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

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HADHA

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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_IDVariantAmino_Acid_ChangeProtein DomainDisplay ACMG CallACMG_Call_Last_Revised_DateVariant_TypeEffect_Typegene_symbolTimes_Observed_RangePMIDArticle_CountPhenotypeDisease subtypeVariant_StartLocation
HADHA_0001c.1480-?_*615+?dupGain (Exons 15-20)Not SpecifiedUncertain Significance05/16/2023HADHA<30LCHAD/TFP1480
HADHA_0002c.?p.Val412LeuNot SpecifiedUncertain Significance03/01/2023HADHA<3146309901LCHAD/TFP
HADHA_0003c.2281T>Gp.Phe761ValNot SpecifiedLikely Pathogenic03/01/2023SNVMissenseHADHA6-1033638202, 354331742Absent deep tendon reflexes, Ataxic gait, Hypotonia, Peripheral neuropathy, StumbleLCHAD/TFP2281Exon 20
HADHA_0004c.2225_2228dupp.Phe744Thrfs*10Not SpecifiedPathogenic03/01/2023InsertionFrameshiftHADHA<312237653, 215496242Liver dysfunctionLCHAD/TFP2225Exon 20
HADHA_0005c.2200A>Tp.Lys734*Not SpecifiedPathogenic05/16/2023SNVNonsenseHADHA<30LCHAD/TFP2200Exon 20
HADHA_0006c.2198T>Cp.Leu733ProNot SpecifiedUncertain Significance03/01/2023SNVMissenseHADHA<387399561LCHAD/TFP2198Exon 20
HADHA_0007c.2146+6_2146+18delIntronicNot SpecifiedUncertain Significance03/01/2023DeletionSplice regionHADHA<3215496241LCHAD/TFP2146Intron 19
HADHA_0008c.2132dupp.Pro712Alafs*26Not SpecifiedPathogenic03/01/2023DuplicationFrameshiftHADHA<392663711LCHAD/TFP2132Exon 19
HADHA_0009c.2131C>Ap.Pro711ThrNot SpecifiedUncertain Significance03/01/2023SNVMissenseHADHA30+0LCHAD/TFP2131Exon 19
HADHA_0010c.2114T>Ap.Val705AspNot SpecifiedLikely Pathogenic03/01/2023SNVMissenseHADHA<3261092581LCHAD/TFP2114Exon 19
HADHA_0011c.2107G>Ap.Gly703ArgNot SpecifiedPathogenic03/01/2023SNVMissenseHADHA3-521103935, 26109258, 348781523Developmental delay, Diarrhea, Fever, Lethargy, Lower limb muscle weakness, Poor swallowing function, Progressive disturbance of consciousness, Weakness of muscles of respirationLCHAD/TFP2107Exon 19
HADHA_0012c.2102A>Gp.Asp701GlyNot SpecifiedLikely Pathogenic03/01/2023SNVMissenseHADHA<314630990, 22030098, 24064340, 26907176, 309122795LCHAD/TFP2102Exon 19
HADHA_0013c.2099delp.Gly700Glufs*30Not SpecifiedPathogenic03/01/2023DeletionFrameshiftHADHA3-532978841, 353839652Hypoglycemia, RhabdomyolysisLCHAD/TFP2099Exon 19
HADHA_0014c.2077A>Gp.Ile693ValNot SpecifiedUncertain Significance05/16/2023SNVMissenseHADHA<30LCHAD/TFP2077Exon 19
HADHA_0015c.2063G>Ap.Cys688TyrNot SpecifiedUncertain Significance03/01/2023SNVMissenseHADHA<3215496241LCHAD/TFP2063Exon 19
HADHA_0016c.2059delp.Met687Cysfs*43Not SpecifiedPathogenic03/01/2023DeletionFrameshiftHADHA<327652820, 306824262Decreased body weight, Deteriorating vision, Lethargy, Night blindnessLCHAD/TFP2059Exon 19
HADHA_0017c.2027G>Tp.Arg676LeuNot SpecifiedUncertain Significance03/01/2023SNVMissenseHADHA3-524305961, 282835302Exercise intolerance, Muscle weakness, MyalgiaLCHAD/TFP2027Exon 19
HADHA_0018c.2027G>Ap.Arg676HisNot SpecifiedLikely Pathogenic05/16/2023SNVMissenseHADHA6-1010352164, 11427448, 15902556, 21549624, 261092585Abnormality of the liver, Bronchiolitis, Cardiac-other, Cardiomyopathy, Encephalopathy, RhabdomyolysisLCHAD/TFP2027Exon 19
HADHA_0019c.2026C>Tp.Arg676CysNot SpecifiedLikely Pathogenic03/01/2023SNVMissenseHADHA<310352164, 146309902Cardiac-otherLCHAD/TFP2026Exon 19
HADHA_0020c.2020dupp.Gln674Profs*11Not SpecifiedPathogenic03/01/2023DuplicationFrameshiftHADHA30+0LCHAD/TFP2020Exon 19
HADHA_0021c.2005T>Gp.Ser669AlaNot SpecifiedUncertain Significance05/16/2023SNVMissenseHADHA<30LCHAD/TFP2005Exon 19
HADHA_0022c.2000+5G>CIntronicNot SpecifiedUncertain Significance05/16/2023SNVSplice regionHADHA<30LCHAD/TFP2000Intron 18
HADHA_0023c.2000+1G>AIntronicNot SpecifiedPathogenic05/16/2023SNVSplice donorHADHA<3146309901LCHAD/TFP2000Intron 18
HADHA_0024c.1981_1999delp.Leu661Serfs*12Not SpecifiedPathogenic03/01/2023DeletionFrameshiftHADHA<3215496241LCHAD/TFP1981Exon 18
HADHA_0025c.1990_1991delp.Lys664Valfs*2Modified residue(N6-acetyllysine)Pathogenic03/01/2023DeletionFrameshiftHADHA<3215496241LCHAD/TFP1990Exon 18
HADHA_0026c.1967delp.Leu656*Not SpecifiedPathogenic03/01/2023DeletionFrameshiftHADHA3-510352164, 18045290, 215496243Abnormal liver morphology, Liver dysfunctionLCHAD/TFP1967Exon 18
HADHA_0027c.1915_1918delp.Tyr639Argfs*4Not SpecifiedPathogenic03/01/2023DeletionFrameshiftHADHA<3352816631LCHAD/TFP1915Exon 18
HADHA_0028c.1893delp.Lys631Asnfs*13Not SpecifiedPathogenic05/16/2023DeletionFrameshiftHADHA<30LCHAD/TFP1893Exon 18
HADHA_0029c.1828C>Gp.Arg610GlyNot SpecifiedLikely Pathogenic03/01/2023SNVMissenseHADHA6-1021103935, 33638202, 354331743Absent deep tendon reflexes, Ataxic gait, Hypotonia, Peripheral neuropathy, StumbleLCHAD/TFP1828Exon 17
HADHA_0030c.1795G>Ap.Val599MetNot SpecifiedUncertain Significance03/01/2023SNVMissenseHADHA<3146309901LCHAD/TFP1795Exon 17
HADHA_0031c.1793_1794delp.His598Argfs*33Not SpecifiedPathogenic05/16/2023DeletionFrameshiftHADHA3-511855930, 12442268, 295192413Abnormality of metabolism/homeostasis, Cardiac-other, Cardiomyopathy, Hypoglycemia, Renal insufficiency/failureLCHAD/TFP1793Exon 17
HADHA_0032c.1712T>Cp.Leu571ProNot SpecifiedPathogenic03/01/2023SNVMissenseHADHA3-524305961, 26109258, 29124685, 324634824Anxiety, Dilated cardiomyopathy, Gastrointestinal-other, SeizureLCHAD/TFP1712Exon 17
HADHA_0033c.1690-2A>GIntronicNot SpecifiedPathogenic03/01/2023SNVSplice acceptorHADHA<3234308571Cardiomyopathy, Decreased liver function, Developmental delay, Dilated cardiomyopathy, Hypoglycemia, Hypotonia, LethargyLCHAD/TFP1690Intron 16
HADHA_0034c.1689+2T>GIntronicNot SpecifiedPathogenic03/01/2023SNVSplice donorHADHA6-1017143551, 27014569, 28515471, 295192414Abnormality of metabolism/homeostasis, Cardiac-other, Coma, Hypoglycemia, Hypotonia, Liver dysfunction, Pulmonary/respiratoryLCHAD/TFP1689Intron 16
HADHA_0035c.1678C>Tp.Arg560*Not SpecifiedPathogenic03/01/2023SNVNonsenseHADHA11-2010352164, 11427448, 14630990, 16040264, 16876451, 16996288, 20589231, 21549624, 22030098, 24064340, 27491397, 30912279, 32463482, 33123633, 886527415Abnormal liver morphology, Abnormality of metabolism/homeostasis, And decreased oral intake, Cardiac-other, Coma, Fetal distress, Hyperpigmented macula, Hypoglycemia, Hypoketotic hypoglycemia, Hypotonia, Irritability, Lethargy, Myalgia, Myoglobinuria, Retinal/choroid disorder, Upper respiratory infection with vomitingLCHAD/TFP1678Exon 16
HADHA_0036c.1663_1665delp.Met555delNot SpecifiedUncertain Significance03/01/2023DeletionDeletionHADHA<3215496241LCHAD/TFP1663Exon 16
HADHA_0037c.1664T>Gp.Met555ArgNot SpecifiedUncertain Significance03/01/2023SNVMissenseHADHA<3347324001LCHAD/TFP1664Exon 16
HADHA_0038c.1646G>Cp.Arg549ThrNot SpecifiedUncertain Significance03/01/2023SNVMissenseHADHA<3345788031LCHAD/TFP1646Exon 16
HADHA_0039c.1620+2_1620+6delIntronicNot SpecifiedPathogenic03/01/2023DeletionSplice donorHADHA<310352164, 16040264, 329994013Cardiac-other, Gait, Liver dysfunction, Muscle weakness, Retinal/choroid disorder, Rhabdomyolysis, SeizureLCHAD/TFP1620Intron 15
HADHA_0040c.1561_1562delp.Thr521Glnfs*19Not SpecifiedPathogenic03/01/2023DeletionFrameshiftHADHA<3306824261LCHAD/TFP1561Exon 15
HADHA_0041c.1533dupp.Ile512Tyrfs*29Not SpecifiedPathogenic03/01/2023DuplicationFrameshiftHADHA<3215496241LCHAD/TFP1533Exon 15
HADHA_0042c.1528G>Cp.Glu510GlnActive SitePathogenic05/16/2023SNVMissenseHADHA30+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, 9593380107Abnormal liver morphology, Abnormality of metabolism/homeostasis, Abnormality of the liver, Absent achilles reflex, Acute decompensation, 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 liver function, Dehydration, Depression, Desaturation, Deteriorating vision, Developmental delay, Diarrhea, Dilated cardiomyopathy, Diminished ankle reflexes, Drowsy, Dry cough, Edema, Elevated hepatic transaminase, Encephalopathy, Exercise intolerance, Feeding difficulties, Feeding problems, Fetal distress, Fetal distress during delivery, Fever, Gait, Gastrointestinal-other, Hepatic failure, Hyperammonemia, Hyperbilirubinemia, Hyperpigmented macula, Hypertrophic cardiomyopathy, Hypoesthesia, Hypoglycemia, Hypoketotic hypoglycemia, Hypopallesthesia, Hypotension, Hypotonia, Irritability, Jaundice, Lethargy, Liver dysfunction, Loss of consciousness, Malaise/fatigue, Microcephaly, Muscle spasm, Muscle weakness, Myalgia, Myoglobinuria, Myopathy, Nausea, Night blindness, Oxygen desaturation, Pain, Paleness, Paresthesia, Peripheral neuropathy, Poor feeding, Poor vision, Pulmonary hemorrhage, Pulmonary/respiratory, Renal insufficiency/failure, Respiratory tract infection, Retinal/choroid disorder, Reye syndrome-like episodes, Rhabdomyolysis, Romberg, Seizure, Sensory ataxia, Somnolence, Thrombocytopenia, Tics, Unconsciousness, Upper respiratory infection with vomiting, Urine discoloration, VomitingLCHAD/TFP1528Exon 15
HADHA_0043c.1493A>Gp.His498ArgHADH Activity SiteLikely Pathogenic03/01/2023SNVMissenseHADHA<327117294, 336382022Decreased body weight, Fever, Gastrointestinal-other, Hypoglycemia, Hypospadias, Peripheral neuropathyLCHAD/TFP1493Exon 15
HADHA_0044c.1480-139C>GIntronicNot SpecifiedUncertain Significance03/01/2023SNVIntronicHADHA<3307473511Abnormality of metabolism/homeostasis, Anemia, Pallor, SeizureLCHAD/TFP1480Intron 14
HADHA_0045c.1393_1479delp.Pro467_Ile495delNot SpecifiedLikely Pathogenic03/01/2023DeletionDeletionHADHA<3261092581LCHAD/TFP1393Exon 14
HADHA_0046c.1433C>Tp.Ala478ValNot SpecifiedUncertain Significance03/01/2023SNVMissenseHADHA<3215496241LCHAD/TFP1433Exon 14
HADHA_0047c.1432delp.Ala478Leufs*17Not SpecifiedPathogenic03/01/2023DeletionFrameshiftHADHA<3353839651LCHAD/TFP1432Exon 14
HADHA_0048c.1432G>Cp.Ala478ProNot SpecifiedUncertain Significance03/01/2023SNVMissenseHADHA<3215496241LCHAD/TFP1432Exon 14
HADHA_0049c.1418C>Ap.Ala473AspNot SpecifiedUncertain Significance03/01/2023SNVMissenseHADHA<3329994011LCHAD/TFP1418Exon 14
HADHA_0050c.1336_1393delp.Glu446*Not SpecifiedPathogenic03/01/2023Copy Number LossHADHA<3243059611Exercise intolerance, Muscle weakness, MyalgiaLCHAD/TFP1336Exon 13-14, Intron 13
HADHA_0051c.1392+1G>AIntronicNot SpecifiedPathogenic03/01/2023SNVSplice donorHADHA3-527014569, 28515471, 357581053Abnormality of metabolism/homeostasis, Cardiac-other, Coma, Developmental delay, Eye movement abnormalities, Hypoglycemia, Hypotonia, Muscle weaknessLCHAD/TFP1392Intron 13
HADHA_0052c.1381delp.Glu461Lysfs*2Not SpecifiedPathogenic03/01/2023DeletionFrameshiftHADHA<3215496241LCHAD/TFP1381Exon 13
HADHA_0053c.1336G>Ap.Glu446LysNot SpecifiedLikely Pathogenic03/01/2023SNVMissenseHADHA<3261092581LCHAD/TFP1336Exon 13
HADHA_0054c.1220+2T>CIntronicNot SpecifiedPathogenic03/01/2023SNVSplice donorHADHA<312237653, 124133762LCHAD/TFP1220Intron 12
HADHA_0055c.1220+1G>CIntronicNot SpecifiedPathogenic03/01/2023SNVSplice donorHADHA<3211039351Liver dysfunctionLCHAD/TFP1220Intron 12
HADHA_0056c.1196G>Ap.Arg399GlnModified residue(Omega-N-methylarginine)Uncertain Significance05/16/2023SNVMissenseHADHA<30LCHAD/TFP1196Exon 12
HADHA_0057c.1195C>Tp.Arg399*Modified residue(Omega-N-methylarginine)Pathogenic03/01/2023SNVNonsenseHADHA<321549624, 336382022Peripheral neuropathyLCHAD/TFP1195Exon 12
HADHA_0058c.1132C>Tp.Gln378*Not SpecifiedPathogenic05/16/2023SNVNonsenseHADHA3-510352164, 11241049, 16040264, 16297647, 22030098, 24064340, 30912279, 7846063, 88093459Liver dysfunctionLCHAD/TFP1132Exon 12
HADHA_0059c.1108G>Ap.Gly370ArgNot SpecifiedUncertain Significance03/01/2023SNVMissenseHADHA<3357826171Congestion, Edema, Muscle weakness, Myalgia, Pulmonary/respiratoryLCHAD/TFP1108Exon 12
HADHA_0060c.1086-3_1092delIntronicNot SpecifiedPathogenic03/01/2023DeletionSplice acceptorHADHA<311241049, 215496242LCHAD/TFP1086Exon 12, Intron 11
HADHA_0061c.1072C>Ap.Gln358LysNot SpecifiedBenign03/01/2023SNVMissenseHADHA3-515533621, 22494076, 22746996, 26109258, 353839655Gastrointestinal-otherLCHAD/TFP1072Exon 11
HADHA_0062c.1058_1059delinsTp.Lys353Ilefs*19Modified residue(N6-acetyllysine)Pathogenic03/01/2023DelinsFrameshiftHADHA<321549624, 322530252Areflexia, Blindness, Exercise intolerance, Hypoketotic hypoglycemia, Rhabdomyolysis, Sensory ataxiaLCHAD/TFP1058Exon 11
HADHA_0063c.1029C>Ap.Tyr343*Not SpecifiedPathogenic05/16/2023SNVNonsenseHADHA<30LCHAD/TFP1029Exon 11
HADHA_0064c.1025T>Cp.Leu342ProNot SpecifiedLikely Pathogenic03/01/2023SNVMissenseHADHA<327117294, 92663712Decreased body weight, Fever, Gastrointestinal-other, Hypoglycemia, HypospadiasLCHAD/TFP1025Exon 11
HADHA_0065c.982G>Ap.Gly328ArgNot SpecifiedLikely Pathogenic03/01/2023SNVMissenseHADHA<326109258, 353839652Gastrointestinal-otherLCHAD/TFP982Exon 11
HADHA_0066c.975+6C>TIntronicNot SpecifiedUncertain Significance03/01/2023SNVSplice regionHADHA30+0LCHAD/TFP975Intron 10
HADHA_0067c.975G>ASilentNot SpecifiedUncertain Significance05/16/2023SNVSilentHADHA<30LCHAD/TFP975Exon 10
HADHA_0068c.955G>Ap.Gly319SerNot SpecifiedLikely Pathogenic03/01/2023SNVMissenseHADHA<330682426, 336382022Absent deep tendon reflexes, Exercise intolerance, Hypotonia, Muscle weakness, Peripheral neuropathyLCHAD/TFP955Exon 10
HADHA_0069c.919-2A>GIntronicNot SpecifiedPathogenic03/01/2023SNVSplice acceptorHADHA<3159025561Malaise/fatigue, Myalgia, Myoglobinuria, Peripheral neuropathy, Pulmonary/respiratory, Renal insufficiency/failure, Retinal/choroid disorder, RhabdomyolysisLCHAD/TFP919Intron 9
HADHA_0070c.918+6T>GIntronicNot SpecifiedUncertain Significance03/01/2023SNVSplice regionHADHA<3215496241LCHAD/TFP918Intron 9
HADHA_0071c.918+1G>AIntronicNot SpecifiedPathogenic03/01/2023SNVSplice donorHADHA3-521549624, 261092582LCHAD/TFP918Intron 9
HADHA_0072c.914T>Ap.Ile305AsnNot SpecifiedPathogenic05/16/2023SNVMissenseHADHA11-2010352164, 2019931, 21549624, 26109258, 29268767, 32253025, 34578803, 97390538Abnormal liver morphology, Ataxia, Bilateral foot drop, Contracture of the achilles tendons, Developmental delay, Distal muscle weakness, Exertion, Fasting, Hepatic failure, Hypoesthesia, Hypoglycemia, Muscle spasm, Muscle weakness, Myalgia, Myoglobinuria, Myoglobinuria (precipitated by infection, Neuromuscular abnormality, Or cold exposure), Paresthesia, Peripheral neuropathy, Retinal/choroid disorder, RhabdomyolysisLCHAD/TFP914Exon 9
HADHA_0073c.914T>Cp.Ile305ThrNot SpecifiedLikely Pathogenic05/16/2023SNVMissenseHADHA<30LCHAD/TFP914Exon 9
HADHA_0074c.896C>Ap.Pro299HisNot SpecifiedUncertain Significance05/16/2023SNVMissenseHADHA<30LCHAD/TFP896Exon 9
HADHA_0075c.871C>Tp.Arg291*Not SpecifiedPathogenic05/16/2023SNVNonsenseHADHA6-1010352164, 18485779, 2019931, 23798014, 97390535Abnormal liver morphology, Bilateral foot drop, Cardiodmyopathy, Contracture of the achilles tendons, Developmental delay, Distal muscle weakness, Exertion, Fasting, Hypoglycemia, Liver dysfunction, Muscle weakness, Myalgia, Myoglobinuria (precipitated by infection, Myopathy, Neuromuscular abnormality, Or cold exposure), Peripheral neuropathyLCHAD/TFP871Exon 9
HADHA_0076c.859delp.Glu287Lysfs*16Not SpecifiedPathogenic03/01/2023DeletionFrameshiftHADHA<3306824261LCHAD/TFP859Exon 9
HADHA_0077c.845T>Ap.Val282AspNot SpecifiedLikely Pathogenic03/01/2023SNVMissenseHADHA3-510352164, 14630990, 7748366, 97390534Dehydration, Dysarthria, Fever, Muscle weakness, Myoglobinuria, Myopathy, Pain, Pulmonary/respiratory, Tremor, VomitingLCHAD/TFP845Exon 9
HADHA_0078c.761_764delp.Lys254Argfs*14Not SpecifiedPathogenic03/01/2023DeletionFrameshiftHADHA<3211039351LCHAD/TFP761Exon 8
HADHA_0079c.731C>Tp.Ala244ValNot SpecifiedUncertain Significance03/01/2023SNVMissenseHADHA<3159025561Malaise/fatigue, Myalgia, Myoglobinuria, Peripheral neuropathy, Pulmonary/respiratory, Renal insufficiency/failure, Retinal/choroid disorder, RhabdomyolysisLCHAD/TFP731Exon 8
HADHA_0080c.703C>Tp.Arg235TrpNot SpecifiedPathogenic05/16/2023SNVMissenseHADHA11-2019433283, 21549624, 28871440, 32928639, 33638202, 34578803, 348781527Absent 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 respirationLCHAD/TFP703Exon 8
HADHA_0081c.677-3T>CIntronicNot SpecifiedUncertain Significance05/16/2023SNVHADHA<30LCHAD/TFP677Intron 7
HADHA_0082c.676+2T>CIntronicNot SpecifiedPathogenic03/01/2023SNVSplice donorHADHA<3215496241LCHAD/TFP676Intron 7
HADHA_0083c.602T>Cp.Met201ThrNot SpecifiedUncertain Significance03/01/2023SNVMissenseHADHA<3336382021LCHAD/TFP602Exon 7
HADHA_0084c.574-2A>GIntronicNot SpecifiedPathogenic03/01/2023SNVSplice acceptorHADHA6-1010352164, 11241049, 11427448, 146309904Dilated cardiomyopathyLCHAD/TFP574Intron 6
HADHA_0085c.573+9_573+10insTIntronicNot SpecifiedUncertain Significance03/01/2023InsertionIntronicHADHA<3227469961LCHAD/TFP573Intron 6
HADHA_0086c.556C>Gp.Gln186GluNot SpecifiedLikely Pathogenic03/01/2023SNVMissenseHADHA3-524305961, 357581052Developmental delay, Exercise intolerance, Eye movement abnormalities, Muscle weakness, MyalgiaLCHAD/TFP556Exon 6
HADHA_0087c.539C>Tp.Pro180LeuNot SpecifiedUncertain Significance03/01/2023SNVMissenseHADHA<3326575931Distal muscle weakness, Peripheral neuropathyLCHAD/TFP539Exon 6
HADHA_0088c.509G>Ap.Gly170AspNot SpecifiedLikely Pathogenic03/01/2023SNVMissenseHADHA<3114274481LCHAD/TFP509Exon 6
HADHA_0089c.479_482delinsAATAp.Ile160_Gln763delinsLysNot SpecifiedLikely Pathogenic03/01/2023DelinsNonsenseHADHA3-510352164, 16876451, 16996288, 20589231, 27491397, 28871440, 329286397Cardiac arrest, Hypoglycemia, Liver dysfunction, RhabdomyolysisLCHAD/TFP479Exon 6
HADHA_0090c.453+1G>AIntronicNot SpecifiedPathogenic03/01/2023SNVSplice donorHADHA<3352816631Dilated cardiomyopathy, Poor perfusion of peripheral tissues, Pulmonary/respiratoryLCHAD/TFP453Intron 5
HADHA_0091c.453+1G>TIntronicNot SpecifiedPathogenic03/01/2023SNVSplice donorHADHA<3306824261Exercise intolerance, Hypotonia, Muscle weakness, Peripheral neuropathyLCHAD/TFP453Intron 5
HADHA_0092c.446G>Tp.Gly149ValNot SpecifiedUncertain Significance03/01/2023SNVMissenseHADHA<3291246851Anxiety, Dilated cardiomyopathy, Gastrointestinal-other, SeizureLCHAD/TFP446Exon 5
HADHA_0093c.442G>Ap.Gly148ArgNot SpecifiedUncertain Significance03/01/2023SNVMissenseHADHA<3215496241LCHAD/TFP442Exon 5
HADHA_0094c.389T>Cp.Leu130ProNot SpecifiedLikely Pathogenic03/01/2023SNVMissenseHADHA3-512442268, 146309902CardiomyopathyLCHAD/TFP389Exon 5
HADHA_0095c.361C>Tp.Gln121*Not SpecifiedPathogenic03/01/2023SNVNonsenseHADHA<3285154711Cardiac-otherLCHAD/TFP361Exon 5
HADHA_0096c.341A>Gp.Gln114ArgNot SpecifiedUncertain Significance05/16/2023SNVMissenseHADHA<30LCHAD/TFP341Exon 5
HADHA_0097c.325G>Ap.Ala109ThrNot SpecifiedUncertain Significance05/16/2023SNVMissenseHADHA<30LCHAD/TFP325Exon 5
HADHA_0098c.315-1G>AIntronicNot SpecifiedPathogenic03/01/2023SNVSplice acceptorHADHA<3198527791LCHAD/TFP315Intron 4
HADHA_0099c.315-2A>TIntronicNot SpecifiedPathogenic03/01/2023SNVSplice acceptorHADHA<310352164, 146309902Cardiomyopathy, Liver dysfunctionLCHAD/TFP315Intron 4
HADHA_0100c.278C>Gp.Ser93*Not SpecifiedPathogenic03/01/2023SNVNonsenseHADHA<3345788031LCHAD/TFP278Exon 4
HADHA_0101c.274_278delp.Ser92Lysfs*10Not SpecifiedPathogenic03/01/2023DeletionFrameshiftHADHA21-3010352164, 11241049, 12237653, 12413376, 12809642, 16040264, 16876451, 16996288, 20589231, 21549624, 24064340, 27491397, 28392417, 30912279, 33204595, 33638202, 3457880317Abnormality of metabolism/homeostasis, Cardiac-other, Decreased liver function, Dry cough, Gastrointestinal-other, Hypoglycemia, Hypoketotic hypoglycemia, Hypotension, Liver dysfunction, Nausea, Oxygen desaturation, Pain, Peripheral neuropathy, Pulmonary/respiratory, Renal insufficiency/failure, Retinal/choroid disorder, Rhabdomyolysis, VomitingLCHAD/TFP274Exon 4
HADHA_0102c.266T>Gp.Val89GlyNot SpecifiedUncertain Significance03/01/2023SNVMissenseHADHA<3211039351LCHAD/TFP266Exon 4
HADHA_0103c.180_180+5delinsATIntronicNot SpecifiedPathogenic05/16/2023DelinsSplice donorHADHA3-510400133, 30682426, 336382023Abnormal liver morphology, Dilated cardiomyopathy, Feeding problems, Hyperammonemia, Hypoglycemia, Lethargy, Pulmonary/respiratory, UnresponsivenessLCHAD/TFP180Exon 3, Intron 3
HADHA_0104c.180+3A>GIntronicNot SpecifiedLikely Pathogenic03/01/2023SNVSplice regionHADHA11-2010352164, 10400133, 14630990, 22030098, 22746996, 23868323, 26109258, 27491397, 29268767, 30682426, 30912279, 33123633, 7738175, 865128214Abnormal liver morphology, Arrhythmia, Cardiac-other, Dilated cardiomyopathy, Diminished ankle reflexes, Feeding problems, Hyperammonemia, Hypoglycemia, Lethargy, Myalgia, Myoglobinuria, Pulmonary/respiratory, Rhabdomyolysis, Unresponsiveness, Urine discolorationLCHAD/TFP180Intron 3
HADHA_0105c.180+1G>AIntronicNot SpecifiedPathogenic03/01/2023SNVSplice donorHADHA3-510352164, 14630990, 7738175, 86512824Arrhythmia, Cardiac-other, Dilated cardiomyopathy, HypoglycemiaLCHAD/TFP180Intron 3
HADHA_0106c.162delp.Asn55Thrfs*7Not SpecifiedPathogenic03/01/2023DeletionFrameshiftHADHA<3122376531Liver dysfunctionLCHAD/TFP162Exon 3
HADHA_0107c.157C>Tp.Arg53*Not SpecifiedPathogenic03/01/2023SNVNonsenseHADHA<3206598131LCHAD/TFP157Exon 3
HADHA_0108c.138dupp.Gly47Argfs*9Not SpecifiedPathogenic03/01/2023DuplicationFrameshiftHADHA<3215496241LCHAD/TFP138Exon 3
HADHA_0109c.72delp.Tyr24*Not SpecifiedPathogenic03/01/2023DeletionFrameshiftHADHA<3146309901LCHAD/TFP72Exon 2
HADHA_0110c.58delp.Arg20Alafs*17Not SpecifiedPathogenic03/01/2023DeletionFrameshiftHADHA<3345788031LCHAD/TFP58Exon 1
HADHA_0111c.13C>Tp.Arg5TrpNot SpecifiedUncertain Significance03/01/2023SNVMissenseHADHA30+0LCHAD/TFP13Exon 1
    Notes:
  • * 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.
    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

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