electron transfer flavoprotein dehydrogenase, HGNC:3483) is a protein-coding gene on chromosome 4q32.1, encoding Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial (Q16134). Accepts electrons from ETF and reduces ubiquinone.

This gene encodes a component of the electron-transfer system in mitochondria and is essential for electron transfer from a number of mitochondrial flavin-containing dehydrogenases to the main respiratory chain. Mutations in this gene are associated with glutaric acidemia. Alternatively spliced transcript variants that encode distinct isoforms have been observed.

Source: NCBI Gene 2110 — RefSeq curated summary.

At a glance

• Gene–disease (curated): multiple acyl-CoA dehydrogenase deficiency (Definitive, ClinGen)
• GWAS associations: 7
• Clinical variants (ClinVar): 1,106 total — 103 pathogenic, 132 likely-pathogenic
• Phenotypes (HPO): 46
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_004453

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3483
Approved symbol	ETFDH
Name	electron transfer flavoprotein dehydrogenase
Location	4q32.1
Locus type	gene with protein product
Status	Approved
Aliases	ETFQO
Ensembl gene	ENSG00000171503
Ensembl biotype	protein_coding
OMIM	231675
Entrez	2110

Gene structure

Transcript identifiers

Ensembl transcripts: 53 — 20 protein_coding, 19 retained_intron, 9 nonsense_mediated_decay, 5 protein_coding_CDS_not_defined

ENST00000307738, ENST00000436096, ENST00000506422, ENST00000507475, ENST00000510353, ENST00000511912, ENST00000512251, ENST00000514148, ENST00000681978, ENST00000682178, ENST00000682345, ENST00000682409, ENST00000682452, ENST00000682456, ENST00000682566, ENST00000682601, ENST00000682613, ENST00000682734, ENST00000682820, ENST00000682910, ENST00000683004, ENST00000683079, ENST00000683081, ENST00000683123, ENST00000683181, ENST00000683209, ENST00000683305, ENST00000683448, ENST00000683478, ENST00000683483, ENST00000683622, ENST00000683750, ENST00000683751, ENST00000683799, ENST00000684036, ENST00000684129, ENST00000684209, ENST00000684296, ENST00000684505, ENST00000684552, ENST00000684611, ENST00000684622, ENST00000684627, ENST00000684641, ENST00000684675, ENST00000684749, ENST00000908056, ENST00000908057, ENST00000908058, ENST00000935955, ENST00000953090, ENST00000953091, ENST00000953092

RefSeq mRNA: 3 — MANE Select: NM_004453 NM_001281737, NM_001281738, NM_004453

CCDS: CCDS3800, CCDS64090, CCDS93661

Canonical transcript exons

ENST00000511912 — 13 exons

Exon	Start	End
ENSE00001126640	158698987	158699130
ENSE00001126648	158697559	158697699
ENSE00001126657	158695497	158695643
ENSE00001126663	158690348	158690425
ENSE00002069017	158708364	158709623
ENSE00003470261	158680467	158680607
ENSE00003510567	158706189	158706371
ENSE00003584328	158685101	158685219
ENSE00003589165	158684592	158684673
ENSE00003593254	158706629	158706850
ENSE00003628977	158682195	158682424
ENSE00003670690	158703423	158703591
ENSE00003891534	158672296	158672490

Expression profiles

Bgee: expression breadth ubiquitous, 285 present calls, max score 98.09.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.4982 / max 139.8351, expressed in 1736 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
50304	8.7494	1690
50302	0.9001	605
50303	0.8487	497

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	98.09	gold quality
heart left ventricle	UBERON:0002084	97.29	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.15	gold quality
right lobe of liver	UBERON:0001114	97.13	gold quality
cardiac ventricle	UBERON:0002082	97.07	gold quality
jejunal mucosa	UBERON:0000399	96.93	gold quality
adrenal tissue	UBERON:0018303	96.87	gold quality
right atrium auricular region	UBERON:0006631	96.65	gold quality
heart right ventricle	UBERON:0002080	96.53	gold quality
gastrocnemius	UBERON:0001388	96.05	gold quality
muscle of leg	UBERON:0001383	96.02	gold quality
right adrenal gland	UBERON:0001233	95.76	gold quality
right adrenal gland cortex	UBERON:0035827	95.73	gold quality
heart	UBERON:0000948	95.37	gold quality
left adrenal gland	UBERON:0001234	95.19	gold quality
cardiac atrium	UBERON:0002081	95.11	gold quality
liver	UBERON:0002107	94.97	gold quality
mucosa of transverse colon	UBERON:0004991	94.97	gold quality
muscle organ	UBERON:0001630	94.94	gold quality
skeletal muscle organ	UBERON:0014892	94.94	gold quality
left adrenal gland cortex	UBERON:0035825	94.79	gold quality
calcaneal tendon	UBERON:0003701	94.42	gold quality
adrenal gland	UBERON:0002369	94.29	gold quality
biceps brachii	UBERON:0001507	94.02	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	93.52	gold quality
adrenal cortex	UBERON:0001235	93.51	gold quality
duodenum	UBERON:0002114	93.48	gold quality
colonic epithelium	UBERON:0000397	93.19	gold quality
lower esophagus mucosa	UBERON:0035834	93.08	gold quality
transverse colon	UBERON:0001157	92.73	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-4850	no	561.16
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PPARA

miRNA regulators (miRDB)

19 targeting ETFDH, 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-3163	100.00	77.23	8605
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-200A-5P	99.76	69.10	949
HSA-MIR-200B-5P	99.76	69.05	948
HSA-MIR-2113	99.58	71.22	1521
HSA-MIR-520F-5P	99.34	70.40	1632
HSA-MIR-4652-3P	99.33	70.02	2742
HSA-MIR-3675-3P	99.09	67.70	968
HSA-MIR-5590-5P	98.81	68.78	969
HSA-MIR-758-3P	98.42	68.60	1122
HSA-MIR-4778-5P	97.96	68.06	1634
HSA-MIR-1302	97.92	67.27	844
HSA-MIR-4298	97.26	66.59	765
HSA-MIR-216B-5P	97.16	66.76	1126
HSA-MIR-600	97.07	66.73	1259
HSA-MIR-100-5P	95.81	70.94	92
HSA-MIR-99A-5P	95.81	70.94	92
HSA-MIR-99B-5P	95.81	70.94	92

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 32)

• expression from a baculovirus vector and kinetic and spectral characteristics (PMID:12049629)
• Mutations are identified by molecular analysis of 20 ETF:QO-deficient patients. Twenty-one different disease-causing mutations were identified on 36 of the 40 chromosomes. (PMID:12359134)
• patients had autosomal recessive mutations in ETFDH, suggesting ETFDH deficiency leads to a secondary CoQ10 deficiency; results indicate that the late-onset form of glutaric aciduria type II & the myopathic form of CoQ10 deficiency are allelic diseases (PMID:17412732)
• study identified ETFDH mutations in all members of a large series of patients with riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency (PMID:17584774)
• We performed mutation analysis in four Taiwanese MADD patients. Three novel ETFDH mutations were identified in four patients and all harbored the p.A84T mutation (PMID:19249206)
• Four novel mutations (3 missenses and 1 deletion) in ETFDH were found in Chinese families that presented with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency. (PMID:19265687)
• lipid storage myopathy caused by ETFDH gene mutations. (PMID:19758981)
• 3 known (c.250G>A, c380T>A, c.524G>T) and 1 novel (c.1831G>A) ETFDH mutation were detected by high resolution melting analysis. The carrier frequency of the hotspot mutation, c.250G>A, in the Taiwanese population was found to be 1:125. (PMID:20138856)
• High frequency of ETFDH c.250G>A mutation in Taiwanese patients with late-onset lipid storage myopathy (PMID:20370797)
• Case Report: ETF dehydrogenase mutations resulting in mild glutaric aciduria type II and complex II-III deficiency in liver and muscle. (PMID:21088898)
• a significant reduced expression of ETFDH was identified in the muscle of ETFDH-deficient patients; ETFDH deficiency is a major cause of riboflavin-responsive MADD in southern China, and c.250G>A is an important mutation (PMID:21347544)
• folding defects in the variant ETF-QO proteins and multiple acyl-CoA dehydrogenation deficiency (PMID:22611163)
• Results show that a predicted benign ETFDH missense variationc.158A>G in exon 2 causes exon skipping and degradation of ETFDH protein in patient samples. (PMID:24123825)
• identified 61 ETFDH mutations, including 31 novel mutations, which were widely distributed within the coding sequence (PMID:24357026)
• Mutations in SLC22A5 and ETFDH are associated with riboflavin responsive-multiple acyl-CoA dehydrogenase deficiency. (PMID:25119904)
• ETFDH mutation is the causative gene in patients with adult-onset multiple acyl-CoA dehydrogenase deficiency with severe sensory neuropathy. (PMID:26821934)
• This study identified three novel compound heterozygous mutations of ETFDH gene in patients with late-onset multiple acyl-CoA dehydrogenase deficiency, and discussed the significant clinical heterogeneity among patients with similar genotype. (PMID:27000805)
• Mtation c.250G>A and mutation c.353G>T in the ETFDH gene are associate with multiple aeyl-CoA dehydrogenase deficiency with severe fatty liver. (PMID:27060313)
• Neurite shortening and impairment in neurite growth was caused by a mutation in ETFDH. (PMID:27935074)
• Multiple acyl-CoA dehydrogenase deficiency is cause by electron transfer flavoprotein ubiquinone oxidoreductase mutation at heterozygotes with c.1354A>G (p.Arg452Gly) and exon 7-8 deletion for Patient 1, and with c.831+3A>C and exon 1-7 deletion for Patient 2. (PMID:30027710)
• This case report extends the spectrum of ETFDH mutations in multiple acyl-CoA dehydrogenase deficiency (MADD), providing further evidence that patients presenting at least one missense mutation in the FAD-binding domain may respond to either carnitine or riboflavin treatment, due to the recovery of some enzymatic activity. (PMID:30424791)
• Molecular and Clinical Investigations on Portuguese Patients with Multiple acyl-CoA Dehydrogenase Deficiency. (PMID:31418342)
• Mutations of the ETFDH gene probably underlie the pathogenesis of lipid storage myopathy in this family (PMID:31598946)
• Low tumor expression of ETFDH was associated with a poorer overall survival in patients with hepatocellular carcinoma. (PMID:31704152)
• A mutation is the most common EFTDH mutation in riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency and is most prevalent in China and South-East Asia where its epidemiology correlates with the distribution and migration patterns of the southern Min population in Southern China and neighbouring countries (PMID:31852447)
• the two variants of ETFDH gene identified probably underlie the pathogenesis of Glutaric acidemia type II in this family, and also enlarge ETFDH genotype-phenotype correlations spectrum. (PMID:32393189)
• Mitochondrial energetic impairment in a patient with late-onset glutaric acidemia Type 2. (PMID:32804429)
• Clinical characteristics and gene mutation analysis of an adult patient with ETFDHrelated multiple acylCoA dehydrogenase deficiency. (PMID:33000234)
• ETF dehydrogenase advances in molecular genetics and impact on treatment. (PMID:33823724)
• Screening of multiple acyl-CoA dehydrogenase deficiency in newborns and follow-up of patients. (PMID:34704421)
• Multiple acyl-CoA dehydrogenase deficiency kills Mycobacterium tuberculosis in vitro and during infection. (PMID:34782606)
• ETFDH mutation involves excessive apoptosis and neurite outgrowth defect via Bcl2 pathway. (PMID:39455656)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	etfdh	ENSDARG00000038834
mus_musculus	Etfdh	ENSMUSG00000027809
rattus_norvegicus	Etfdh	ENSRNOG00000009538
drosophila_melanogaster	Etf-QO	FBGN0286783
caenorhabditis_elegans		WBGENE00002855

Protein

Protein identifiers

Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial — Q16134 (reviewed: Q16134)

Alternative names: Electron-transferring-flavoprotein dehydrogenase

All UniProt accessions (15): Q16134, A0A804HI48, A0A804HI70, A0A804HI73, A0A804HI80, A0A804HJK8, A0A804HJT7, A0A804HK05, A0A804HK08, A0A804HK66, A0A804HKB8, A0A804HKY7, A0A804HL81, A0A804HL84, B4DEQ0

UniProt curated annotations — full annotation on UniProt →

Function. Accepts electrons from ETF and reduces ubiquinone.

Subunit / interactions. Monomer.

Subcellular location. Mitochondrion inner membrane.

Disease relevance. Glutaric aciduria 2C (GA2C) [MIM:231680] An autosomal recessively inherited disorder of fatty acid, amino acid, and choline metabolism. It is characterized by multiple acyl-CoA dehydrogenase deficiencies resulting in large excretion not only of glutaric acid, but also of lactic, ethylmalonic, butyric, isobutyric, 2-methyl-butyric, and isovaleric acids. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 [4Fe-4S] cluster.

Similarity. Belongs to the ETF-QO/FixC family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q16134-1	1	yes
Q16134-3	2

RefSeq proteins (3): NP_001268666, NP_001268667, NP_004444* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007859	ETF-QO/FixX_C	Domain
IPR017896	4Fe4S_Fe-S-bd	Domain
IPR036188	FAD/NAD-bd_sf	Homologous_superfamily
IPR040156	ETF-QO	Family
IPR049398	ETF-QO/FixC_UQ-bd	Domain

Pfam: PF01946, PF05187, PF21162

Enzyme classification (BRENDA):

• EC 1.5.5.1 — electron-transferring-flavoprotein dehydrogenase (BRENDA: 15 organisms, 56 substrates, 10 inhibitors, 36 Km, 32 kcat entries)

Substrate kinetics (BRENDA)

23 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ELECTRON-TRANSFERRING FLAVOPROTEIN	0.0001–5400	9
UBIQUINONE-1	0.0045–6900	4
DECYLUBIQUINONE	0.0079–0.0084	2
SEMIQUINONE ELECTRON-TRANSFERRING FLAVOPROTEIN	0.0077–0.0154	2
UBIQUINONE-2	0.0023–0.0049	2
6-(10-BROMODECYL)UBIQUINONE	0.0026	1
6-(10-HYDROXYDECYL)UBIQUINONE	0.0018	1
6-BIS(ISOPRENYL)UBIQUINONE	0.0069	1
6-HEPTYLUBIQUINONE	0.002	1
6-ISOPRENYLUBIQUINONE	0.0095	1
6-NONYLUBIQUINONE	0.0016	1
BROMODECYLUBIQUINONE	0.0089	1
DUROQUINONE	0.0195	1
HEPTYLUBIQUINONE	0.0082	1
HYDROQUINONE ELECTRON-TRANSFERRING FLAVOPROTEIN	0.0003	1

Catalyzed reactions (Rhea), 1 shown:

• a ubiquinone + reduced [electron-transfer flavoprotein] = a ubiquinol + oxidized [electron-transfer flavoprotein] + H(+) (RHEA:24052)

UniProt features (46 total): sequence variant 26, binding site 7, modified residue 5, intramembrane region 2, sequence conflict 2, transit peptide 1, chain 1, splice variant 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q16134-F1	93.60	0.91

Functional residue map

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

Ligand- & substrate-binding residues (7): 589; 592; 71–85; 305; 306; 561; 586

Post-translational modifications (5): 96, 132, 223, 357, 551

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-611105	Respiratory electron transport

MSigDB gene sets: 286 (showing top): GOBP_LIPID_MODIFICATION, GOBP_FATTY_ACID_CATABOLIC_PROCESS, MULLIGHAN_NPM1_SIGNATURE_3_UP, chr4q32, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, BROWNE_HCMV_INFECTION_16HR_UP, TGACCTY_ERR1_Q2, LUCAS_HNF4A_TARGETS_UP, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_FATTY_ACID_BETA_OXIDATION_USING_ACYL_COA_DEHYDROGENASE, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, MARTINEZ_RB1_TARGETS_UP, MCBRYAN_PUBERTAL_BREAST_4_5WK_DN, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS

GO Biological Process (4): response to oxidative stress (GO:0006979), electron transport chain (GO:0022900), respiratory electron transport chain (GO:0022904), fatty acid beta-oxidation using acyl-CoA dehydrogenase (GO:0033539)

GO Molecular Function (10): electron-transferring-flavoprotein dehydrogenase activity (GO:0004174), electron transfer activity (GO:0009055), oxidoreductase activity (GO:0016491), metal ion binding (GO:0046872), quinone binding (GO:0048038), ubiquinone binding (GO:0048039), flavin adenine dinucleotide binding (GO:0050660), 4 iron, 4 sulfur cluster binding (GO:0051539), protein binding (GO:0005515), iron-sulfur cluster binding (GO:0051536)

GO Cellular Component (6): nucleoplasm (GO:0005654), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), cytosol (GO:0005829), mitochondrial membrane (GO:0031966), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Aerobic respiration and respiratory electron transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cytoplasm	2
response to stress	1
generation of precursor metabolites and energy	1
electron transport chain	1
cellular respiration	1
acyl-CoA dehydrogenase activity	1
fatty acid beta-oxidation	1
electron transfer activity	1
oxidoreductase activity, acting on the CH-NH group of donors, quinone or similar compound as acceptor	1
respiratory electron transport chain	1
molecular_function	1
catalytic activity	1
cation binding	1
small molecule binding	1
quinone binding	1
nucleotide binding	1
anion binding	1
iron-sulfur cluster binding	1
binding	1
metal cluster binding	1
nuclear lumen	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
mitochondrion	1
mitochondrial envelope	1
organelle membrane	1

Protein interactions and networks

STRING

1978 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ETFDH	ETFB	P38117	996
ETFDH	ETFA	P13804	995
ETFDH	FLAD1	Q8NFF5	765
ETFDH	PDSS1	Q5T2R2	716
ETFDH	PDSS2	Q86YH6	711
ETFDH	COQ9	O75208	699
ETFDH	ACADVL	P49748	690
ETFDH	COQ2	Q96H96	676
ETFDH	ACADS	P16219	658
ETFDH	COQ4	Q9Y3A0	650
ETFDH	DHODH	Q02127	647
ETFDH	SLC25A32	Q9H2D1	643
ETFDH	COQ6	Q9Y2Z9	642
ETFDH	ACADL	P28330	633
ETFDH	COQ8A	Q8NI60	631

IntAct

29 interactions, top by confidence:

A	B	Type	Score
ETFDH	TRIM69	psi-mi:“MI:0915”(physical association)	0.560
ETFDH	ZNF581	psi-mi:“MI:0915”(physical association)	0.560
ETFDH	KRTAP11-1	psi-mi:“MI:0915”(physical association)	0.560
GSC2	ETFDH	psi-mi:“MI:0915”(physical association)	0.560
ETFDH	KRTAP13-2	psi-mi:“MI:0915”(physical association)	0.560
OTX1	ETFDH	psi-mi:“MI:0915”(physical association)	0.560
MYH7B	ETFDH	psi-mi:“MI:0915”(physical association)	0.560
GCDH	ETFDH	psi-mi:“MI:0945”(oxidoreductase activity electron transfer reaction)	0.440
ETFDH	HBB	psi-mi:“MI:0915”(physical association)	0.400
COQ9	NDUFS8	psi-mi:“MI:0914”(association)	0.350
SLC25A16	TOMM70	psi-mi:“MI:0914”(association)	0.350
SLC25A32	CS	psi-mi:“MI:0914”(association)	0.350
ETFDH	TRIM69	psi-mi:“MI:0915”(physical association)	0.000
ETFDH	ZNF581	psi-mi:“MI:0915”(physical association)	0.000
ETFDH	MYH7B	psi-mi:“MI:0915”(physical association)	0.000
ETFDH	KRTAP11-1	psi-mi:“MI:0915”(physical association)	0.000
ETFDH	GSC2	psi-mi:“MI:0915”(physical association)	0.000
ETFDH	KRTAP13-2	psi-mi:“MI:0915”(physical association)	0.000
OTX1	ETFDH	psi-mi:“MI:0915”(physical association)	0.000
ETFDH	rnb	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (24): ETFDH (Affinity Capture-RNA), ETFDH (Affinity Capture-RNA), ETFDH (Two-hybrid), ETFDH (Affinity Capture-MS), ETFDH (Co-fractionation), ETFDH (Co-fractionation), ETFDH (Co-fractionation), ETFDH (Co-fractionation), ETFDH (Co-fractionation), ETFDH (Co-fractionation), ETFDH (Two-hybrid), ETFDH (Two-hybrid), ETFDH (Two-hybrid), ETFDH (Two-hybrid), KRTAP11-1 (Two-hybrid)

ESM2 similar proteins: A2QGH7, B8BJ39, B9N1F9, C8VBV0, O04300, O04499, O09171, O22666, O22718, O23877, O35490, O54734, O80526, O89000, P11029, P11497, P21343, P41345, P50554, P55931, P61922, P80607, Q06364, Q12882, Q13085, Q16134, Q28007, Q28943, Q2KIG0, Q2QNG7, Q2QZ86, Q2RAK2, Q41141, Q4W1X2, Q4WU59, Q5FVD6, Q5R895, Q5RDD3, Q5SWU9, Q6NYG8

Diamond homologs: O22854, P09821, P55931, P87111, P94132, Q08822, Q11190, Q16134, Q2KIG0, Q337B8, Q54XM6, Q5RDD3, Q6UPE1, Q921G7, Q9HZP5, A6UV59, A7I9P9, Q975R0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1106 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	103
Likely pathogenic	132
Uncertain significance	291
Likely benign	401
Benign	21

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1066475	NM_004453.4(ETFDH):c.1785del (p.Asp596fs)	Pathogenic
1069043	NM_004453.4(ETFDH):c.1227A>C (p.Leu409Phe)	Pathogenic
1069044	NM_004453.4(ETFDH):c.1522C>A (p.Pro508Thr)	Pathogenic
1072316	NM_004453.4(ETFDH):c.1285+2T>G	Pathogenic
1073007	NM_004453.4(ETFDH):c.432_438del (p.Glu144fs)	Pathogenic
1073008	NM_004453.4(ETFDH):c.1623del (p.Asp541fs)	Pathogenic
1076856	NM_004453.4(ETFDH):c.386del (p.Pro129fs)	Pathogenic
1177574	NM_004453.4(ETFDH):c.946G>T (p.Glu316Ter)	Pathogenic
12027	NM_004453.4(ETFDH):c.36del (p.Tyr13fs)	Pathogenic
12028	NM_004453.4(ETFDH):c.250G>A (p.Ala84Thr)	Pathogenic
12029	NM_004453.4(ETFDH):c.524G>T (p.Arg175Leu)	Pathogenic
1341351	NM_004453.4(ETFDH):c.1629dup (p.Ile544fs)	Pathogenic
1351346	NM_004453.4(ETFDH):c.463A>T (p.Arg155Ter)	Pathogenic
1375348	NM_004453.4(ETFDH):c.1650_1651del (p.Ser551fs)	Pathogenic
1376584	NM_004453.4(ETFDH):c.1512dup (p.Ile505fs)	Pathogenic
1403937	NM_004453.4(ETFDH):c.999C>A (p.Tyr333Ter)	Pathogenic
1413722	NM_004453.4(ETFDH):c.265C>T (p.Gln89Ter)	Pathogenic
1417327	NM_004453.4(ETFDH):c.1666C>T (p.Pro556Ser)	Pathogenic
1417698	NM_004453.4(ETFDH):c.1062del (p.Gly355fs)	Pathogenic
1422520	NM_004453.4(ETFDH):c.98G>A (p.Trp33Ter)	Pathogenic
1437786	NM_004453.4(ETFDH):c.71dup (p.Asn24fs)	Pathogenic
1451332	NM_004453.4(ETFDH):c.1378G>T (p.Gly460Ter)	Pathogenic
1451429	NM_004453.4(ETFDH):c.1433T>A (p.Leu478Ter)	Pathogenic
1451843	NM_004453.4(ETFDH):c.1464_1465del (p.His488fs)	Pathogenic
1453914	NM_004453.4(ETFDH):c.872T>G (p.Val291Gly)	Pathogenic
1456129	NM_004453.4(ETFDH):c.1699G>T (p.Glu567Ter)	Pathogenic
1456455	NM_004453.4(ETFDH):c.380T>G (p.Leu127Arg)	Pathogenic
1456462	NM_004453.4(ETFDH):c.1395T>G (p.Tyr465Ter)	Pathogenic
1459947	NC_000004.11:g.(?159611480)(159620302_?)del	Pathogenic
1495835	NM_004453.4(ETFDH):c.151C>T (p.Arg51Trp)	Pathogenic

SpliceAI

2589 predictions. Top by Δscore:

Variant	Effect	Δscore
4:158672282:G:GT	donor_gain	1.0000
4:158680525:AAGAT:A	acceptor_gain	1.0000
4:158680526:A:G	acceptor_gain	1.0000
4:158682191:CCAG:C	acceptor_loss	1.0000
4:158682193:A:AG	acceptor_gain	1.0000
4:158682194:G:GC	acceptor_loss	1.0000
4:158682194:G:GG	acceptor_gain	1.0000
4:158682194:GGA:G	acceptor_gain	1.0000
4:158682194:GGAGT:G	acceptor_gain	1.0000
4:158682344:A:G	donor_gain	1.0000
4:158682413:A:T	donor_gain	1.0000
4:158682421:GGGG:G	donor_gain	1.0000
4:158682422:GGGG:G	donor_gain	1.0000
4:158682423:GG:G	donor_gain	1.0000
4:158682424:GG:G	donor_gain	1.0000
4:158684584:A:AG	acceptor_gain	1.0000
4:158684585:T:G	acceptor_gain	1.0000
4:158684590:A:AG	acceptor_gain	1.0000
4:158684590:A:T	acceptor_loss	1.0000
4:158684590:AG:A	acceptor_gain	1.0000
4:158684591:G:GT	acceptor_gain	1.0000
4:158684591:GG:G	acceptor_gain	1.0000
4:158684591:GGC:G	acceptor_gain	1.0000
4:158684591:GGCT:G	acceptor_gain	1.0000
4:158684591:GGCTC:G	acceptor_gain	1.0000
4:158684671:CAG:C	donor_loss	1.0000
4:158684673:GGT:G	donor_loss	1.0000
4:158684674:GTAAG:G	donor_loss	1.0000
4:158684675:T:A	donor_loss	1.0000
4:158684877:GCCTT:G	donor_gain	1.0000

AlphaMissense

4025 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:158706770:T:C	L537S	0.999
4:158706841:T:C	C561R	0.999
4:158708448:G:A	C592Y	0.999
4:158708480:T:A	W603R	0.999
4:158708480:T:C	W603R	0.999
4:158697562:T:A	W279R	0.998
4:158697562:T:C	W279R	0.998
4:158706766:C:G	H536D	0.998
4:158706842:G:A	C561Y	0.998
4:158706843:T:G	C561W	0.998
4:158708438:T:C	C589R	0.998
4:158708439:G:A	C589Y	0.998
4:158708442:A:T	K590I	0.998
4:158708447:T:C	C592R	0.998
4:158708482:G:C	W603C	0.998
4:158708482:G:T	W603C	0.998
4:158682333:A:T	K105I	0.997
4:158695556:C:G	C248W	0.997
4:158695640:G:C	K276N	0.997
4:158695640:G:T	K276N	0.997
4:158697649:T:C	F308L	0.997
4:158697651:C:A	F308L	0.997
4:158697651:C:G	F308L	0.997
4:158706733:A:C	S525R	0.997
4:158706735:T:A	S525R	0.997
4:158706735:T:G	S525R	0.997
4:158708428:C:A	N585K	0.997
4:158708428:C:G	N585K	0.997
4:158708429:T:A	C586S	0.997
4:158708429:T:C	C586R	0.997

dbSNP variants (sampled 300 via entrez): RS1000113510 (4:158672157 G>A,C), RS1000142991 (4:158707450 C>A,T), RS1000186776 (4:158698692 G>C), RS1000308938 (4:158677914 C>T), RS1000355136 (4:158684484 G>A), RS1000530270 (4:158688529 T>C), RS1000532136 (4:158697102 AT>A,ATT), RS1000660872 (4:158691629 A>G), RS1000709011 (4:158695736 A>C), RS1000741484 (4:158695975 G>A), RS1000917605 (4:158701931 C>A,G), RS1000964460 (4:158688648 G>C), RS1001089564 (4:158690485 G>A,C), RS1001116968 (4:158708802 G>A), RS1001146490 (4:158696795 A>G)

Disease associations

OMIM: gene MIM:231675 | disease phenotypes: MIM:231680

GenCC curated gene-disease

Disease	Classification	Inheritance
multiple acyl-CoA dehydrogenase deficiency	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
multiple acyl-CoA dehydrogenase deficiency	Definitive	AR

Mondo (6): multiple acyl-CoA dehydrogenase deficiency (MONDO:0009282), glutaric acidemia IIc (MONDO:0700076), myopathy (MONDO:0005336), hypertrophic cardiomyopathy (MONDO:0005045), distal hereditary motor neuropathy (MONDO:0018894), megacolon (MONDO:0001273)

Orphanet (3): Multiple acyl-CoA dehydrogenase deficiency (Orphanet:26791), Rare hypertrophic cardiomyopathy (Orphanet:217569), Distal hereditary motor neuropathy (Orphanet:53739)

HPO phenotypes

46 total (30 of 46 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000078	Abnormality of the genital system
HP:0000113	Polycystic kidney dysplasia
HP:0000114	Proximal tubulopathy
HP:0000256	Macrocephaly
HP:0000260	Wide anterior fontanel
HP:0000348	High forehead
HP:0000377	Abnormal pinna morphology
HP:0000506	Telecanthus
HP:0000519	Developmental cataract
HP:0000803	Renal cortical cysts
HP:0000952	Jaundice
HP:0001252	Hypotonia
HP:0001302	Pachygyria
HP:0001324	Muscle weakness
HP:0001325	Hypoglycemic coma
HP:0001397	Hepatic steatosis
HP:0001639	Hypertrophic cardiomyopathy
HP:0001733	Pancreatitis
HP:0001941	Acidosis
HP:0001943	Hypoglycemia
HP:0001999	Abnormal facial shape
HP:0002013	Vomiting
HP:0002018	Nausea
HP:0002089	Pulmonary hypoplasia
HP:0002098	Respiratory distress
HP:0002171	Gliosis
HP:0002240	Hepatomegaly
HP:0002254	Intermittent diarrhea
HP:0002614	Hepatic periportal necrosis

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST000550_2	Metabolite levels	4.000000e-24
GCST001217_7	Metabolic traits	6.000000e-15
GCST006249_17	Serum metabolite levels	5.000000e-12
GCST006249_83	Serum metabolite levels	2.000000e-12
GCST009698_61	Metabolite levels	5.000000e-08
GCST012020_291	Serum metabolite levels	9.000000e-16
GCST012020_292	Serum metabolite levels	2.000000e-17

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004725	metabolite measurement
EFO:0005059	acylcarnitine measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D002312	Cardiomyopathy, Hypertrophic	C14.280.238.100; C14.280.484.048.750.070.160
D008531	Megacolon	C06.405.469.158.701

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs11559290	Efficacy	3	methylphenidate	Attention Deficit Disorder with Hyperactivity

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs11559290	ETFDH	3	0.00	1	methylphenidate

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	6
Cyclosporine	decreases expression	3
Acetaminophen	affects cotreatment, decreases expression, increases expression	2
Arsenic	affects methylation, decreases expression, increases abundance	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Particulate Matter	decreases expression, decreases reaction, increases abundance	2
bisphenol F	increases expression	1
dicrotophos	decreases expression	1
sodium arsenate	decreases expression, increases abundance	1
perfluorooctanoic acid	increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression, decreases reaction	1
dorsomorphin	affects cotreatment, increases expression	1
perfluorobutanesulfonic acid	decreases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1
Sunitinib	decreases expression	1
Vorinostat	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Atrazine	increases expression	1
Vehicle Emissions	decreases expression, decreases reaction	1
Benzo(a)pyrene	decreases expression	1
Carbamazepine	affects expression	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_C1UQ	LZUSHI002-A	Induced pluripotent stem cell	Male
CVCL_D0G3	INNDSUi002-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00120055	PHASE4	COMPLETED	Association Between Systemic Exposure of Atorvastatin and Metabolites and Atorvastatin-induced Myotoxicity
NCT03633565	PHASE4	UNKNOWN	Comparative Study of Strategies for Management of Duchenne Myopathy (DM)
NCT00879060	PHASE4	COMPLETED	Clinical and Therapeutic Implications of Fibrosis in Hypertrophic Cardiomyopathy
NCT01721967	PHASE4	COMPLETED	Ranolazine for the Treatment of Chest Pain in HCM Patients
NCT02948998	PHASE4	UNKNOWN	Evaluating the Effect of Spironolactone on Hypertrophic Cardiomyopathy
NCT03249272	PHASE4	TERMINATED	Microvascular Dysfunction in Nonischemic Cardiomyopathy: Insights From CMR Assessment of Coronary Flow Reserve
NCT04133532	PHASE4	COMPLETED	Effect of Metoprolol in Post Alcohol Septal Ablation Patients With Hypertrophic Cardiomyopathy
NCT06401343	PHASE4	RECRUITING	Use of SGLT2i in noHCM With HFpEF
NCT07103655	PHASE4	NOT_YET_RECRUITING	The Therapeutic Value of Mavacamten in Hypertrophic Cardiomyopathy With Mid-to-Apical Left Ventricular Obstruction
NCT07600177	PHASE4	RECRUITING	Mavacamten to Aficamten Transition in Patients With Obstructive Hypertrophic Cardiomyopathy
NCT01225614	PHASE3	UNKNOWN	Efficacy and Tolerance of Early Launching of Nocturnal Non Invasive
NCT00317967	PHASE3	COMPLETED	Study to Determine if Atorvastatin Reduces Size and Stiffness of Muscle in the Left Ventricle of the Heart
NCT00698074	PHASE3	UNKNOWN	Diastolic Ventricular Interaction and the Effects of Biventricular Pacing in Hypertrophic Cardiomyopathy
NCT00821353	PHASE3	COMPLETED	Antiarrhythmic Therapy Versus Catheter Ablation for Atrial Fibrillation in Hypertrophic Cardiomyopathy
NCT02431221	PHASE3	WITHDRAWN	Efficacy, Safety, and Tolerability of Perhexiline in Subjects With Hypertrophic Cardiomyopathy and Heart Failure
NCT03470545	PHASE3	COMPLETED	Clinical Study to Evaluate Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy
NCT05174416	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Mavacamten in Chinese Adults With Symptomatic Obstructive HCM
NCT05182658	PHASE3	ACTIVE_NOT_RECRUITING	Empagliflozin in Hypertrophic Cardiomyopathy
NCT05186818	PHASE3	COMPLETED	Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM
NCT05767346	PHASE3	COMPLETED	Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Metoprolol Succinate in Adults With Symptomatic oHCM
NCT06116968	PHASE3	COMPLETED	An Open-Label Study of Aficamten for Chinese Patients With Symptomatic oHCM
NCT06873828	PHASE3	NOT_YET_RECRUITING	Evaluation of the Efficacy and Safety of Wearable ECG (AT-Patch) in Patients With Hypertrophic Cardiomyopathy Requiring 48-Hour Holter MonitoringEvaluation of the Efficacy and Safety of Wearable ECG (AT-Patch) in Patients With Hypertrophic Cardiomyopathy Requiring 48-Hour Holter Monitoring
NCT07021976	PHASE3	RECRUITING	A Phase III Trial of HRS-1893 in Patients With Obstructive Hypertrophic Cardiomyopathy
NCT07023341	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Learn More About How Well Aficamten Works in Japanese Participants With Symptomatic Obstructive Hypertrophic Cardiomyopathy
NCT07202897	PHASE3	NOT_YET_RECRUITING	LA-HCM Study : Rivaroxaban for Antithrombotic Prevention in Hypertrophic Cardiomyopathy Patients With Abnormal Left Atrial Strain.
NCT00001631	PHASE2	COMPLETED	Study of Blood Flow in Heart Muscle
NCT00001894	PHASE2	COMPLETED	A Comparison of Two Treatments: Pacemaker and Percutaneous Transluminal Septal Ablation for Hypertrophic Cardiomyopathy
NCT00001960	PHASE2	COMPLETED	Studying the Effectiveness of Pacemaker Therapy in Children Who Have Thickened Heart Muscle
NCT00011076	PHASE2	COMPLETED	Pirfenidone to Treat Hypertrophic Cardiomyopathy
NCT00035386	PHASE2	COMPLETED	Alcohol Septal Ablation in Obstructive Hypertrophic Cardiomyopathy: A Pilot Study
NCT00430833	PHASE2	UNKNOWN	CHANCE - Candesartan in Hypertrophic Cardiomyopathy
NCT00500552	PHASE2	COMPLETED	Perhexiline Therapy in Patients With Hypertrophic Cardiomyopathy
NCT01150461	PHASE2	COMPLETED	Effect of Losartan in Patients With Nonobstructive Hypertrophic Cardiomyopathy
NCT01230918	PHASE2	TERMINATED	Study to Develop a Non-invasive Marker for Monitoring Myocardial Fibrosis
NCT01447654	PHASE2	COMPLETED	Inhibition of the Renin Angiotensin System With Losartan in Patients With Hypertrophic Cardiomyopathy
NCT01696370	PHASE2	UNKNOWN	Trimetazidine Therapy in Hypertrophic Cardiomyopathy
NCT01912534	PHASE2	COMPLETED	Valsartan for Attenuating Disease Evolution In Early Sarcomeric HCM
NCT02590809	PHASE2	COMPLETED	Hypertrophic Cardiomyopathy Symptom Release by BX1514M
NCT03496168	PHASE2	COMPLETED	Extension Study of Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Previously Enrolled in PIONEER
NCT03532802	PHASE2	COMPLETED	The Effect of Metoprolol in Patients With Hypertrophic Obstructive Cardiomyopathy.