HADHA

hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha

Basic information

Region (hg38): 2:26190635-26244672

Links

ENSG00000084754 ∙ NCBI:3030 ∙ OMIM:600890 ∙ HGNC:4801 ∙ Uniprot:P40939 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (Definitive), mode of inheritance: AR
• long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (Strong), mode of inheritance: AR
• mitochondrial trifunctional protein deficiency (Supportive), mode of inheritance: AR
• long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (Supportive), mode of inheritance: AR
• long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (Definitive), mode of inheritance: AR
• long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (Strong), mode of inheritance: AR
• mitochondrial trifunctional protein deficiency (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency; Mitochondrial trifunctional protein deficiency 1	AR	Biochemical	Early diagnosis to allow interventions such as avoidance of fasting and urgent metabolic care in the setting of acute metabolic decompensation can reduce morbidity and mortality; Medical management (such as with triheptanoin) has been described as beneficial	Biochemical; Cardiovascular; Gastrointestinal; Musculoskeletal; Neurologic; Ophthalmologic	7813533; 7811722; 7846063; 8770876; 10518281; 12621125; 17143551; 21549624; 21103935; 21630065; 33744096
Variants are also related to maternal HELLP syndrome and Acute fatty liver of pregnancy

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the HADHA gene.

• Mitochondrial trifunctional protein deficiency;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (30 variants)
• Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency;Mitochondrial trifunctional protein deficiency (28 variants)
• Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (9 variants)
• not provided (7 variants)
• Mitochondrial trifunctional protein deficiency (5 variants)
• Inborn genetic diseases (2 variants)
• Mitochondrial trifunctional protein deficiency 1 (2 variants)
• not specified (1 variants)
• HADHA-related disorder (1 variants)
• LCHAD deficiency with maternal acute fatty liver of pregnancy (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HADHA gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	265	2	269
missense	1	11	145	9	3	169
nonsense	15	28	1			44
start loss		2				2
frameshift	40	57	1			98
inframe indel			7			7
splice donor/acceptor (+/-2bp)	9	32	1			42
splice region		1	11	42	3	57
non coding			22	195	46	263
Total	65	130	179	469	51

Highest pathogenic variant AF is 0.00101

Variants in HADHA

This is a list of pathogenic ClinVar variants found in the HADHA region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
2-26190664-C-T		Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency • Mitochondrial trifunctional protein deficiency	Uncertain significance (Jan 13, 2018)
2-26190689-G-A		Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency • Mitochondrial trifunctional protein deficiency	Benign (Jan 12, 2018)
2-26190740-T-A		Mitochondrial trifunctional protein deficiency • Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	Benign (Jan 12, 2018)
2-26190756-C-A		Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency • Mitochondrial trifunctional protein deficiency	Uncertain significance (Jan 13, 2018)
2-26190761-C-T		Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency • Mitochondrial trifunctional protein deficiency	Uncertain significance (Jan 13, 2018)
2-26190784-GCA-G		Mitochondrial trifunctional protein deficiency • Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	Uncertain significance (Jun 14, 2016)
2-26190813-A-T		Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency • Mitochondrial trifunctional protein deficiency	Uncertain significance (Mar 02, 2018)
2-26190845-G-A		Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency • Mitochondrial trifunctional protein deficiency	Uncertain significance (Jan 12, 2018)
2-26190847-G-A		Mitochondrial trifunctional protein deficiency • Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	Uncertain significance (Jan 12, 2018)
2-26190861-G-C		Mitochondrial trifunctional protein deficiency • Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	Uncertain significance (Jan 13, 2018)
2-26190873-GAC-G		Mitochondrial trifunctional protein deficiency • Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	Uncertain significance (Jun 14, 2016)
2-26190895-G-A		Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency • Mitochondrial trifunctional protein deficiency	Uncertain significance (Jan 13, 2018)
2-26190919-A-G		Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency • Mitochondrial trifunctional protein deficiency	Benign (Jan 13, 2018)
2-26190948-C-T		Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency • Mitochondrial trifunctional protein deficiency	Benign (Jun 19, 2018)
2-26191011-G-A		Mitochondrial trifunctional protein deficiency • Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	Uncertain significance (Apr 27, 2017)
2-26191048-C-T		Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency • Mitochondrial trifunctional protein deficiency	Benign (Jun 14, 2018)
2-26191068-G-A		Mitochondrial trifunctional protein deficiency • Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	Uncertain significance (Jan 13, 2018)
2-26191140-C-T		Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency • Mitochondrial trifunctional protein deficiency	Uncertain significance (Mar 30, 2018)
2-26191147-T-A		Mitochondrial trifunctional protein deficiency • Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	Uncertain significance (Apr 27, 2017)
2-26191191-G-A		Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency • Mitochondrial trifunctional protein deficiency	Uncertain significance (Jan 13, 2018)
2-26191204-C-T		Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency • Mitochondrial trifunctional protein deficiency	Uncertain significance (Apr 27, 2017)
2-26191251-C-T		Mitochondrial trifunctional protein deficiency;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	Likely benign (Jan 06, 2024)
2-26191253-C-T		Mitochondrial trifunctional protein deficiency;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	Likely benign (Jul 06, 2023)
2-26191256-G-A		Mitochondrial trifunctional protein deficiency;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	Likely benign (Jul 07, 2019)
2-26191259-G-A		Mitochondrial trifunctional protein deficiency;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	Likely benign (Aug 03, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HADHA	protein_coding	protein_coding	ENST00000380649	20	54091

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00000444	1.00	125668	0	80	125748	0.000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.821	355	401	0.885	0.0000218	4942
Missense in Polyphen		119	163.63	0.72726		2019
Synonymous	-0.580	161	152	1.06	0.00000880	1532
Loss of Function	3.43	16	39.1	0.409	0.00000204	500

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000560	0.000560
Ashkenazi Jewish	0.00	0.00
East Asian	0.000272	0.000272
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.000378	0.000352
Middle Eastern	0.000272	0.000272
South Asian	0.000523	0.000523
Other	0.000326	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Bifunctional subunit.
• Disease: DISEASE: Mitochondrial trifunctional protein deficiency (MTPD) [MIM:609015]: A disease biochemically characterized by loss of all enzyme activities of the mitochondrial trifunctional protein complex. Variable clinical manifestations include hypoglycemia, cardiomyopathy, delayed psychomotor development, sensorimotor axonopathy, generalized weakness, hepatic dysfunction, respiratory failure. Sudden infant death may occur. Most patients die from heart failure. {ECO:0000269|PubMed:9739053}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Long-chain 3-hydroxyl-CoA dehydrogenase deficiency (LCHAD deficiency) [MIM:609016]: The clinical features are very similar to TFP deficiency. Biochemically, LCHAD deficiency is characterized by reduced long-chain 3-hydroxyl-CoA dehydrogenase activity, while the other enzyme activities of the TFP complex are normal or only slightly reduced. {ECO:0000269|PubMed:7811722, ECO:0000269|PubMed:9266371}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Maternal acute fatty liver of pregnancy (AFLP) [MIM:609016]: Severe maternal illness occurring during pregnancies with affected fetuses. This disease is associated with LCHAD deficiency and characterized by sudden unexplained infant death or hypoglycemia and abnormal liver enzymes (Reye-like syndrome). {ECO:0000269|PubMed:7846063}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Tryptophan metabolism - Homo sapiens (human);Butanoate metabolism - Homo sapiens (human);beta-Alanine metabolism - Homo sapiens (human);Lysine degradation - Homo sapiens (human);Propanoate metabolism - Homo sapiens (human);Biosynthesis of unsaturated fatty acids - Homo sapiens (human);Fatty acid degradation - Homo sapiens (human);Fatty acid elongation - Homo sapiens (human);Valine, leucine and isoleucine degradation - Homo sapiens (human);Long chain acyl-CoA dehydrogenase deficiency (LCAD);Trifunctional protein deficiency;Long-chain-3-hydroxyacyl-coa dehydrogenase deficiency (LCHAD);Carnitine palmitoyl transferase deficiency (II);Very-long-chain acyl coa dehydrogenase deficiency (VLCAD);Medium chain acyl-coa dehydrogenase deficiency (MCAD);Fatty Acid Elongation In Mitochondria;Short Chain Acyl CoA Dehydrogenase Deficiency (SCAD Deficiency);Fatty acid Metabolism;Valproic Acid Metabolism Pathway;Glutaric Aciduria Type I;Ethylmalonic Encephalopathy;Mitochondrial Beta-Oxidation of Medium Chain Saturated Fatty Acids;Mitochondrial Beta-Oxidation of Long Chain Saturated Fatty Acids;Carnitine palmitoyl transferase deficiency (I);Fatty Acid Beta Oxidation;Mitochondrial LC-Fatty Acid Beta-Oxidation;Valproic acid pathway;Liver steatosis AOP;Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways;Butanoate metabolism;Metabolism of lipids;Beta oxidation of myristoyl-CoA to lauroyl-CoA;Beta oxidation of decanoyl-CoA to octanoyl-CoA-CoA;Beta oxidation of octanoyl-CoA to hexanoyl-CoA;Beta oxidation of hexanoyl-CoA to butanoyl-CoA;mitochondrial fatty acid beta-oxidation of saturated fatty acids;Mitochondrial Fatty Acid Beta-Oxidation;3-oxo-10R-octadecatrienoate beta-oxidation;Leukotriene metabolism;Saturated fatty acids beta-oxidation;Trihydroxycoprostanoyl-CoA beta-oxidation;Metabolism;Lysine degradation;Fatty acid metabolism;Acyl chain remodeling of CL;Propanoate metabolism;valine degradation;Mono-unsaturated fatty acid beta-oxidation;Omega-6 fatty acid metabolism;Valine, leucine and isoleucine degradation;Butanoate metabolism;Propanoate metabolism;Dimethyl-branched-chain fatty acid mitochondrial beta-oxidation;Di-unsaturated fatty acid beta-oxidation;Vitamin E metabolism;isoleucine degradation;Beta oxidation of palmitoyl-CoA to myristoyl-CoA;Tryptophan degradation;Beta oxidation of lauroyl-CoA to decanoyl-CoA-CoA;Glycerophospholipid biosynthesis;Phospholipid metabolism;Valine Leucine Isoleucine degradation (Consensus)

Recessive Scores

• pRec: 0.516

Intolerance Scores

• loftool: 0.347
• rvis_EVS: -0.64
• rvis_percentile_EVS: 16.63

Haploinsufficiency Scores

• pHI: 0.0614
• hipred: N
• hipred_score: 0.426
• ghis: 0.603

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.958

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Hadha
• Phenotype: renal/urinary system phenotype; liver/biliary system phenotype; embryo phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); growth/size/body region phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); muscle phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: fatty acid beta-oxidation;response to insulin;response to drug
• Cellular component: mitochondrion;mitochondrial inner membrane;mitochondrial fatty acid beta-oxidation multienzyme complex;mitochondrial nucleoid
• Molecular function: fatty-acyl-CoA binding;3-hydroxyacyl-CoA dehydrogenase activity;acetyl-CoA C-acetyltransferase activity;enoyl-CoA hydratase activity;protein binding;long-chain-enoyl-CoA hydratase activity;long-chain-3-hydroxyacyl-CoA dehydrogenase activity;protein-containing complex binding;NAD binding