ETFB

protein-coding

electron transfer flavoprotein subunit beta

Gene summary

This gene encodes electron-transfer-flavoprotein, beta polypeptide, which shuttles electrons between primary flavoprotein dehydrogenases involved in mitochondrial fatty acid and amino acid catabolism and the membrane-bound electron transfer flavoprotein ubiquinone oxidoreductase. The gene deficiencies have been implicated in type II glutaricaciduria. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001985.3

Inheritance

ClinVar variants

P:44U:94B:116

Top phenotype

Multiple acyl-CoA dehydrogenase deficiency (Glutaric aciduria IIB)

gnomAD constraint

pLI —, LoF o/e 0.39

Max pathogenic AF

—

Genomic locus

chr19:51,345,169-51,366,388

External References & Databases

Ensembl (ENSG00000105379)

Transcript & Mutation Effects

hg38 • Region Span ~21.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

multiple acyl-CoA dehydrogenase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009282

Submitter: ClinGen

*ETFB* (MIM 130410) was first reported in relation to autosomal recessive multiple acyl-CoA dehydrogenase deficiency (MADD) in 1994 (Colombo I, et al., 1994; PMID: 7912128). MADD occurs in a neonatal onset (severe) form and a late onset (mild) form. In the severe form, hypotonia, hypoglycemia, metabolic acidosis and/or hyperammonemia are present with/without anomalies such as dysplastic kidney and/or congenital heart disease. Eighteen variants (including missense, in-frame deletions, nonsense, splicing, and frameshift) have been reported in 11 probands in 9 publications (PMIDs: 11420420, 7912128, 12706375, 12815589, 16510302, 27081516, 18289905, 36406819, 34573316) and are included in this curation. This gene-disease relationship is also supported by experimental evidence including its biochemical function as a subunit of electron transfer flavoprotein (PMID: 25416781) where it interacts with the additional disease-causing gene *ETFA* (PMID: 15159392), and the altered function found in patients (PMID: 12815589) which can be rescued with wildtype (PMID: 79121280), as well as an expression pattern consistent with disease (PMID: 8504797). In summary, there is definitive evidence to support the relationship between *ETFB* and autosomal recessive MADD. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated as Moderate by the FAO GCEP on 06/12/2018 and 12/16/2020. It was reevaluated on 03/29/2023. Additional genetic evidence was curated from new publications (PMIDs: 36406819, 34573316). As a result of this reevaluation, the classification increased to Definitive (SOPv9). Data provided by the ClinGen Prenatal GCEP from April 22, 2025 secondary analysis Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder of fatty acid oxidation due to deficiency of the mitochondrial electron transfer chain. MADD can be caused by deficiencies in any of three proteins within the electron transfer flavoprotein (ETF) system, including ETFA, ETFB, and ETFDH. Pathogenic variants in the *ETFB* gene are responsible for only about 2% of cases of MADD. Although genetically heterogeneous, there does not appear to be a gene specific difference in clinical phenotypes. The severity of disease is correlated with residual protein function and ranges from a severe neonatal form with or without congenital anomalies to a milder, later onset form. Neonatal forms present with hypotonia, severe metabolic acidosis, hyperammonemia, hypoglycemia, respiratory distress, hepatomegaly, and a sweaty feet odor. Prenatal features and congenital physical anomalies can include cystic/dysplastic kidneys with sequelae of oligohydramnios/anhydramnios, hypertrophic cardiomyopathy, dysmorphic facial features including midface hypoplasia, tented upper lip, low set ears, or high anterior hairline. Most severely affected newborns die in the first week of life. (PMID: 32550677, 7912128, 18289905, 36406819, 36406819, 27081516, 33450351)

multiple acyl-CoA dehydrogenase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009282

Submitter: Labcorp Genetics (formerly Invitae)

multiple acyl-CoA dehydrogenase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009282

Submitter: PanelApp Australia

multiple acyl-CoA dehydrogenase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009282

Submitter: G2P

Clinical Genomic Database (CGD)

Multiple acyl-CoA dehydrogenase deficiency (Glutaric aciduria IIB)AR

Manifestation: Biochemical; Gastrointestinal; Musculoskeletal; Neurologic; Renal

Intervention: Biochemical

Rationale: Dietary measures (fasting avoidance and low-fat diet, as well as supplementation, such as with riboflavin and carnitine) may be beneficial

Refs: 7145508; 8771170; 7912128; 12706375; 12815589; 18289905; 22231380

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ETFB variants in ClinVar

9 Conditions Cataloged

Multiple acyl-CoA dehydrogenase deficiencyTotal: 298

not providedTotal: 75

not specifiedTotal: 46

Inborn genetic diseasesTotal: 42

ETFB-related disorderTotal: 20

Glutaric acidemia IIbTotal: 3

Chronic kidney diseaseTotal: 1

Fetal anomalies with a likely genetic causeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001985.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				106 clinvar		106
missense		10 clinvar	89 clinvar	9 clinvar	1 clinvar	109
nonsense	1 clinvar	8 clinvar				9
start loss		1 clinvar				1
frameshift	5 clinvar	9 clinvar	2 clinvar			16
splice donor/acceptor (+/-2bp)	1 clinvar	9 clinvar	3 clinvar			13
Total	7	37	94	115	1	254

Highest pathogenic variant AF is 0.000018600153

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 35 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001985.3	RefSeq	NP_001976.1	6	MANE Select
ENST00000309244.9	Ensembl	ENSP00000311930.3	6	MANE Select
NM_001014763.1	RefSeq	NP_001014763.1	5	Standard
ENST00000354232.8	Ensembl	ENSP00000346173.3	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Post-translational protein modification
Metabolism of proteins
Respiratory electron transport
The citric acid (TCA) cycle and respiratory electron transport
Metabolism

Biological Process

electron transport chain
fatty acid beta-oxidation using acyl-CoA dehydrogenase

Molecular Function

protein binding
electron transfer activity

Cellular Component

mitochondrion
mitochondrial matrix
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000354232
Coding exons: 5
Length: 21250
Individuals with no LoFs: 125740
Homozygous LoFs: 0
Heterozygous LoFs: 8
Defined: 125748
p: 0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.423	183	200	0.916	0.0000123	2185
Missense (PolyPhen)		73	80.486	0.90699		807
Synonymous	0.111	88	89.3	0.985	0.00000577	776
Loss of Function	2.01	5	12.7	0.393	6.92e-7	140

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000035	0.000035	rare
South Asian	0.000033	0.000033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Heterodimeric electron transfer flavoprotein that accepts electrons from several mitochondrial dehydrogenases, including acyl-CoA dehydrogenases, glutaryl-CoA and sarcosine dehydrogenase (PubMed:25416781, PubMed:15159392, PubMed:15975918). It transfers the electrons to the main mitochondrial respiratory chain via ETF-ubiquinone oxidoreductase (Probable). Required for normal mitochondrial fatty acid oxidation and normal amino acid metabolism (PubMed:12815589, PubMed:7912128). ETFB binds an AMP molecule that probably has a purely structural role (PubMed:8962055, PubMed:15159392, PubMed:15975918). {ECO:0000269|PubMed:12815589, ECO:0000269|PubMed:15159392, ECO:0000269|PubMed:15975918, ECO:0000269|PubMed:25416781, ECO:0000269|PubMed:7912128, ECO:0000269|PubMed:8962055, ECO:0000303|PubMed:17941859, ECO:0000305}.;
Disease: DISEASE: Glutaric aciduria 2B (GA2B) [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. {ECO:0000269|PubMed:12815589, ECO:0000269|PubMed:7912128}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.278

Intolerance Scores

LoFtool: 0.122
RVIS EVS: 0.64
RVIS percentile EVS: 83.98

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.961

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	Medium	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High