HADHB

Introduction

The HADHB gene, hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit beta, is located on chromosome 2p23.3 and has 16 exons spanning ~475kb (1). It encodes the 475 amino acid protein beta subunit of the mitochondrial trifunctional protein (2), which catalyzes the last three steps of mitochondrial beta-oxidation of long chain fatty acids (3-5). Among the enzymes involved in this pathway, the trifunctional enzyme exhibits specificity for long-chain fatty acids (2).

Mitochondrial trifunctional enzyme is a heterotetrameric complex composed of two proteins, the trifunctional enzyme subunit alpha/HADHA carries the 2,3-enoyl-CoA hydratase and the 3-hydroxyacyl-CoA dehydrogenase activities, while the trifunctional enzyme subunit beta/HADHB described here bears the 3-ketoacyl-CoA thiolase activity (3-5).The protein is expressed in heart, duodenum and other tissues(6). The encoded protein can also bind RNA and decreases the stability of some mRNAs (2).

More than 102 disease-causing variants in the HADHB gene have been identified in patients and are represented in this database. The variants occur across the entire length of the gene and include frameshift, splice site, copy-number, nonsense and missense variants (7).

Variant List

To see more information, click on the Variant in the table. Hover on the Variant in the table to see its location on the gene . For more information on table headers, HGVS nomenclature, and ACMG classification please use the following links here.

Gene Structure

Variant ID	Variant	Amino Acid Change	Gene Symbol	Variant Type	Effect Type	Display ACMG Call	Disease Subtype	Times Observed Range	Phenotype	PMID	Location

HADHB_0003	c.1150-?_1389+?del	Deletion (Exons 14-15)	HADHB			Likely Pathogenic	TFP	<3
HADHB_0002	c.210-?_354+?del	Deletion (Exons 5-6)	HADHB			Pathogenic	TFP	<3
HADHB_0001	c.(-9+1_-8-1)_(109+1_110-1)del	p.?	HADHB			Pathogenic	TFP	<3	Hypoglycemia, Rhabdomyolysis	28392417
HADHB_0004	c.-8-2780_109+2924del	Intronic	HADHB	Copy Number Loss		Pathogenic	TFP	<3		21549624	Exon 2-3, Intron 1-3
HADHB_0005	c.18C>A	p.Tyr6*	HADHB	SNV	Nonsense	Pathogenic	TFP	<3	Abnormality of metab....	35383965	Exon 2
HADHB_0006	c.88_91del	p.Gln31Tyrfs*15	HADHB	Deletion	Frameshift	Pathogenic	TFP	<3	Cardiomyopathy, Hypoglycemia, Myopathy	20659813	Exon 3
HADHB_0007	c.106C>T	p.Pro36Ser	HADHB	SNV	Missense	Uncertain Significance	TFP	<3		23665194	Exon 3
HADHB_0008	c.166G>T	p.Val56Leu	HADHB	SNV	Missense	Uncertain Significance	TFP	<3			Exon 4
HADHB_0009	c.170_172del	p.Val57del	HADHB	Deletion	Deletion	Uncertain Significance	TFP	<3		21549624	Exon 4
HADHB_0010	c.176G>A	p.Gly59Asp	HADHB	SNV	Missense	Uncertain Significance	TFP	<3	Cardiomyopathy, Myopathy, Peripheral neuropathy	12754706	Exon 4
HADHB_0011	c.181C>T	p.Arg61Cys	HADHB	SNV	Missense	Likely Pathogenic	TFP	6-10	Abnormality of metab....	12754706, 31527676, 35383965	Exon 4
HADHB_0012	c.182G>A	p.Arg61His	HADHB	SNV	Missense	Likely Pathogenic	TFP	3-5	3-hydroxydicarboxyli....	12754706, 15617873, 16423905, 35383965, 35782614, 8651282	Exon 4
HADHB_0013	c.184A>G	p.Thr62Ala	HADHB	SNV	Missense	Uncertain Significance	TFP	<3	Arrhythmia, Elevated....	24379101	Exon 4
HADHB_0014	c.206C>T	p.Thr69Ile	HADHB	SNV	Missense	Uncertain Significance	TFP	<3		30193751	Exon 4
HADHB_0015	c.209+1G>C	Intronic	HADHB	SNV	Splice donor	Pathogenic	TFP	6-10	Abnormal gait, Abnor....	21549624, 28685493, 33123633, 35383965, 35403730	Intron 4
HADHB_0016	c.210-1G>C	Intronic	HADHB	SNV	Splice acceptor	Pathogenic	TFP	3-5	Abnormal motor nerve....	24314034	Intron 4
HADHB_0017	c.248C>G	p.Ala83Gly	HADHB	SNV	Missense	Likely Pathogenic	TFP	<3	Muscle weakness	35403730	Exon 5
HADHB_0018	c.254+1G>A	Intronic	HADHB	SNV	Splice donor	Pathogenic	TFP	<3	Arrhythmia, Elevated....	24379101, 28641477	Intron 5
HADHB_0019	c.254+5G>A	Intronic	HADHB	SNV	Splice region	Uncertain Significance	TFP	<3	Abnormality of metab....	35383965	Intron 5
HADHB_0020	c.255-713_811+86del	p.Gly86Lysfs*8	HADHB	Copy Number Loss		Uncertain Significance	TFP	<3	Cardiomyopathy, Elev....	32257295	Exon 6-9, Intron 5-9
HADHB_0021	c.255-1G>A	Intronic	HADHB	SNV	Splice acceptor	Pathogenic	TFP	<3	Decreased body weight, Decreased endurance	33123633, 35433169	Intron 5
HADHB_0022	c.340A>G	p.Asn114Asp	HADHB	SNV	Missense	Likely Pathogenic	TFP	3-5	Abnormality of metab....	17143551, 29519241	Exon 6
HADHB_0023	c.341A>G	p.Asn114Ser	HADHB	SNV	Missense	Pathogenic	TFP	3-5		15902556, 17431731, 26109258	Exon 6
HADHB_0024	c.349A>G	p.Arg117Gly	HADHB	SNV	Missense	Pathogenic	TFP	<3	Myopathy, Peripheral neuropathy	12754706	Exon 6
HADHB_0025	c.354+5del	Intronic	HADHB	Deletion	Splice region	Uncertain Significance	TFP	<3	Abnormality of metab....	35383965	Intron 6
HADHB_0026	c.357dup	p.Ala120Cysfs*8	HADHB	Duplication	Frameshift	Pathogenic	TFP	<3	Abnormality of metab....	19880769	Exon 7
HADHB_0027	c.362T>C	p.Leu121Pro	HADHB	SNV	Missense	Uncertain Significance	TFP	<3		12754706	Exon 7
HADHB_0028	c.392C>T	p.Ala131Val	HADHB	SNV	Missense	Uncertain Significance	TFP	<3	Elevated circulating....	32348839	Exon 7
HADHB_0030	c.397A>C	p.Thr133Pro	HADHB	SNV	Missense	Likely Pathogenic	TFP	<3	Hellp syndrome, Myopathy	12754706	Exon 7
HADHB_0029	c.397A>G	p.Thr133Ala	HADHB	SNV	Missense	Likely Pathogenic	TFP	6-10	Abnormal gait, Exerc....	35383965, 35403730	Exon 7
HADHB_0031	c.407T>C	p.Met136Thr	HADHB	SNV	Missense	Likely Pathogenic	TFP	3-5	Diminished tendon re....	31521624, 32348839	Exon 7
HADHB_0032	c.421G>A	p.Ala141Thr	HADHB	SNV	Missense	Uncertain Significance	TFP	<3	Diminished tendon re....	31521624	Exon 7
HADHB_0033	c.426C>A	p.Asn142Lys	HADHB	SNV	Missense	Uncertain Significance	TFP	<3		11196108, 15902556	Exon 7
HADHB_0034	c.427C>G	p.Gln143Glu	HADHB	SNV	Missense	Uncertain Significance	TFP	<3	Elevated circulating....	32348839	Exon 7
HADHB_0035	c.442+614A>G	Intronic	HADHB	SNV	Intronic	Likely Pathogenic	TFP	3-5	Abnormality of metab....	15056246, 18693053, 27014569	Intron 7
HADHB_0036	c.442+663A>G	Intronic	HADHB	SNV	Intronic	Uncertain Significance	TFP	<3	Abnormality of metab....	30029694	Intron 7
HADHB_0037	c.443-20_624delinsCACACAAG	Intronic	HADHB	Delins		Uncertain Significance	TFP	<3	Abnormality of metabolism/homeostasis	31575911	Exon 8, Intron 7
HADHB_0038	c.443-10T>C	Intronic	HADHB	SNV	Intronic	Uncertain Significance	TFP	<3			Intron 7
HADHB_0039	c.490G>A	p.Gly164Ser	HADHB	SNV	Missense	Uncertain Significance	TFP	<3	Distal muscle weakness, Rhabdomyolysis	34712195	Exon 8
HADHB_0040	c.520C>T	p.Arg174Cys	HADHB	SNV	Missense	Pathogenic	TFP	3-5	Apparent life-threat....	22000755, 28515471, 32348839	Exon 8
HADHB_0041	c.522dup	p.His175Serfs*11	HADHB	Duplication	Frameshift	Pathogenic	TFP	<3	Abnormality of metab....	11196108, 15902556	Exon 8
HADHB_0042	c.527C>G	p.Ser176*	HADHB	SNV	Nonsense	Pathogenic	TFP	<3		12754706	Exon 8
HADHB_0043	c.565G>A	p.Ala189Thr	HADHB	SNV	Missense	Uncertain Significance	TFP	<3			Exon 8
HADHB_0044	c.574A>G	p.Met192Val	HADHB	SNV	Missense	Uncertain Significance	TFP	<3			Exon 8
HADHB_0045	c.580C>T	p.Gln194*	HADHB	SNV	Nonsense	Pathogenic	TFP	<3		30682426, 33638202	Exon 8
HADHB_0046	c.584G>A	p.Arg195Gln	HADHB	SNV	Missense	Uncertain Significance	TFP	<3			Exon 8
HADHB_0047	c.607C>T	p.Arg203*	HADHB	SNV	Nonsense	Pathogenic	TFP	<3	Myopathy, Peripheral neuropathy	12754706	Exon 8
HADHB_0048	c.631-1G>A	Intronic	HADHB	SNV	Splice acceptor	Pathogenic	TFP	<3	Abnormality of metab....	30682426, 35383965	Intron 8
HADHB_0049	c.640G>A	p.Val214Ile	HADHB	SNV	Missense	Uncertain Significance	TFP	<3			Exon 9
HADHB_0050	c.646G>T	p.Glu216*	HADHB	SNV	Nonsense	Pathogenic	TFP	<3			Exon 9
HADHB_0051	c.685C>T	p.Arg229*	HADHB	SNV	Nonsense	Pathogenic	TFP	<3		12754706	Exon 9
HADHB_0053	c.686G>T	p.Arg229Leu	HADHB	SNV	Missense	Pathogenic	TFP	3-5	Abnormal motor nerve....	24314034	Exon 9
HADHB_0052	c.686G>A	p.Arg229Gln	HADHB	SNV	Missense	Likely Pathogenic	TFP	3-5	Bulb atrophy, Distal....	30990523, 34712195	Exon 9
HADHB_0054	c.693del	p.Ala232Leufs*20	HADHB	Deletion	Frameshift	Pathogenic	TFP	<3	Hypoglycemia	12754706	Exon 9
HADHB_0055	c.694G>A	p.Ala232Thr	HADHB	SNV	Missense	Likely Pathogenic	TFP	6-10	Developmental delay, Muscle weakness	35403730, 35433169	Exon 9
HADHB_0056	c.712C>T	p.Arg238Trp	HADHB	SNV	Missense	Uncertain Significance	TFP	<3	Abnormal fibre size ....	30682426	Exon 9
HADHB_0057	c.713G>A	p.Arg238Gln	HADHB	SNV	Missense	Uncertain Significance	TFP	<3			Exon 9
HADHB_0058	c.725A>G	p.Asp242Gly	HADHB	SNV	Missense	Likely Pathogenic	TFP	<3	Hypoglycemia	12754706	Exon 9
HADHB_0059	c.739C>T	p.Arg247Cys	HADHB	SNV	Missense	Likely Pathogenic	TFP	6-10	Abnormality of metab....	19699128, 22841441, 28649548, 29519241, 29915090	Exon 9
HADHB_0060	c.740G>A	p.Arg247His	HADHB	SNV	Missense	Likely Pathogenic	TFP	3-5	3-hydroxydicarboxyli....	12754706, 15617873, 8651282	Exon 9
HADHB_0061	c.776_777insT	p.Leu260Thrfs*4	HADHB	Insertion	Frameshift	Pathogenic	TFP	<3	Abnormality of metab....	19699128, 28515471, 8645256, 9259266	Exon 9
HADHB_0062	c.788A>G	p.Asp263Gly	HADHB	SNV	Missense	Pathogenic	TFP	3-5	Hypoglycemia, Rhabdomyolysis	21549624, 28392417, 8163672, 8651282	Exon 9
HADHB_0063	c.811+82A>G	Intronic	HADHB	SNV	Intronic	Uncertain Significance	TFP	<3	Cardiomyopathy, Elev....	32257295	Intron 9
HADHB_0064	c.817del	p.Asp273Ilefs*20	HADHB	Deletion	Frameshift	Pathogenic	TFP	<3	Abnormality of metab....	19699128, 22841441	Exon 10
HADHB_0065	c.839G>A	p.Gly280Asp	HADHB	SNV	Missense	Uncertain Significance	TFP	<3	Hypoglycemia	12754706	Exon 10
HADHB_0066	c.845G>A	p.Arg282His	HADHB	SNV	Missense	Uncertain Significance	TFP	<3			Exon 10
HADHB_0068	c.881C>G	p.Pro294Arg	HADHB	SNV	Missense	Likely Pathogenic	TFP	<3	Hellp syndrome, Hypoglycemia, Myopathy	12754706	Exon 10
HADHB_0067	c.881C>T	p.Pro294Leu	HADHB	SNV	Missense	Likely Pathogenic	TFP	<3	Myopathy, Peripheral neuropathy	12754706	Exon 10
HADHB_0069	c.901G>A	p.Gly301Ser	HADHB	SNV	Missense	Uncertain Significance	TFP	6-10		12754706, 12809642, 16040264, 16996288, 20589231, 27491397	Exon 10
HADHB_0070	c.902G>A	p.Gly301Asp	HADHB	SNV	Missense	Likely Pathogenic	TFP	<3		11196108, 15902556	Exon 10
HADHB_0071	c.919A>G	p.Asn307Asp	HADHB	SNV	Missense	Likely Pathogenic	TFP	3-5	Abnormality of metab....	17143551, 29519241	Exon 10
HADHB_0072	c.965C>A	p.Ala322Glu	HADHB	SNV	Missense	Uncertain Significance	TFP	<3			Exon 11
HADHB_0073	c.976G>C	p.Ala326Pro	HADHB	SNV	Missense	Likely Pathogenic	TFP	6-10	Abnormality of metab....	12548384	Exon 11
HADHB_0074	c.980T>C	p.Leu327Pro	HADHB	SNV	Missense	Uncertain Significance	TFP	<3	Abnormality of metab....	28685493	Exon 11
HADHB_0075	c.998C>T	p.Pro333Leu	HADHB	SNV	Missense	Uncertain Significance	TFP	<3	Decreased body weight, Decreased endurance	35433169	Exon 11
HADHB_0076	c.1000A>C	p.Lys334Gln	HADHB	SNV	Missense	Uncertain Significance	TFP	30+			Exon 11
HADHB_0077	c.1059del	p.Gly354Aspfs*10	HADHB	Deletion	Frameshift	Pathogenic	TFP	3-5		26334177, 27995076, 28617419	Exon 12
HADHB_0078	c.1091A>G	p.Glu364Gly	HADHB	SNV	Missense	Uncertain Significance	TFP	<3		34578803	Exon 13
HADHB_0079	c.1115A>T	p.Asp372Val	HADHB	SNV	Missense	Likely Pathogenic	TFP	<3		33638202	Exon 13
HADHB_0080	c.1136A>G	p.His379Arg	HADHB	SNV	Missense	Pathogenic	TFP	6-10	Abnormality of metab....	15056246, 18693053, 25420603, 29519241	Exon 13
HADHB_0081	c.1137del	p.His379Glnfs*76	HADHB	Deletion	Frameshift	Pathogenic	TFP	<3		21549624	Exon 13
HADHB_0082	c.1148C>T	p.Ser383Leu	HADHB	SNV	Missense	Likely Pathogenic	TFP	<3	Difficulty running, ....	29519241	Exon 13
HADHB_0083	c.1149+4A>G	Intronic	HADHB	SNV	Splice region	Uncertain Significance	TFP	<3			Intron 13
HADHB_0084	c.1154A>C	p.Gln385Pro	HADHB	SNV	Missense	Uncertain Significance	TFP	3-5	Asphyxiation, Cardio....	28112527	Exon 14
HADHB_0085	c.1165A>G	p.Asn389Asp	HADHB	SNV	Missense	Pathogenic	TFP	6-10	Myoglobinuria, Myopa....	17143551, 21549624, 28392417, 29519241, 29915090	Exon 14
HADHB_0086	c.1175C>T	p.Ala392Val	HADHB	SNV	Missense	Likely Pathogenic	TFP	6-10	Abnormality of metab....	24664533, 28515471, 32509533	Exon 14
HADHB_0087	c.1175_1177del	p.Ala392_Met393delinsVal	HADHB	Deletion	Deletion	Uncertain Significance	TFP	<3		21549624	Exon 14
HADHB_0088	c.1191G>A	p.Trp397*	HADHB	SNV	Nonsense	Pathogenic	TFP	<3		21549624	Exon 14
HADHB_0089	c.1192T>C	p.Phe398Leu	HADHB	SNV	Missense	Uncertain Significance	TFP	<3	Malaise/fatigue, Mus....	28132977	Exon 14
HADHB_0090	c.1198G>T	p.Glu400*	HADHB	SNV	Nonsense	Pathogenic	TFP	<3	Abnormality of metab....	30029694	Exon 14
HADHB_0091	c.1211dup	p.Arg405*	HADHB	Duplication	Frameshift	Pathogenic	TFP	<3	Abnormality of metab....	29519241	Exon 14
HADHB_0092	c.1228_1240del	p.Gly410Trpfs*41	HADHB	Deletion	Frameshift	Pathogenic	TFP	<3	Dilated cardiomyopathy	31527676	Exon 15
HADHB_0093	c.1279G>A	p.Gly427Arg	HADHB	SNV	Missense	Uncertain Significance	TFP	<3			Exon 15
HADHB_0094	c.1280G>A	p.Gly427Glu	HADHB	SNV	Missense	Uncertain Significance	TFP	<3		30193751	Exon 15
HADHB_0095	c.1289T>C	p.Phe430Ser	HADHB	SNV	Missense	Likely Pathogenic	TFP	3-5	Abnormality of metab....	16423905, 35383965, 35403730, 35782614	Exon 15
HADHB_0096	c.1331G>A	p.Arg444Lys	HADHB	SNV	Missense	Likely Pathogenic	TFP	11-20	Abnormality of metab....	11239956, 19699128, 22000755, 26109258, 28515471, 8645256, 9259266, 9305349	Exon 15
HADHB_0097	c.1336C>T	p.Arg446Trp	HADHB	SNV	Missense	Uncertain Significance	TFP	<3			Exon 15
HADHB_0098	c.1348G>T	p.Gly450Cys	HADHB	SNV	Missense	Uncertain Significance	TFP	<3		34578803	Exon 15
HADHB_0099	c.1364T>G	p.Val455Gly	HADHB	SNV	Missense	Pathogenic	TFP	6-10	Abnormality of metab....	19699128, 19880769, 27014569, 28515471, 32509533	Exon 15
HADHB_0100	c.1376C>A	p.Ala459Glu	HADHB	SNV	Missense	Uncertain Significance	TFP	<3	Abnormality of metab....	11196108, 15902556	Exon 15
HADHB_0101	c.1390-515_1390-499del	Intronic	HADHB	Deletion	Intronic	Likely Pathogenic	TFP	<3		28283530	Intron 15
HADHB_0102	c.1409A>C	p.Glu470Ala	HADHB	SNV	Missense	Uncertain Significance	TFP	<3			Exon 16

Notes:

* Click the PMID number to go to the corresponding publication.
* All variants are referencing NM_000183.2 and NM_000183.3 and there is no change between these versions with respect to the coding sequence.
* Genomic coordinates are calculated based on variant data provided: in some cases coordinates are estimated in order to allow users to sort the variants linearly, by approximation.

Definition of acronyms:

"*": Referenced a stop codon insertion when listed under amino acid change.
ACMG: American College of Medical Genetics and Genomics
CNV: Copy number variant which here describes a change 100 DNA nucleotides or larger.
SNV: Single DNA nucleotide variant
del: Deletion
dup: Duplication
fs: Frameshift
ins: Insertion

References:

1. Sims, H. F. et al., The molecular basis of pediatric long chain 3-hydroxyacyl-CoA dehydrogenase deficiency associated with maternal acute fatty liver of pregnancy. Proc Natl Acad Sci USA. 1995 Jan 31;92(3):841-5.
https://www.ncbi.nlm.nih.gov/gene/3032
Kamijo, T. et al., Structural analysis of cDNAs for subunits of human mitochondrial fatty acid beta-oxidation trifunctional protein. Biochem Biophys Res Commun. 1994 Mar 15;199(2):818-2.
Liang, K. et al. Cryo-EM structure of human mitochondrial trifunctional protein. Proc Natl Acad Sci USA. 2018 Jul 3;115(27):7039-7044.
Xia, C. et al., Crystal structure of human mitochondrial trifunctional protein, a fatty acid β-oxidation metabolon. Proc Natl Acad Sci USA. 2019 Mar 26;116(13):6069-6074.
https://www.uniprot.org/uniprotkb/P55084/entry
Richbourg et al. Phenotype associations from a comprehensive database of long-chain fatty acid oxidation disorder gene variants (Abstract and poster presentation, American Society of Human Genetics 2023).

Introduction

Variant List

Gene Structure

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