Rare Disease Genes

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 474 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

Show entries

Search by any gene or variant detail to filter the table below:

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

HADHB_0002	c.210-?_354+?del	Deletion (Exons 5-6)	HADHB			Pathogenic	TFP	<5	Elevated circulating creatine kinase concentration			Unknown
HADHB_0003	c.1150-?_1389+?del	Deletion (Exons 14-15)	HADHB			Likely Pathogenic	TFP	<5	Myopathy, Peripheral neuropathy			Unknown
HADHB_0004	c.-8-2780_109+2924del	Intronic	HADHB	Copy Number Loss	Deletion	Pathogenic	TFP	<5		21549624	Exon 2-3, Intron 1-3	No
HADHB_0005	c.18C>A	p.Tyr6*	HADHB	SNV	Nonsense	Pathogenic	TFP	<5	Abnormality of metabolism/homeostasis, Cardiomyopathy	35383965	Exon 2	No
HADHB_0006	c.88_91del	p.Gln31Tyrfs*15	HADHB	Deletion	Frameshift	Pathogenic	TFP	<5	Cardiomyopathy, Hypoglycemia, Myopathy	20659813	Exon 3	No
HADHB_0007	c.106C>T	p.Pro36Ser	HADHB	SNV	Missense	Uncertain Significance	TFP	<5	Progressive encephalopathy, Severe	23665194	Exon 3	Yes
HADHB_0008	c.166G>T	p.Val56Leu	HADHB	SNV	Missense	Uncertain Significance	TFP	<5	Elevated circulating creatine kinase concentration		Exon 4	Yes
HADHB_0009	c.170_172del	p.Val57del	HADHB	Deletion	Deletion	Uncertain Significance	TFP	<5		21549624	Exon 4	No
HADHB_0010	c.176G>A	p.Gly59Asp	HADHB	SNV	Missense	Uncertain Significance	TFP	<5	Cardiomyopathy, Myopathy, Peripheral neuropathy	12754706	Exon 4	No
HADHB_0011	c.181C>T	p.Arg61Cys	HADHB	SNV	Missense	Likely Pathogenic	TFP	5-10	Abnormality of metabolism/homeostasis, Cardiomyopathy, Hellp syndrome, Hypoglycemia, Myopathy, Peripheral neuropathy	12754706, 31527676, 35383965	Exon 4	Yes

Showing 1 to 10 of 109 entries

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Column Name	Table View	Detail View
Variant ID
Variant
Amino Acid Change
Gene Symbol
Variant Type
Effect Type
Display ACMG Call
Disease Subtype
Times Observed
Phenotype
PMID
Article Count
Location
Protein Domain
ACMG Call Last Revised Date
GRCh38
Record Last Revised Date
Present in ClinVar
ACMG Call
Predicted ACMG Call
Thousand Genomes Allele Frequency
Ontology Relations
ExAC Allele Frequency
GnomAD Alleles
Associated Geography
Variants Seen With

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.
Click the Present in ClinVar link to go to the corresponding ClinVar VariationID.
Don’t see a variant of interest? Contribute data through the Register Variant form.
Explore considerations about Variants of Uncertain Significance (VUS)

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).

Trifunctional Protein (TFP) Deficiency

Introduction

Variant List

Gene Structure