HADHA

Long-Chain 3-Hydroxyl-acyl-CoA Dehydrogenase (LCHAD) Deficiency, Trifunctional Protein (TFP) Deficiency

Introduction

The HADHA gene, hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha, is located on chromosome 2p23.3 and has 20 exons spanning ~52kb (1, 2). It encodes the 764 amino acid alpha subunit of the mitochondrial trifunctional protein (TFP), which catalyzes the last three steps of mitochondrial beta-oxidation of long-chain fatty acids (2-4).

The mitochondrial membrane-bound heterocomplex is composed of four alpha and four beta subunits, with the alpha subunit catalyzing the 3-hydroxyacyl-CoA dehydrogenase and enoyl-CoA hydratase activities (1). Among the enzymes involved in the beta-oxidation pathway, the trifunctional enzyme exhibits specificity for long-chain fatty acids (6).

In addition, the alpha subunit of TFP participates in cardiolipin remodeling, and TFP physically interacts with mitochondrial respiratory chain complex 1 (7-9). Resemblance of TFP deficiency to mitochondrial respiratory chain disorders (e.g., elevated lactic acid, cardiomyopathy, polyneuropathy, retinopathy) may be explained by these functional and physical interactions of TFP with the respiratory chain (7).

Independently of the subunit beta, the trifunctional enzyme subunit alpha/HADHA also has a monolysocardiolipin acyltransferase activity. It acylates monolysocardiolipin into cardiolipin, a major mitochondrial membrane phospholipid which plays a key role in apoptosis and supports mitochondrial respiratory chain complexes in the generation of ATP (6-7).

Variants in this gene result in trifunctional protein deficiency or LCHAD deficiency (1-5). In LCHAD deficiency, there is an isolated deficiency of the dehydrogenase activity with normal hydratase activity and moderately decreased thiolase activity (59% of control) (10).

More than 111 disease-causing variants in the HADHA gene have been identified and are represented in this database (11). The variants occur across the entire length of the gene and include frameshift, splice site, copy-number, nonsense and missense variants (11).

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

HADHA_0001	c.1480-?_*615+?dup	Gain (Exons 15-20)	HADHA			Uncertain Significance	LCHAD/TFP	<5	Developmental delay			Unknown
HADHA_0002	c.?	p.Val412Leu	HADHA			Uncertain Significance	LCHAD/TFP	<5		14630990		Unknown
HADHA_0003	c.2281T>G	p.Phe761Val	HADHA	SNV	Missense	Likely Pathogenic	LCHAD/TFP	5-10	Absent deep tendon reflexes, Ataxic gait, Hypotonia, Peripheral neuropathy, Stumble	33638202, 35433174	Exon 20	No
HADHA_0004	c.2225_2228dup	p.Phe744Thrfs*10	HADHA	Insertion	Frameshift	Pathogenic	LCHAD/TFP	<5	Liver abnormality	12237653, 21549624	Exon 20	Yes
HADHA_0005	c.2200A>T	p.Lys734*	HADHA	SNV	Nonsense	Pathogenic	LCHAD/TFP	<5			Exon 20	Yes
HADHA_0006	c.2198T>C	p.Leu733Pro	HADHA	SNV	Missense	Uncertain Significance	LCHAD/TFP	<5		8739956	Exon 20	Yes
HADHA_0007	c.2146+6_2146+18del	Intronic	HADHA	Deletion	Splice region	Uncertain Significance	LCHAD/TFP	<5		21549624	Intron 19	No
HADHA_0008	c.2132dup	p.Pro712Alafs*26	HADHA	Duplication	Frameshift	Pathogenic	LCHAD/TFP	<5		9266371	Exon 19	Yes
HADHA_0009	c.2131C>A	p.Pro711Thr	HADHA	SNV	Missense	Uncertain Significance	LCHAD/TFP	<5			Exon 19	Yes
HADHA_0010	c.2114T>A	p.Val705Asp	HADHA	SNV	Missense	Likely Pathogenic	LCHAD/TFP	<5		26109258	Exon 19	Yes
HADHA_0011	c.2107G>A	p.Gly703Arg	HADHA	SNV	Missense	Pathogenic	LCHAD/TFP	<5	"Developmental delay, Diarrhea, Fever, Lethargy, Lower limb muscle weakness, Poor swallowing function, Progressive disturbance of consciousness, Weakness of muscles of respiration"	21103935, 26109258, 34878152	Exon 19	Yes
HADHA_0012	c.2102A>G	p.Asp701Gly	HADHA	SNV	Missense	Likely Pathogenic	LCHAD/TFP	<5		14630990, 22030098, 24064340, 26907176, 30912279	Exon 19	Yes
HADHA_0013	c.2099del	p.Gly700Glufs*30	HADHA	Deletion	Frameshift	Pathogenic	LCHAD/TFP	<5	Hypoglycemia, Rhabdomyolysis	32978841, 35383965	Exon 19	No
HADHA_0014	c.2077A>G	p.Ile693Val	HADHA	SNV	Missense	Uncertain Significance	LCHAD/TFP	<5			Exon 19	Yes
HADHA_0015	c.2063G>A	p.Cys688Tyr	HADHA	SNV	Missense	Uncertain Significance	LCHAD/TFP	<5		21549624	Exon 19	Yes
HADHA_0016	c.2059del	p.Met687Cysfs*43	HADHA	Deletion	Frameshift	Pathogenic	LCHAD/TFP	<5	Decreased body weight, Deteriorating vision, Lethargy, Night blindness	27652820, 30682426	Exon 19	Yes
HADHA_0018	c.2027G>A	p.Arg676His	HADHA	SNV	Missense	Likely Pathogenic	LCHAD/TFP	5-10	Bronchiolitis, Cardiac-other, Cardiomyopathy, Encephalopathy, Liver abnormality, Rhabdomyolysis	10352164, 11427448, 15902556, 21549624, 26109258	Exon 19	Yes
HADHA_0017	c.2027G>T	p.Arg676Leu	HADHA	SNV	Missense	Uncertain Significance	LCHAD/TFP	5-10	Exercise intolerance, Muscle weakness, Myalgia	24305961, 28283530	Exon 19	Yes
HADHA_0019	c.2026C>T	p.Arg676Cys	HADHA	SNV	Missense	Likely Pathogenic	LCHAD/TFP	<5	Cardiac-other	10352164, 14630990	Exon 19	Yes
HADHA_0020	c.2020dup	p.Gln674Profs*11	HADHA	Duplication	Frameshift	Pathogenic	LCHAD/TFP	<5			Exon 19	Yes
HADHA_0021	c.2005T>G	p.Ser669Ala	HADHA	SNV	Missense	Uncertain Significance	LCHAD/TFP	<5			Exon 19	Yes
HADHA_0022	c.2000+5G>C	Intronic	HADHA	SNV	Splice region	Uncertain Significance	LCHAD/TFP	<5			Intron 18	Yes
HADHA_0023	c.2000+1G>A	Intronic	HADHA	SNV	Splice donor	Pathogenic	LCHAD/TFP	<5	Elevated circulating creatine kinase concentration, Myopathy, Rhabdomyolysis	14630990	Intron 18	Yes
HADHA_0024	c.1981_1999del	p.Leu661Serfs*12	HADHA	Deletion	Frameshift	Pathogenic	LCHAD/TFP	<5		21549624	Exon 18	Yes
HADHA_0025	c.1990_1991del	p.Lys664Valfs*2	HADHA	Deletion	Frameshift	Pathogenic	LCHAD/TFP	<5		21549624	Exon 18	No
HADHA_0112	c.1970C>T	p.Ala657Val	HADHA	SNV	Missense	Uncertain Significance	LCHAD/TFP	<5			Exon 18	No
HADHA_0026	c.1967del	p.Leu656*	HADHA	Deletion	Frameshift	Pathogenic	LCHAD/TFP	<5	Liver abnormality	10352164, 18045290, 21549624	Exon 18	Yes
HADHA_0113	c.1965T>G	p.Ile655Met	HADHA	SNV	Missense	Uncertain Significance	LCHAD/TFP	<5			Exon 18	No
HADHA_0114	c.1925G>T	p.Gly642Val	HADHA	SNV	Missense	Uncertain Significance	LCHAD/TFP	<5			Exon 18	Yes
HADHA_0027	c.1915_1918del	p.Tyr639Argfs*4	HADHA	Deletion	Frameshift	Pathogenic	LCHAD/TFP	<5		35281663	Exon 18	Yes
HADHA_0028	c.1893del	p.Lys631Asnfs*13	HADHA	Deletion	Frameshift	Pathogenic	LCHAD/TFP	<5	Cardiomyopathy		Exon 18	Yes
HADHA_0029	c.1828C>G	p.Arg610Gly	HADHA	SNV	Missense	Likely Pathogenic	LCHAD/TFP	5-10	Absent deep tendon reflexes, Ataxic gait, Hypotonia, Peripheral neuropathy, Stumble	21103935, 33638202, 35433174	Exon 17	Yes
HADHA_0030	c.1795G>A	p.Val599Met	HADHA	SNV	Missense	Uncertain Significance	LCHAD/TFP	<5		14630990	Exon 17	No
HADHA_0031	c.1793_1794del	p.His598Argfs*33	HADHA	Deletion	Frameshift	Pathogenic	LCHAD/TFP	5-10	Abnormality of metabolism/homeostasis, Cardiac-other, Cardiomyopathy, Hypoglycemia, Renal insufficiency/failure	11855930, 12442268, 29519241	Exon 17	Yes
HADHA_0032	c.1712T>C	p.Leu571Pro	HADHA	SNV	Missense	Pathogenic	LCHAD/TFP	<5	Anxiety, Cardiomyopathy, Gastrointestinal-other, Seizure	24305961, 26109258, 29124685, 32463482	Exon 17	Yes
HADHA_0033	c.1690-2A>G	Intronic	HADHA	SNV	Splice acceptor	Pathogenic	LCHAD/TFP	<5	Cardiomyopathy, Developmental delay, Hypoglycemia, Hypotonia, Lethargy, Liver abnormality	23430857	Intron 16	Yes
HADHA_0034	c.1689+2T>G	Intronic	HADHA	SNV	Splice donor	Pathogenic	LCHAD/TFP	11-20	Abnormality of metabolism/homeostasis, Cardiac-other, Coma, Hypoglycemia, Hypotonia, Liver abnormality, Pulmonary/respiratory	17143551, 27014569, 28515471, 29519241	Intron 16	Yes
HADHA_0035	c.1678C>T	p.Arg560*	HADHA	SNV	Nonsense	Pathogenic	LCHAD/TFP	11-20	"Abnormality of metabolism/homeostasis, And decreased oral intake, Cardiac-other, Coma, Fetal distress, Hyperpigmented macula, Hypoglycemia, Hypotonia, Irritability, Lethargy, Liver abnormality, Myalgia, Myoglobinuria, Retinal/choroid disorder, Upper respiratory infection with vomiting"	10352164, 11427448, 14630990, 16040264, 16876451, 16996288, 20589231, 21549624, 22030098, 24064340, 27491397, 30912279, 32463482, 33123633, 8865274	Exon 16	Yes
HADHA_0036	c.1663_1665del	p.Met555del	HADHA	Deletion	Deletion	Uncertain Significance	LCHAD/TFP	<5		21549624	Exon 16	No
HADHA_0037	c.1664T>G	p.Met555Arg	HADHA	SNV	Missense	Uncertain Significance	LCHAD/TFP	<5		34732400	Exon 16	No
HADHA_0116	c.1655C>T	p.Ala552Val	HADHA	SNV	Missense	Uncertain Significance	LCHAD/TFP	<5			Exon 16	Yes
HADHA_0038	c.1646G>C	p.Arg549Thr	HADHA	SNV	Missense	Uncertain Significance	LCHAD/TFP	<5		34578803	Exon 16	No
HADHA_0039	c.1620+2_1620+6del	Intronic	HADHA	Deletion	Splice donor	Pathogenic	LCHAD/TFP	<5	Cardiac-other, Gait, Liver abnormality, Muscle weakness, Retinal/choroid disorder, Rhabdomyolysis, Seizure	10352164, 16040264, 32999401	Intron 15	Yes
HADHA_0040	c.1561_1562del	p.Thr521Glnfs*19	HADHA	Deletion	Frameshift	Pathogenic	LCHAD/TFP	<5		30682426	Exon 15	No
HADHA_0041	c.1533dup	p.Ile512Tyrfs*29	HADHA	Duplication	Frameshift	Pathogenic	LCHAD/TFP	<5		21549624	Exon 15	Yes
HADHA_0042	c.1528G>C	p.Glu510Gln	HADHA	SNV	Missense	Pathogenic	LCHAD/TFP	30+	"Abnormal eye movements, Abnormality of metabolism/homeostasis, Absent achilles reflex, Absent deep tendon reflexes, Absent tendon reflexes, Acute cardiac insufficiency, Acute decompensation, Acute fatty liver of pregnancy with hepatic coma, Acute hepatic failure, Anaemia, And decreased oral intake, Areflexia, Arrhythmia, Asphyxia, Ataxia, Axial hypotonia, Blindness, Bronchiolitis, Capillary leakage syndrome, Cardiac arrest, Cardiac-other, Cardiomyopathy, Cataract, Circulatory collapse, Coma, Congestion, Decreased body weight, Decreased orientation, Dehydration, Depression, Desaturation, Deteriorating vision, Developmental delay, Diarrhea, Diminished ankle reflexes, Distal weakness of the lower limbs, Drowsy, Dry cough, Edema, Elevated circulating creatine kinase concentration, Encephalopathy, Episodic migranes, Epithelioid inflammatory myofibroblastic sarcoma, Exercise intolerance, Feeding difficulties, Feeding problems, Fetal distress, Fetal distress during delivery, Fever, Firm hepatomegaly, Gait, Gastrointestinal-other, Generalized tonic clonic seizures, Gerd, Hyperammonemia, Hyperbilirubinemia, Hyperpigmented macula, Hypoesthesia, Hypoglycemia, Hypopallesthesia, Hypotension, Hypothermia, Hypotonia, Intermittent loss of consciousness, Intraventricular -intraparenchymal hemorrhage, Irritability, Jaundice, Lethargy, Liver abnormality, Loss of consciousness, Malaise/fatigue, Marked hypopigmentation of macula, Microcephaly, Migraine, Moderate choriocapillaris atrophy, Moderate jaundice, Multiple rhabdomyolysis episodes, Muscle spasm, Muscle weakness, Myalgia, Myoglobinuria, Myolysis with muscle pain, Myopathic gait, Myopathy, Nausea, Neonatal hypothermia, Night blindness, Non-ketotic hypoglycaemia, Other, Oxygen desaturation, Pain, Pale stools, Paleness, Paresthesia, Peripheral neuropathy, Periventricular leukomalacia, Polyps, Poor feeding, Poor vision, Pulmonary hemorrhage, Pulmonary/respiratory, Reduced tendon reflexes, Renal insufficiency/failure, Respiratory tract infection, Retinal/choroid disorder, Reye syndrome-like episodes, Rhabdomyolysis, Romberg, Rsv bronchiolitis, Seizure, Sensory ataxia, Severe liver failure, Severe metabolic decompensation, Somnolence, Thrombocytopenia, Tics, Unconsciousness, Upper respiratory infection with vomiting, Urine discoloration, Vesicoureteric reflux, Vomiting"	10352164, 10384386, 10518281, 10789927, 11045847, 11241049, 11427446, 11427448, 11719334, 11773547, 11855930, 12162610, 12208138, 12237653, 12413376, 12660866, 12745572, 12809642, 12872842, 14605499, 14630990, 15902556, 16040264, 16183823, 16297647, 16876451, 16996288, 17160563, 17431731, 18045290, 18162058, 18240871, 18408953, 18662835, 19399638, 19852779, 20363656, 20583174, 20589231, 20659813, 21103935, 21549624, 22030098, 22473002, 22494076, 22859334, 23430524, 23430857, 23798014, 23868323, 24064340, 24305961, 25141826, 26109258, 26545880, 26653362, 26676313, 26907176, 27117294, 27334895, 27491397, 27590926, 27652820, 27769081, 28245050, 28392417, 28871440, 29268767, 30029694, 30364125, 30682426, 30912279, 30990523, 31025818, 32253025, 32463482, 32581083, 32706845, 32793418, 32928639, 32978841, 32999401, 33123633, 33204595, 33638202, 34578803, 34732400, 35281663, 35383965, 35677112, 35782617, 35822088, 36109795, 7811722, 7846063, 8294091, 8736409, 8739956, 8809345, 8865274, 8871579, 8938697, 9003853, 9266371, 9403664, 9539533, 9593380	Exon 15	Yes
HADHA_0043	c.1493A>G	p.His498Arg	HADHA	SNV	Missense	Likely Pathogenic	LCHAD/TFP	<5	Decreased body weight, Fever, Gastrointestinal-other, Hypoglycemia, Hypospadias, Peripheral neuropathy	27117294, 33638202	Exon 15	Yes
HADHA_0044	c.1480-139C>G	Intronic	HADHA	SNV	Intronic	Uncertain Significance	LCHAD/TFP	<5	Abnormality of metabolism/homeostasis, Anemia, Pallor, Seizure	30747351	Intron 14	Yes
HADHA_0045	c.1393_1479del	p.Pro467_Ile495del	HADHA	Deletion	Deletion	Likely Pathogenic	LCHAD/TFP	<5		26109258	Exon 14	No
HADHA_0046	c.1433C>T	p.Ala478Val	HADHA	SNV	Missense	Uncertain Significance	LCHAD/TFP	<5		21549624	Exon 14	No
HADHA_0047	c.1432del	p.Ala478Leufs*17	HADHA	Deletion	Frameshift	Pathogenic	LCHAD/TFP	<5		35383965	Exon 14	Yes
HADHA_0048	c.1432G>C	p.Ala478Pro	HADHA	SNV	Missense	Uncertain Significance	LCHAD/TFP	<5		21549624	Exon 14	Yes
HADHA_0049	c.1418C>A	p.Ala473Asp	HADHA	SNV	Missense	Uncertain Significance	LCHAD/TFP	<5	"Absent reflexes in lower extremities, Bilateral hand tremors, Cardiac-other, Cardiomyopathy, Developmental delay, Sensory polyneuropathy, Waddling gait, Walking difficulty"	32999401	Exon 14	Yes
HADHA_0117	c.1393G>C	p.Val465Leu	HADHA	SNV	Missense	Uncertain Significance	LCHAD/TFP	<5			Exon 14	Yes
HADHA_0050	c.1336_1393del	p.Glu446*	HADHA	Copy Number Loss	Deletion	Pathogenic	LCHAD/TFP	<5	Exercise intolerance, Muscle weakness, Myalgia	24305961	Exon 13-14, Intron 13	No
HADHA_0051	c.1392+1G>A	Intronic	HADHA	SNV	Splice donor	Pathogenic	LCHAD/TFP	5-10	Abnormality of metabolism/homeostasis, Cardiac-other, Coma, Developmental delay, Eye movement abnormalities, Hypoglycemia, Hypotonia, Muscle weakness	27014569, 28515471, 35758105	Intron 13	No
HADHA_0052	c.1381del	p.Glu461Lysfs*2	HADHA	Deletion	Frameshift	Pathogenic	LCHAD/TFP	<5		21549624	Exon 13	No
HADHA_0053	c.1336G>A	p.Glu446Lys	HADHA	SNV	Missense	Likely Pathogenic	LCHAD/TFP	<5		26109258	Exon 13	No
HADHA_0054	c.1220+2T>C	Intronic	HADHA	SNV	Splice donor	Pathogenic	LCHAD/TFP	<5		12237653, 12413376	Intron 12	No
HADHA_0055	c.1220+1G>C	Intronic	HADHA	SNV	Splice donor	Pathogenic	LCHAD/TFP	<5	Liver abnormality	21103935	Intron 12	No
HADHA_0056	c.1196G>A	p.Arg399Gln	HADHA	SNV	Missense	Uncertain Significance	LCHAD/TFP	<5			Exon 12	Yes
HADHA_0057	c.1195C>T	p.Arg399*	HADHA	SNV	Nonsense	Pathogenic	LCHAD/TFP	<5	Peripheral neuropathy	21549624, 33638202	Exon 12	Yes
HADHA_0058	c.1132C>T	p.Gln378*	HADHA	SNV	Nonsense	Pathogenic	LCHAD/TFP	5-10	Liver abnormality, Retinal/choroid disorder, Rhabdomyolysis	10352164, 11241049, 16040264, 16297647, 22030098, 24064340, 30912279, 7846063, 8809345	Exon 12	Yes
HADHA_0118	c.1117G>A	p.Gly373Arg	HADHA	SNV	Missense	Uncertain Significance	LCHAD/TFP	<5			Exon 12	No
HADHA_0059	c.1108G>A	p.Gly370Arg	HADHA	SNV	Missense	Uncertain Significance	LCHAD/TFP	<5	Congestion, Edema, Muscle weakness, Myalgia, Pulmonary/respiratory	35782617	Exon 12	No
HADHA_0060	c.1086-3_1092del	Intronic	HADHA	Deletion	Splice acceptor	Pathogenic	LCHAD/TFP	<5		11241049, 21549624	Exon 12, Intron 11	Yes
HADHA_0061	c.1072C>A	p.Gln358Lys	HADHA	SNV	Missense	Benign	LCHAD/TFP	5-10	"Asterixis, Athetoid movement, Bilateral pulmonary hypoplasia, Developmental delay, Gastrointestinal-other, Hyperbilirubinemia, Hypotonia, Icterus, Intravascular coagulopathy, Lethargy, Pancreatitis, Peripheral edema, Renal insufficiency/failure, Tender abdomen, Thrombocytopenia"	15533621, 22494076, 22746996, 26109258, 35383965	Exon 11	Yes
HADHA_0062	c.1058_1059delinsT	p.Lys353Ilefs*19	HADHA	Delins	Frameshift	Pathogenic	LCHAD/TFP	<5	Areflexia, Blindness, Exercise intolerance, Hypoglycemia, Rhabdomyolysis, Sensory ataxia	21549624, 32253025	Exon 11	No
HADHA_0063	c.1029C>A	p.Tyr343*	HADHA	SNV	Nonsense	Pathogenic	LCHAD/TFP	<5	Liver abnormality, Myopathy, Other		Exon 11	Yes
HADHA_0064	c.1025T>C	p.Leu342Pro	HADHA	SNV	Missense	Likely Pathogenic	LCHAD/TFP	<5	Decreased body weight, Fever, Gastrointestinal-other, Hypoglycemia, Hypospadias	27117294, 9266371	Exon 11	Yes
HADHA_0065	c.982G>A	p.Gly328Arg	HADHA	SNV	Missense	Likely Pathogenic	LCHAD/TFP	<5	Gastrointestinal-other	26109258, 35383965	Exon 11	Yes
HADHA_0066	c.975+6C>T	Intronic	HADHA	SNV	Splice region	Uncertain Significance	LCHAD/TFP	<5			Intron 10	Yes
HADHA_0124	c.975G>A	p.Gln325=	HADHA	SNV	Silent	Uncertain Significance	LCHAD/TFP	<5	Elevated circulating creatine kinase concentration, Hypoglycemia, Myopathy, Retinal/choroid disorder, Rhabdomyolysis		Exon 10	Yes
HADHA_0068	c.955G>A	p.Gly319Ser	HADHA	SNV	Missense	Likely Pathogenic	LCHAD/TFP	<5	Absent deep tendon reflexes, Exercise intolerance, Hypotonia, Muscle weakness, Peripheral neuropathy	30682426, 33638202	Exon 10	Yes
HADHA_0069	c.919-2A>G	Intronic	HADHA	SNV	Splice acceptor	Pathogenic	LCHAD/TFP	<5	"Malaise/fatigue, Myalgia, Myoglobinuria, Peripheral neuropathy, Pulmonary/respiratory, Renal insufficiency/failure, Retinal/choroid disorder, Rhabdomyolysis"	15902556	Intron 9	Yes
HADHA_0070	c.918+6T>G	Intronic	HADHA	SNV	Splice region	Uncertain Significance	LCHAD/TFP	<5		21549624	Intron 9	No
HADHA_0071	c.918+1G>A	Intronic	HADHA	SNV	Splice donor	Pathogenic	LCHAD/TFP	<5		21549624, 26109258	Intron 9	No
HADHA_0073	c.914T>C	p.Ile305Thr	HADHA	SNV	Missense	Likely Pathogenic	LCHAD/TFP	<5	Liver abnormality, Other, Reye syndrome-like episodes, Rhabdomyolysis		Exon 9	Yes
HADHA_0072	c.914T>A	p.Ile305Asn	HADHA	SNV	Missense	Pathogenic	LCHAD/TFP	11-20	"Ataxia, Bilateral foot drop, Contracture of the achilles tendons, Developmental delay, Distal muscle weakness, Exertion, Fasting, Hypoesthesia, Hypoglycemia, Liver abnormality, Muscle spasm, Muscle weakness, Myalgia, Myoglobinuria, Myoglobinuria (precipitated by infection, Neuromuscular abnormality, Or cold exposure), Paresthesia, Peripheral neuropathy, Retinal/choroid disorder, Rhabdomyolysis"	10352164, 2019931, 21549624, 26109258, 29268767, 32253025, 34578803, 9739053	Exon 9	Yes
HADHA_0074	c.896C>A	p.Pro299His	HADHA	SNV	Missense	Uncertain Significance	LCHAD/TFP	<5			Exon 9	Yes
HADHA_0075	c.871C>T	p.Arg291*	HADHA	SNV	Nonsense	Pathogenic	LCHAD/TFP	5-10	"Bilateral foot drop, Cardiomyopathy, Contracture of the achilles tendons, Developmental delay, Distal muscle weakness, Elevated circulating creatine kinase concentration, Exertion, Fasting, Hypoglycemia, Liver abnormality, Muscle weakness, Myalgia, Myoglobinuria (precipitated by infection, Myopathy, Neuromuscular abnormality, Or cold exposure), Peripheral neuropathy, Retinal/choroid disorder, Rhabdomyolysis"	10352164, 18485779, 2019931, 23798014, 9739053	Exon 9	Yes
HADHA_0076	c.859del	p.Glu287Lysfs*16	HADHA	Deletion	Frameshift	Pathogenic	LCHAD/TFP	<5		30682426	Exon 9	No
HADHA_0077	c.845T>A	p.Val282Asp	HADHA	SNV	Missense	Likely Pathogenic	LCHAD/TFP	5-10	Dehydration, Dysarthria, Fever, Muscle weakness, Myoglobinuria, Myopathy, Pain, Pulmonary/respiratory, Tremor, Vomiting	10352164, 14630990, 7748366, 9739053	Exon 9	Yes
HADHA_0125	c.799+1G>A	Intronic	HADHA	SNV	Splice donor	Likely Pathogenic	LCHAD/TFP	<5	Elevated circulating creatine kinase concentration		Intron 8	Yes
HADHA_0078	c.761_764del	p.Lys254Argfs*14	HADHA	Deletion	Frameshift	Pathogenic	LCHAD/TFP	<5		21103935	Exon 8	Yes
HADHA_0079	c.731C>T	p.Ala244Val	HADHA	SNV	Missense	Uncertain Significance	LCHAD/TFP	<5	"Malaise/fatigue, Myalgia, Myoglobinuria, Peripheral neuropathy, Pulmonary/respiratory, Renal insufficiency/failure, Retinal/choroid disorder, Rhabdomyolysis"	15902556	Exon 8	No
HADHA_0080	c.703C>T	p.Arg235Trp	HADHA	SNV	Missense	Pathogenic	LCHAD/TFP	11-20	"Absent deep tendon reflexes, Anemia, Cardiac arrest, Developmental delay, Diarrhea, Encephalopathy, Fever, Head lag, Hypotonia, Lethargy, Lower limb muscle weakness, Muscle weakness, Peripheral neuropathy, Poor swallowing function, Progressive disturbance of consciousness, Respiratory tract infection, Rhabdomyolysis, Thrombocytosis, Weakness of muscles of respiration"	19433283, 21549624, 28871440, 32928639, 33638202, 34578803, 34878152	Exon 8	Yes
HADHA_0081	c.677-3T>C	Intronic	HADHA	SNV	Splice region	Uncertain Significance	LCHAD/TFP	<5			Intron 7	Yes
HADHA_0082	c.676+2T>C	Intronic	HADHA	SNV	Splice donor	Pathogenic	LCHAD/TFP	<5		21549624	Intron 7	Yes
HADHA_0120	c.653T>C	p.Val218Ala	HADHA	SNV	Missense	Uncertain Significance	LCHAD/TFP	<5	Elevated circulating creatine kinase concentration, Hypoglycemia, Liver abnormality, Other		Exon 7	No
HADHA_0083	c.602T>C	p.Met201Thr	HADHA	SNV	Missense	Uncertain Significance	LCHAD/TFP	<5		33638202	Exon 7	No
HADHA_0084	c.574-2A>G	Intronic	HADHA	SNV	Splice acceptor	Pathogenic	LCHAD/TFP	5-10	Cardiomyopathy	10352164, 11241049, 11427448, 14630990	Intron 6	Yes
HADHA_0085	c.573+9_573+10insT	Intronic	HADHA	Insertion	Intronic	Uncertain Significance	LCHAD/TFP	<5	Bilateral pulmonary hypoplasia	22746996	Intron 6	No
HADHA_0086	c.556C>G	p.Gln186Glu	HADHA	SNV	Missense	Likely Pathogenic	LCHAD/TFP	<5	Developmental delay, Exercise intolerance, Eye movement abnormalities, Muscle weakness, Myalgia	24305961, 35758105	Exon 6	No
HADHA_0087	c.539C>T	p.Pro180Leu	HADHA	SNV	Missense	Uncertain Significance	LCHAD/TFP	<5	Distal muscle weakness, Peripheral neuropathy	32657593	Exon 6	Yes
HADHA_0088	c.509G>A	p.Gly170Asp	HADHA	SNV	Missense	Likely Pathogenic	LCHAD/TFP	<5		11427448	Exon 6	Yes
HADHA_0089	c.479_482delinsAATA	p.Ile160_Gln763delinsLys	HADHA	Delins	Nonsense	Likely Pathogenic	LCHAD/TFP	<5	Cardiac arrest, Hypoglycemia, Liver abnormality, Rhabdomyolysis	10352164, 16876451, 16996288, 20589231, 27491397, 28871440, 32928639	Exon 6	No
HADHA_0091	c.453+1G>T	Intronic	HADHA	SNV	Splice donor	Pathogenic	LCHAD/TFP	<5	Exercise intolerance, Hypotonia, Muscle weakness, Peripheral neuropathy	30682426	Intron 5	No
HADHA_0090	c.453+1G>A	Intronic	HADHA	SNV	Splice donor	Pathogenic	LCHAD/TFP	<5	Cardiomyopathy, Poor perfusion of peripheral tissues, Pulmonary/respiratory	35281663	Intron 5	Yes
HADHA_0092	c.446G>T	p.Gly149Val	HADHA	SNV	Missense	Uncertain Significance	LCHAD/TFP	<5	Anxiety, Cardiomyopathy, Gastrointestinal-other, Seizure	29124685	Exon 5	No
HADHA_0093	c.442G>A	p.Gly148Arg	HADHA	SNV	Missense	Uncertain Significance	LCHAD/TFP	<5		21549624	Exon 5	No
HADHA_0094	c.389T>C	p.Leu130Pro	HADHA	SNV	Missense	Likely Pathogenic	LCHAD/TFP	<5	Cardiomyopathy	12442268, 14630990	Exon 5	No
HADHA_0095	c.361C>T	p.Gln121*	HADHA	SNV	Nonsense	Pathogenic	LCHAD/TFP	<5	Cardiac-other	28515471	Exon 5	No
HADHA_0096	c.341A>G	p.Gln114Arg	HADHA	SNV	Missense	Uncertain Significance	LCHAD/TFP	<5			Exon 5	Yes
HADHA_0097	c.325G>A	p.Ala109Thr	HADHA	SNV	Missense	Uncertain Significance	LCHAD/TFP	<5	Myopathy, Rhabdomyolysis		Exon 5	Yes
HADHA_0121	c.323C>A	p.Ala108Asp	HADHA	SNV	Missense	Uncertain Significance	LCHAD/TFP	<5	Hypoglycemia, Liver abnormality		Exon 5	Yes
HADHA_0098	c.315-1G>A	Intronic	HADHA	SNV	Splice acceptor	Pathogenic	LCHAD/TFP	<5		19852779	Intron 4	Yes
HADHA_0099	c.315-2A>T	Intronic	HADHA	SNV	Splice acceptor	Pathogenic	LCHAD/TFP	<5	Cardiomyopathy, Liver abnormality	10352164, 14630990	Intron 4	Yes
HADHA_0100	c.278C>G	p.Ser93*	HADHA	SNV	Nonsense	Pathogenic	LCHAD/TFP	<5		34578803	Exon 4	No
HADHA_0101	c.274_278del	p.Ser92Lysfs*10	HADHA	Deletion	Frameshift	Pathogenic	LCHAD/TFP	21-30	"Abnormality of metabolism/homeostasis, Cardiac-other, Dry cough, Gastrointestinal-other, Hypoglycemia, Hypotension, Liver abnormality, Nausea, Oxygen desaturation, Pain, Peripheral neuropathy, Pulmonary/respiratory, Renal insufficiency/failure, Retinal/choroid disorder, Rhabdomyolysis, Vomiting"	10352164, 11241049, 12237653, 12413376, 12809642, 16040264, 16876451, 16996288, 20589231, 21549624, 24064340, 27491397, 28392417, 30912279, 33204595, 33638202, 34578803	Exon 4	Yes
HADHA_0102	c.266T>G	p.Val89Gly	HADHA	SNV	Missense	Uncertain Significance	LCHAD/TFP	<5		21103935	Exon 4	No
HADHA_0122	c.240G>A	p.Trp80*	HADHA	SNV	Nonsense	Pathogenic	LCHAD/TFP	<5			Exon 4	Yes
HADHA_0103	c.180_180+5delinsAT	Intronic	HADHA	Delins	Splice donor	Pathogenic	LCHAD/TFP	5-10	"Cardiomyopathy, Elevated circulating creatine kinase concentration, Feeding problems, Hyperammonemia, Hypoglycemia, Lethargy, Liver abnormality, Pulmonary/respiratory, Unresponsiveness"	10400133, 30682426, 33638202	Exon 3, Intron 3	Yes
HADHA_0104	c.180+3A>G	Intronic	HADHA	SNV	Splice region	Likely Pathogenic	LCHAD/TFP	11-20	"Arrhythmia, Bowed femurs, Cardiac-other, Cardiomyopathy, Complex congenital heart disease, Diminished ankle reflexes, Feeding problems, Hyperammonemia, Hypoglycemia, Lethargy, Liver abnormality, Myalgia, Myoglobinuria, Pulmonary/respiratory, Rhabdomyolysis, Small thoracic circumference, Unresponsiveness, Urine discoloration"	10352164, 10400133, 14630990, 22030098, 22746996, 23868323, 26109258, 27491397, 29268767, 30682426, 30912279, 33123633, 7738175, 8651282	Intron 3	Yes
HADHA_0105	c.180+1G>A	Intronic	HADHA	SNV	Splice donor	Pathogenic	LCHAD/TFP	<5	Arrhythmia, Cardiac-other, Cardiomyopathy, Hypoglycemia	10352164, 14630990, 7738175, 8651282	Intron 3	Yes
HADHA_0123	c.167C>G	p.Ser56Cys	HADHA	SNV	Missense	Uncertain Significance	LCHAD/TFP	<5			Exon 3	No
HADHA_0106	c.162del	p.Asn55Thrfs*7	HADHA	Deletion	Frameshift	Pathogenic	LCHAD/TFP	<5	Liver abnormality	12237653	Exon 3	No
HADHA_0107	c.157C>T	p.Arg53*	HADHA	SNV	Nonsense	Pathogenic	LCHAD/TFP	<5		20659813	Exon 3	Yes
HADHA_0108	c.138dup	p.Gly47Argfs*9	HADHA	Duplication	Frameshift	Pathogenic	LCHAD/TFP	<5		21549624	Exon 3	No
HADHA_0109	c.72del	p.Tyr24*	HADHA	Deletion	Frameshift	Pathogenic	LCHAD/TFP	<5		14630990	Exon 2	Yes
HADHA_0110	c.58del	p.Arg20Alafs*17	HADHA	Deletion	Frameshift	Pathogenic	LCHAD/TFP	<5		34578803	Exon 1	No
HADHA_0111	c.13C>T	p.Arg5Trp	HADHA	SNV	Missense	Uncertain Significance	LCHAD/TFP	<5			Exon 1	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_000182.4 and NM_000182.5 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:

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/3030
https://www.uniprot.org/uniprotkb/P40939/entry
Prasun, P. et al., Long-Chain Hydroxyacyl-CoA Dehydrogenase Deficiency / Trifunctional Protein Deficiency. In: GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993. 2022 Sep 1.
https://www.omim.org/entry/600890?search=HADHA
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.
Taylor, W. et al., Human trifunctional protein alpha links cardiolipin remodeling to beta-oxidation. PLOS One. 2012;7(11):e48628.
Miklas, J. W. et al., TFPa/HADHA is required for fatty acid beta-oxidation and cardiolipin re-modeling in human cardiomyocytes. Nat Commun. 2019 Oct 11;10(1):4671.
Wang, Y., et al., Mitochondrial fatty acid oxidation and the electron transport chain comprise a multifunctional mitochondrial protein complex. J Biol Chem. 2019 Aug 16;294(33):12380-12391.
IJIst, L. et al., Common missense mutation G1528C in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Characterization and expression of the mutant protein, mutation analysis on genomic DNA and chromosomal localization of the mitochondrial trifunctional protein alpha subunit gene. J Clin Invest. 1996 Aug 15;98(4):1028-33.
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).

Long-Chain 3-Hydroxyl-acyl-CoA Dehydrogenase (LCHAD) Deficiency​, Trifunctional Protein (TFP) Deficiency

Introduction

Variant List

Gene Structure

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Long-Chain 3-Hydroxyl-acyl-CoA Dehydrogenase (LCHAD) Deficiency, Trifunctional Protein (TFP) Deficiency