HADHB

Trifunctional Protein (TFP) Deficiency

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	Phenotype	PMID	Location	Present in ClinVar

HADHB_0003	c.1150-?_1389+?del	Deletion (Exons 14-15)	HADHB			Likely Pathogenic	TFP	<5	Myopathy, Peripheral neuropathy			Unknown
HADHB_0002	c.210-?_354+?del	Deletion (Exons 5-6)	HADHB			Pathogenic	TFP	<5	Elevated circulating creatine kinase concentration			Unknown
HADHB_0110	c.(-9+1_-8-1)_(109+1_110-1)del	Intronic	HADHB			Pathogenic	TFP	<5	Hypoglycemia, Rhabdomyolysis	28392417		No
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_0103	c.109+5A>G	Intronic	HADHB	SNV	Splice region	Uncertain Significance	TFP	<5	Elevated circulating creatine kinase concentration, Myopathy, Peripheral neuropathy		Intron 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
HADHB_0012	c.182G>A	p.Arg61His	HADHB	SNV	Missense	Likely Pathogenic	TFP	5-10	"3-hydroxydicarboxylic aciduria, Abnormality of metabolism/homeostasis, Cardiac-other, Cardiomyopathy, Decreased body weight, Feeding difficulties, Hyaline membrane disease of the lungs, Hyperammonemia, Hypoglycemia, Hypotonia, Intestinal pseudo-obstruction, Liver abnormality, Muscle weakness, Myopathy, Peripheral neuropathy, Pulmonary/respiratory, Respiratory tract infection, Rhabdomyolysis, Vomiting"	12754706, 15617873, 16423905, 35383965, 35782614, 8651282	Exon 4	Yes
HADHB_0013	c.184A>G	p.Thr62Ala	HADHB	SNV	Missense	Uncertain Significance	TFP	<5	"Arrhythmia, Elevated circulating creatine kinase concentration, Fever, Herpetic gingivostomatitis, Hypotonia, Lethargy, Malaise/fatigue, Muscle weakness, Poor feeding, Rhabdomyolysis"	24379101	Exon 4	Yes
HADHB_0014	c.206C>T	p.Thr69Ile	HADHB	SNV	Missense	Uncertain Significance	TFP	<5		30193751	Exon 4	No
HADHB_0015	c.209+1G>C	Intronic	HADHB	SNV	Splice donor	Pathogenic	TFP	5-10	"Abnormal gait, Abnormality of metabolism/homeostasis, Areflexia, Arrhythmia, Cardiac-other, Cardiomyopathy, Diarrhea, Difficulty moving arms, Difficulty speaking, Difficulty swallowing, Dyspnoea, Elevated circulating creatine kinase concentration, Fever, Gastrointestinal-other, Hypoesthesia, Hypoparathyroidism, Hypotonia, Loss of balance, Muscle spasm, Muscle weakness, Myalgia, Pain, Peripheral neuropathy, Pes cavus, Rhabdomyolysis, Sensory deficits, Shuddering attacks, Upper quadrant abdominal tenderness, Urine discoloration, Vomiting"	21549624, 28685493, 33123633, 35383965, 35403730	Intron 4	Yes
HADHB_0016	c.210-1G>C	Intronic	HADHB	SNV	Splice acceptor	Pathogenic	TFP	<5	"Abnormal motor nerve conduction velocities, Absent deep tendon reflexes, Atrophy, Atrophy of bilateral distal muscles, Bilateral foot drop, Distal muscle weakness, Disturbed vibration and position senses, Gait disability, Gait disturbance, Loss of sensory and tendon reflexes, Lower limb muscle weakness, Muscle weakness, Peripheral neuropathy, Toe and heel gait defect, Walking difficulties"	24314034	Intron 4	Yes
HADHB_0111	c.210-1G>T	Intronic	HADHB	SNV	Splice acceptor	Pathogenic	TFP	<5	Cardiomyopathy, Elevated circulating creatine kinase concentration, Myopathy		Intron 4	Yes
HADHB_0105	c.219C>A	p.Asp73Glu	HADHB	SNV	Missense	Uncertain Significance	TFP	<5	Hypoglycemia, Other, Retinal/choroid disorder		Exon 5	No
HADHB_0017	c.248C>G	p.Ala83Gly	HADHB	SNV	Missense	Likely Pathogenic	TFP	<5	Muscle weakness	35403730	Exon 5	No
HADHB_0018	c.254+1G>A	Intronic	HADHB	SNV	Splice donor	Pathogenic	TFP	<5	"Arrhythmia, Elevated circulating creatine kinase concentration, Fever, Herpetic gingivostomatitis, Hypotonia, Idiopathic hydrops, Lethargy, Malaise/fatigue, Muscle weakness, Poor feeding, Rhabdomyolysis"	24379101, 28641477	Intron 5	Yes
HADHB_0019	c.254+5G>A	Intronic	HADHB	SNV	Splice region	Uncertain Significance	TFP	<5	Abnormality of metabolism/homeostasis, Cardiomyopathy, Hypoglycemia	35383965	Intron 5	No
HADHB_0020	c.255-713_811+86del	p.Gly86Lysfs*8	HADHB	Copy Number Loss	Deletion	Uncertain Significance	TFP	<5	Cardiomyopathy, Elevated circulating creatine kinase concentration, Liver abnormality, Weak motor skills	32257295	Exon 6-9, Intron 5-9	No
HADHB_0021	c.255-1G>A	Intronic	HADHB	SNV	Splice acceptor	Pathogenic	TFP	<5	Decreased body weight, Decreased endurance	33123633, 35433169	Intron 5	Yes
HADHB_0106	c.305T>C	p.Ile102Thr	HADHB	SNV	Missense	Uncertain Significance	TFP	<5			Exon 6	No
HADHB_0022	c.340A>G	p.Asn114Asp	HADHB	SNV	Missense	Likely Pathogenic	TFP	<5	"Abnormality of metabolism/homeostasis, Difficulty climbing stairs, Difficulty running, Lethargy, Liver abnormality, Peripheral neuropathy, Positive gowers sign, Rhabdomyolysis, Urine discoloration"	17143551, 29519241	Exon 6	Yes
HADHB_0023	c.341A>G	p.Asn114Ser	HADHB	SNV	Missense	Pathogenic	TFP	<5	"Achilles tendon tightness, Acute rhabdomyolysis, Ataxia, Delayed motor milestones, Difficulty climbing stairs, Difficulty getting up, Extreme fatigability, Gait abnormalities, Mixed motor neuropathy, Muscle weakness, Peripheral motor and sensory neuropathy, Retinal/choroid disorder, Rhabdomyolysis, Rise in creatine kinase, Very mild pigmentary retinopathy"	15902556, 17431731, 26109258	Exon 6	Yes
HADHB_0107	c.346G>T	p.Ala116Ser	HADHB	SNV	Missense	Uncertain Significance	TFP	<5			Exon 6	Yes
HADHB_0024	c.349A>G	p.Arg117Gly	HADHB	SNV	Missense	Pathogenic	TFP	<5	Myopathy, Peripheral neuropathy	12754706	Exon 6	No
HADHB_0025	c.354+5del	Intronic	HADHB	Deletion	Splice region	Uncertain Significance	TFP	<5	Abnormality of metabolism/homeostasis, Cardiac-other, Cardiomyopathy, Hypoglycemia, Pulmonary/respiratory	35383965	Intron 6	No
HADHB_0026	c.357dup	p.Ala120Cysfs*8	HADHB	Duplication	Frameshift	Pathogenic	TFP	<5	"Abnormality of metabolism/homeostasis, Cardiac-other, Cardiomyopathy, Chest retractions with grunting sounds, Decreased activity, Hypotension, Liquefaction of hemorrhages, Pale appearance, Pulmonary/respiratory, Renal insufficiency/failure, Seizure"	19880769	Exon 7	Yes
HADHB_0027	c.362T>C	p.Leu121Pro	HADHB	SNV	Missense	Uncertain Significance	TFP	<5	"Episodic muscle pain, Episodic myoglobinuria, Exercise or illness-induced episodes of rhabdomyolysis, Hypoventilation, Intermittent oxygen dependence, Muscle fiber atrophy, Myelin degeneration, Progressive peripheral neuropathy, Pulmonary/respiratory"	12754706	Exon 7	Yes
HADHB_0028	c.392C>T	p.Ala131Val	HADHB	SNV	Missense	Uncertain Significance	TFP	<5	Elevated circulating creatine kinase concentration, Mitochondrial myopathy, Recurrent attacks	32348839	Exon 7	Yes
HADHB_0029	c.397A>G	p.Thr133Ala	HADHB	SNV	Missense	Uncertain Significance	TFP	5-10	"Abnormal gait, Elevated circulating creatine kinase concentration, Exercise intolerance, Hypotonia, Loss of balance, Muscle weakness, Myalgia, Rhabdomyolysis"	35383965, 35403730	Exon 7	Yes
HADHB_0030	c.397A>C	p.Thr133Pro	HADHB	SNV	Missense	Likely Pathogenic	TFP	<5	Hellp syndrome, Myopathy	12754706	Exon 7	No
HADHB_0031	c.407T>C	p.Met136Thr	HADHB	SNV	Missense	Likely Pathogenic	TFP	<5	"Diminished tendon reflex, Elevated circulating creatine kinase concentration, Exercise intolerance, Malaise/fatigue, Mitochondrial myopathy, Muscle weakness, Myalgia, Myoglobinuria, Recurrent attacks, Rhabdomyolysis, Urine discoloration"	31521624, 32348839	Exon 7	Yes
HADHB_0032	c.421G>A	p.Ala141Thr	HADHB	SNV	Missense	Uncertain Significance	TFP	<5	"Diminished tendon reflex, Elevated circulating creatine kinase concentration, Exercise intolerance, Malaise/fatigue, Muscle weakness, Myalgia, Myoglobinuria, Rhabdomyolysis, Urine discoloration"	31521624	Exon 7	No
HADHB_0033	c.426C>A	p.Asn142Lys	HADHB	SNV	Missense	Uncertain Significance	TFP	<5	Abnormality of metabolism/homeostasis, Cardiomyopathy, Hypoglycemia	11196108, 15902556	Exon 7	No
HADHB_0034	c.427C>G	p.Gln143Glu	HADHB	SNV	Missense	Uncertain Significance	TFP	<5	Elevated circulating creatine kinase concentration, Mitochondrial myopathy, Recurrent attacks	32348839	Exon 7	Yes
HADHB_0035	c.442+614A>G	Intronic	HADHB	SNV	Intronic	Likely Pathogenic	TFP	<5	"Abnormality of metabolism/homeostasis, Anuria, Cardiac-other, Cyanosis, Elevated circulating creatine kinase concentration, Hyperammonemia, Hypoglycemia, Intraventricular and pulmonary hemorrhage, Pulmonary/respiratory, Renal insufficiency/failure, Seizure, Vomiting"	15056246, 18693053, 27014569	Intron 7	No
HADHB_0036	c.442+663A>G	Intronic	HADHB	SNV	Intronic	Uncertain Significance	TFP	<5	Abnormality of metabolism/homeostasis, Cardiac-other, Cardiomyopathy	30029694	Intron 7	Yes
HADHB_0037	c.443-20_624delinsCACACAAG	Intronic	HADHB	Delins	Splice acceptor	Uncertain Significance	TFP	<5	Abnormality of metabolism/homeostasis	31575911	Exon 8, Intron 7	No
HADHB_0038	c.443-10T>C	Intronic	HADHB	SNV	Intronic	Uncertain Significance	TFP	<5	Myopathy, Peripheral neuropathy		Intron 7	Yes
HADHB_0039	c.490G>A	p.Gly164Ser	HADHB	SNV	Missense	Uncertain Significance	TFP	<5	Distal muscle weakness, Rhabdomyolysis	34712195	Exon 8	Yes
HADHB_0040	c.520C>T	p.Arg174Cys	HADHB	SNV	Missense	Pathogenic	TFP	<5	"Apparent life-threatening event, Difficulty in moving, Elevated circulating creatine kinase concentration, Elevated circulating myoglobin concentration, Malaise/fatigue, Mitochondrial myopathy, Myalgia, Peripheral neuropathy, Recurrent attacks, Rhabdomyolysis"	22000755, 28515471, 32348839	Exon 8	Yes
HADHB_0041	c.522dup	p.His175Serfs*11	HADHB	Duplication	Frameshift	Pathogenic	TFP	<5	Abnormality of metabolism/homeostasis, Encephalopathy, Hypotension, Lethargy, Liver abnormality, Neutropenia, Pulmonary/respiratory, Vomiting	11196108, 15902556	Exon 8	No
HADHB_0042	c.527C>G	p.Ser176*	HADHB	SNV	Nonsense	Pathogenic	TFP	<5	Cardiomyopathy, Hypoglycemia	12754706	Exon 8	Yes
HADHB_0043	c.565G>A	p.Ala189Thr	HADHB	SNV	Missense	Uncertain Significance	TFP	<5			Exon 8	Yes
HADHB_0044	c.574A>G	p.Met192Val	HADHB	SNV	Missense	Uncertain Significance	TFP	<5	Elevated circulating creatine kinase concentration		Exon 8	Yes
HADHB_0045	c.580C>T	p.Gln194*	HADHB	SNV	Nonsense	Pathogenic	TFP	<5		30682426, 33638202	Exon 8	No
HADHB_0046	c.584G>A	p.Arg195Gln	HADHB	SNV	Missense	Uncertain Significance	TFP	<5			Exon 8	Yes
HADHB_0047	c.607C>T	p.Arg203*	HADHB	SNV	Nonsense	Pathogenic	TFP	<5	Myopathy, Peripheral neuropathy	12754706	Exon 8	Yes
HADHB_0048	c.631-1G>A	Intronic	HADHB	SNV	Splice acceptor	Pathogenic	TFP	<5	Abnormality of metabolism/homeostasis, Cardiomyopathy	30682426, 35383965	Intron 8	Yes
HADHB_0049	c.640G>A	p.Val214Ile	HADHB	SNV	Missense	Uncertain Significance	TFP	<5			Exon 9	Yes
HADHB_0050	c.646G>T	p.Glu216*	HADHB	SNV	Nonsense	Pathogenic	TFP	<5	Other, Reye syndrome-like episodes		Exon 9	Yes
HADHB_0051	c.685C>T	p.Arg229*	HADHB	SNV	Nonsense	Pathogenic	TFP	<5	Cardiomyopathy, Hypoglycemia	12754706	Exon 9	Yes
HADHB_0053	c.686G>T	p.Arg229Leu	HADHB	SNV	Missense	Pathogenic	TFP	<5	"Abnormal motor nerve conduction velocities, Absent deep tendon reflexes, Atrophy, Atrophy of bilateral distal muscles, Bilateral foot drop, Distal muscle weakness, Disturbed vibration and position senses, Gait disability, Gait disturbance, Loss of sensory and tendon reflexes, Lower limb muscle weakness, Muscle weakness, Peripheral neuropathy, Toe and heel gait defect, Walking difficulties"	24314034	Exon 9	Yes
HADHB_0052	c.686G>A	p.Arg229Gln	HADHB	SNV	Missense	Likely Pathogenic	TFP	<5	Bulb atrophy, Distal muscle weakness, Malaise/fatigue, Muscle weakness, Myopathy, Neovascular glaucoma, Pain, Peripheral neuropathy, Rhabdomyolysis	30990523, 34712195	Exon 9	Yes
HADHB_0054	c.693del	p.Ala232Leufs*20	HADHB	Deletion	Frameshift	Pathogenic	TFP	<5	Hypoglycemia	12754706	Exon 9	Yes
HADHB_0055	c.694G>A	p.Ala232Thr	HADHB	SNV	Missense	Likely Pathogenic	TFP	5-10	Developmental delay, Muscle weakness	35403730, 35433169	Exon 9	Yes
HADHB_0056	c.712C>T	p.Arg238Trp	HADHB	SNV	Missense	Uncertain Significance	TFP	<5	"Abnormal fibre size variations, Abnormal renal morphology, Areflexia, Distal muscular atrophy, Elevated circulating creatine kinase concentration, Muscle weakness, Peripheral neuropathy, Rhabdomyolysis, Sensorimotor deficits, Small stature"	30682426	Exon 9	Yes
HADHB_0057	c.713G>A	p.Arg238Gln	HADHB	SNV	Missense	Uncertain Significance	TFP	<5			Exon 9	Yes
HADHB_0058	c.725A>G	p.Asp242Gly	HADHB	SNV	Missense	Likely Pathogenic	TFP	<5	Hypoglycemia	12754706	Exon 9	No
HADHB_0059	c.739C>T	p.Arg247Cys	HADHB	SNV	Missense	Likely Pathogenic	TFP	5-10	"Abnormality of metabolism/homeostasis, Arrhythmia, Coma, Developmental delay, Difficulty climbing stairs, Difficulty running, Dragging gait, Elevated circulating creatine kinase concentration, Exercise intolerance, Fever, High-arched feet, Lethargy, Liver abnormality, Loss of achilles tendon reflex, Loss of knee jerk reflex, Lower limb muscle weakness, Myalgia, Peripheral neuropathy, Reduced lower extremity muscle volume, Rhabdomyolysis, Seizure, Trouble climbing stairs"	19699128, 22841441, 28649548, 29519241, 29915090	Exon 9	Yes
HADHB_0060	c.740G>A	p.Arg247His	HADHB	SNV	Missense	Likely Pathogenic	TFP	<5	"3-hydroxydicarboxylic aciduria, Cardiomyopathy, Decreased body weight, Hyperammonemia, Hypoglycemia, Intestinal pseudo-obstruction, Liver abnormality, Muscle weakness, Myopathy, Peripheral neuropathy, Rhabdomyolysis, Vomiting"	12754706, 15617873, 8651282	Exon 9	Yes
HADHB_0061	c.776_777insT	p.Leu260Thrfs*4	HADHB	Insertion	Frameshift	Pathogenic	TFP	<5	"Abnormality of metabolism/homeostasis, Cardiac arrest, Cardiomyopathy, Developmental delay, Elevated circulating creatine kinase concentration, Encephalopathy, Hypoparathyroidism, Hypotonia, Lethargy, Liver abnormality, Pulmonary/respiratory"	19699128, 28515471, 8645256, 9259266	Exon 9	Yes
HADHB_0062	c.788A>G	p.Asp263Gly	HADHB	SNV	Missense	Pathogenic	TFP	5-10	Cardiac-other, Hypoglycemia, Rhabdomyolysis, Severe hypotonia	21549624, 28392417, 8163672, 8651282	Exon 9	Yes
HADHB_0063	c.811+82A>G	Intronic	HADHB	SNV	Intronic	Uncertain Significance	TFP	<5	Cardiomyopathy, Elevated circulating creatine kinase concentration, Liver abnormality, Weak motor skills	32257295	Intron 9	Yes
HADHB_0064	c.817del	p.Asp273Ilefs*20	HADHB	Deletion	Frameshift	Pathogenic	TFP	<5	Abnormality of metabolism/homeostasis, Coma, Developmental delay, Liver abnormality, Seizure	19699128, 22841441	Exon 10	No
HADHB_0065	c.839G>A	p.Gly280Asp	HADHB	SNV	Missense	Uncertain Significance	TFP	<5	Hypoglycemia	12754706	Exon 10	No
HADHB_0066	c.845G>A	p.Arg282His	HADHB	SNV	Missense	Uncertain Significance	TFP	<5			Exon 10	Yes
HADHB_0067	c.881C>T	p.Pro294Leu	HADHB	SNV	Missense	Likely Pathogenic	TFP	<5	Myopathy, Peripheral neuropathy	12754706	Exon 10	No
HADHB_0068	c.881C>G	p.Pro294Arg	HADHB	SNV	Missense	Likely Pathogenic	TFP	<5	Hellp syndrome, Hypoglycemia, Myopathy	12754706	Exon 10	Yes
HADHB_0069	c.901G>A	p.Gly301Ser	HADHB	SNV	Missense	Uncertain Significance	TFP	5-10	"Elevated circulating creatine kinase concentration, Episodic muscle pain, Episodic myoglobinuria, Exercise or illness-induced episodes of rhabdomyolysis, Hypoglycemia, Muscle fiber atrophy, Myoglobinuria, Myopathy, Peripheral neuropathy, Progressive peripheral neuropathy, Retinal/choroid disorder, Rhabdomyolysis"	12754706, 12809642, 16040264, 16996288, 20589231, 27491397	Exon 10	Yes
HADHB_0070	c.902G>A	p.Gly301Asp	HADHB	SNV	Missense	Likely Pathogenic	TFP	<5	"Abnormality of metabolism/homeostasis, Encephalopathy, Hypocalcaemic seizures, Hypoglycemia, Liver abnormality, Myopathy, Neutropenia, Sideroblastic anaemia"	11196108, 15902556	Exon 10	No
HADHB_0071	c.919A>G	p.Asn307Asp	HADHB	SNV	Missense	Likely Pathogenic	TFP	<5	"Abnormality of metabolism/homeostasis, Difficulty running, Lethargy, Liver abnormality, Myoglobinuria, Pericardial effusion, Peripheral neuropathy, Positive gowers sign, Renal insufficiency/failure, Respiratory tract infection, Rhabdomyolysis, Urine discoloration, Walk with assistance"	17143551, 29519241	Exon 10	Yes
HADHB_0072	c.965C>A	p.Ala322Glu	HADHB	SNV	Missense	Uncertain Significance	TFP	<5			Exon 11	Yes
HADHB_0073	c.976G>C	p.Ala326Pro	HADHB	SNV	Missense	Likely Pathogenic	TFP	5-10	"Abnormality of metabolism/homeostasis, Bilateral hydrothoraces, Cardiac-other, Elevated circulating creatine kinase concentration, Hydrops generalisatus, Hypotonia, Myopathy, Pulmonary/respiratory"	12548384	Exon 11	No
HADHB_0074	c.980T>C	p.Leu327Pro	HADHB	SNV	Missense	Uncertain Significance	TFP	<5	"Abnormality of metabolism/homeostasis, Areflexia, Arrhythmia, Diarrhea, Difficulty moving arms, Difficulty speaking, Difficulty swallowing, Dyspnoea, Elevated circulating creatine kinase concentration, Fever, Hypoesthesia, Hypoparathyroidism, Muscle spasm, Muscle weakness, Myalgia, Pain, Peripheral neuropathy, Pes cavus, Rhabdomyolysis, Sensory deficits, Shuddering attacks, Upper quadrant abdominal tenderness, Urine discoloration, Vomiting"	28685493	Exon 11	No
HADHB_0075	c.998C>T	p.Pro333Leu	HADHB	SNV	Missense	Uncertain Significance	TFP	<5	Decreased body weight, Decreased endurance	35433169	Exon 11	Yes
HADHB_0076	c.1000A>C	p.Lys334Gln	HADHB	SNV	Missense	Uncertain Significance	TFP	<5			Exon 11	Yes
HADHB_0108	c.1044A>C	p.Lys348Asn	HADHB	SNV	Missense	Uncertain Significance	TFP	<5	Elevated circulating creatine kinase concentration, Hypoglycemia, Liver abnormality		Exon 12	Yes
HADHB_0077	c.1059del	p.Gly354Aspfs*10	HADHB	Deletion	Frameshift	Pathogenic	TFP	<5	Abnormality of metabolism/homeostasis, Critical hypoglycemia, Decreased body weight, Feeding intolerance, Severe metabolic acidosis	26334177, 27995076, 28617419	Exon 12	Yes
HADHB_0078	c.1091A>G	p.Glu364Gly	HADHB	SNV	Missense	Uncertain Significance	TFP	<5		34578803	Exon 13	No
HADHB_0079	c.1115A>T	p.Asp372Val	HADHB	SNV	Missense	Likely Pathogenic	TFP	<5		33638202	Exon 13	Yes
HADHB_0080	c.1136A>G	p.His379Arg	HADHB	SNV	Missense	Pathogenic	TFP	5-10	"Abnormality of metabolism/homeostasis, Anuria, Cardiac-other, Cardiomyopathy, Cyanosis, Elevated circulating creatine kinase concentration, Hyperammonemia, Hypoglycemia, Intraventricular and pulmonary hemorrhage, Pulmonary/respiratory, Renal insufficiency/failure, Seizure, Vomiting"	15056246, 18693053, 25420603, 29519241	Exon 13	No
HADHB_0081	c.1137del	p.His379Glnfs*76	HADHB	Deletion	Frameshift	Pathogenic	TFP	<5		21549624	Exon 13	Yes
HADHB_0082	c.1148C>T	p.Ser383Leu	HADHB	SNV	Missense	Likely Pathogenic	TFP	<5	Difficulty running, Peripheral neuropathy, Rhabdomyolysis	29519241	Exon 13	Yes
HADHB_0083	c.1149+4A>G	Intronic	HADHB	SNV	Splice region	Uncertain Significance	TFP	<5			Intron 13	Yes
HADHB_0084	c.1154A>C	p.Gln385Pro	HADHB	SNV	Missense	Uncertain Significance	TFP	<5	Asphyxiation, Cardiomyopathy, Hypoglycemia, Liver abnormality	28112527	Exon 14	Yes
HADHB_0085	c.1165A>G	p.Asn389Asp	HADHB	SNV	Missense	Pathogenic	TFP	5-10	"Myoglobinuria, Myopathy, Pericardial effusion, Peripheral neuropathy, Renal insufficiency/failure, Respiratory tract infection, Rhabdomyolysis, Walk with assistance"	17143551, 21549624, 28392417, 29519241, 29915090	Exon 14	Yes
HADHB_0086	c.1175C>T	p.Ala392Val	HADHB	SNV	Missense	Likely Pathogenic	TFP	5-10	"Abnormality of metabolism/homeostasis, Absence of achilles and patellar tendon reflexes, Atrophy, Cardiac arrest, Difficulty walking, Diminished touch senses, Drop foot, Elevated circulating creatine kinase concentration, Fever, Hammer toes, Hypoglycemia, Hypoparathyroidism, Muscle weakness, Myoglobinuria, Peripheral neuropathy, Pulmonary/respiratory, Rhabdomyolysis, Seizure"	24664533, 28515471, 32509533	Exon 14	Yes
HADHB_0087	c.1175_1177del	p.Ala392_Met393delinsVal	HADHB	Deletion	Deletion	Uncertain Significance	TFP	<5		21549624	Exon 14	No
HADHB_0088	c.1191G>A	p.Trp397*	HADHB	SNV	Nonsense	Pathogenic	TFP	<5		21549624	Exon 14	No
HADHB_0089	c.1192T>C	p.Phe398Leu	HADHB	SNV	Missense	Uncertain Significance	TFP	<5	Malaise/fatigue, Muscle weakness, Peripheral neuropathy, Rhabdomyolysis, Sensory disturbances, Urine discoloration	28132977	Exon 14	No
HADHB_0090	c.1198G>T	p.Glu400*	HADHB	SNV	Nonsense	Pathogenic	TFP	<5	Abnormality of metabolism/homeostasis, Cardiac-other, Cardiomyopathy	30029694	Exon 14	No
HADHB_0091	c.1211dup	p.Arg405*	HADHB	Duplication	Frameshift	Pathogenic	TFP	<5	Abnormality of metabolism/homeostasis, Cardiomyopathy, Pulmonary/respiratory	29519241	Exon 14	Yes
HADHB_0092	c.1228_1240del	p.Gly410Trpfs*41	HADHB	Deletion	Frameshift	Pathogenic	TFP	<5	Cardiomyopathy	31527676	Exon 15	No
HADHB_0093	c.1279G>A	p.Gly427Arg	HADHB	SNV	Missense	Uncertain Significance	TFP	<5	Elevated circulating creatine kinase concentration, Hypoglycemia, Liver abnormality, Myopathy, Other		Exon 15	Yes
HADHB_0094	c.1280G>A	p.Gly427Glu	HADHB	SNV	Missense	Uncertain Significance	TFP	<5		30193751	Exon 15	Yes
HADHB_0095	c.1289T>C	p.Phe430Ser	HADHB	SNV	Missense	Pathogenic	TFP	5-10	"Abnormality of metabolism/homeostasis, Cardiac-other, Cardiomyopathy, Elevated circulating creatine kinase concentration, Feeding difficulties, Hyaline membrane disease of the lungs, Hypoglycemia, Hypotonia, Myalgia, Pulmonary/respiratory, Respiratory tract infection, Rhabdomyolysis"	16423905, 35383965, 35403730, 35782614	Exon 15	Yes
HADHB_0096	c.1331G>A	p.Arg444Lys	HADHB	SNV	Missense	Likely Pathogenic	TFP	11-20	"Abnormality of metabolism/homeostasis, Apparent life-threatening event, Cardiac arrest, Cardiomyopathy, Developmental delay, Difficulty in moving, Difficulty in walking, Diminished muscle stretch reflexes, Elevated circulating creatine kinase concentration, Elevated circulating myoglobin concentration, Encephalopathy, Hypoparathyroidism, Hypotonia, Lethargy, Liver abnormality, Malaise/fatigue, Muscle weakness, Myalgia, Myoglobinuria, Nausea, Peripheral neuropathy, Pigmenturia, Pulmonary/respiratory, Rhabdomyolysis, Urine discoloration"	11239956, 19699128, 22000755, 26109258, 28515471, 8645256, 9259266, 9305349	Exon 15	Yes
HADHB_0097	c.1336C>T	p.Arg446Trp	HADHB	SNV	Missense	Uncertain Significance	TFP	<5			Exon 15	Yes
HADHB_0098	c.1348G>T	p.Gly450Cys	HADHB	SNV	Missense	Uncertain Significance	TFP	<5		34578803	Exon 15	No
HADHB_0099	c.1364T>G	p.Val455Gly	HADHB	SNV	Missense	Pathogenic	TFP	5-10	"Abnormality of metabolism/homeostasis, Cardiac arrest, Cardiac-other, Cardiomyopathy, Chest retractions with grunting sounds, Cyanosis, Decreased activity, Elevated circulating creatine kinase concentration, Hyperammonemia, Hypoglycemia, Hypoparathyroidism, Hypotension, Liquefaction of hemorrhages, Liver abnormality, Pale appearance, Pulmonary/respiratory, Renal insufficiency/failure, Rhabdomyolysis, Seizure"	19699128, 19880769, 27014569, 28515471, 32509533	Exon 15	Yes
HADHB_0109	c.1369G>A	p.Ala457Thr	HADHB	SNV	Missense	Uncertain Significance	TFP	<5	Retinal/choroid disorder		Exon 15	No
HADHB_0100	c.1376C>A	p.Ala459Glu	HADHB	SNV	Missense	Uncertain Significance	TFP	<5	Abnormality of metabolism/homeostasis, Encephalopathy, Hypotension, Lethargy, Liver abnormality, Neutropenia, Pulmonary/respiratory, Vomiting	11196108, 15902556	Exon 15	No
HADHB_0101	c.1390-515_1390-499del	Intronic	HADHB	Deletion	Intronic	Likely Pathogenic	TFP	<5		28283530	Intron 15	No
HADHB_0102	c.1409A>C	p.Glu470Ala	HADHB	SNV	Missense	Uncertain Significance	TFP	<5	Elevated circulating creatine kinase concentration, Myopathy, Rhabdomyolysis		Exon 16	Yes

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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.

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

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