HADHB

hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit beta

Basic information

Region (hg38): 2:26243170-26290465

Links

ENSG00000138029 ∙ NCBI:3032 ∙ OMIM:143450 ∙ HGNC:4803 ∙ Uniprot:P55084 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• mitochondrial trifunctional protein deficiency (Strong), mode of inheritance: AR
• mitochondrial trifunctional protein deficiency (Strong), mode of inheritance: AR
• mitochondrial trifunctional protein deficiency (Supportive), mode of inheritance: AR
• mitochondrial trifunctional protein deficiency (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Mitochondrial trifunctional protein deficiency 2	AR	Biochemical	Early diagnosis to allow interventions such as avoidance of fasting and urgent metabolic care in the setting of acute metabolic decompensation may reduce morbidity and mortality	Biochemical; Cardiovascular; Gastrointestinal; Musculoskeletal; Neurologic; Ophthalmologic	8163672; 7738175; 8651282; 9259266; 12754706; 19699128; 21549624; 22000755; 21630065; 24664533; 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 HADHB gene.

• Mitochondrial trifunctional protein deficiency (28 variants)
• not provided (5 variants)
• Mitochondrial trifunctional protein deficiency 1 (4 variants)
• Mitochondrial trifunctional protein deficiency 2 with myopathy and neuropathy (1 variants)
• HADHB-related disorder (1 variants)
• Mitochondrial trifunctional protein deficiency 2 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HADHB 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				113	4	117
missense	4	19	113	2		138
nonsense	11	6				17
start loss	1					1
frameshift	9	7	1			17
inframe indel		1			2	3
splice donor/acceptor (+/-2bp)	4	25				29
splice region		1	8	21	4	34
non coding	1	1	12	121	26	161
Total	30	59	126	236	32

Highest pathogenic variant AF is 0.0000879

Variants in HADHB

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

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

Position	Type	Phenotype	Significance	ClinVar
2-26244479-C-A		Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	Benign (Jun 10, 2021)
2-26244512-C-A		Mitochondrial trifunctional protein deficiency;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	Likely benign (Jun 16, 2023)
2-26244512-C-T		Mitochondrial trifunctional protein deficiency;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	Likely benign (Jan 28, 2024)
2-26244513-C-G		not specified • Mitochondrial trifunctional protein deficiency;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	Conflicting classifications of pathogenicity (Jan 31, 2024)
2-26244514-C-G		Mitochondrial trifunctional protein deficiency;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	Likely benign (Aug 02, 2023)
2-26244516-C-T		Mitochondrial trifunctional protein deficiency;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	Likely benign (Jan 02, 2024)
2-26244517-G-C		Mitochondrial trifunctional protein deficiency;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	Likely benign (Jan 06, 2023)
2-26244521-A-G		Mitochondrial trifunctional protein deficiency;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	Likely benign (Jun 28, 2023)
2-26244527-C-T		Mitochondrial trifunctional protein deficiency;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency • Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	Uncertain significance (Aug 16, 2022)
2-26244529-C-T		Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	Likely pathogenic (Nov 29, 2021)
2-26244533-G-A		Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	Likely pathogenic (Feb 13, 2018)
2-26244534-G-A		Mitochondrial trifunctional protein deficiency;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	Likely benign (Jun 20, 2023)
2-26244540-G-C		Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency;Mitochondrial trifunctional protein deficiency	Likely benign (Dec 14, 2023)
2-26244541-A-C			Uncertain significance (Sep 03, 2019)
2-26244552-G-A		Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency;Mitochondrial trifunctional protein deficiency	Likely benign (Oct 15, 2023)
2-26244556-G-A		Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency • Inborn genetic diseases • Mitochondrial trifunctional protein deficiency;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	Conflicting classifications of pathogenicity (Oct 26, 2023)
2-26244561-G-T		Mitochondrial trifunctional protein deficiency;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	Likely benign (May 25, 2022)
2-26244564-G-A		Mitochondrial trifunctional protein deficiency;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	Likely benign (Sep 08, 2023)
2-26244567-G-C		Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency;Mitochondrial trifunctional protein deficiency	Likely benign (Aug 23, 2019)
2-26244567-G-T		Mitochondrial trifunctional protein deficiency;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	Likely benign (Nov 19, 2023)
2-26244568-A-G		Inborn genetic diseases	Uncertain significance (Sep 20, 2023)
2-26244570-G-A		Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency • Mitochondrial trifunctional protein deficiency • Mitochondrial trifunctional protein deficiency;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	Conflicting classifications of pathogenicity (Jan 25, 2024)
2-26244573-G-T		Mitochondrial trifunctional protein deficiency;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	Likely benign (Oct 06, 2021)
2-26244572-T-TGCCAATCGCCCGGCAGGCC		Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency;Mitochondrial trifunctional protein deficiency	Pathogenic (Dec 24, 2021)
2-26244580-G-A		Mitochondrial trifunctional protein deficiency;Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	Likely benign (Sep 10, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HADHB	protein_coding	protein_coding	ENST00000317799	15	47299

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.52e-11	0.565	125685	0	63	125748	0.000251

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.649	234	264	0.887	0.0000142	3071
Missense in Polyphen		91	111.7	0.8147		1336
Synonymous	0.387	88	92.7	0.949	0.00000493	941
Loss of Function	1.39	21	29.1	0.722	0.00000180	322

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000560	0.000560
Ashkenazi Jewish	0.00	0.00
East Asian	0.000326	0.000326
Finnish	0.000231	0.000231
European (Non-Finnish)	0.000255	0.000255
Middle Eastern	0.000326	0.000326
South Asian	0.000196	0.000196
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• 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:12754706, ECO:0000269|PubMed:8651282, ECO:0000269|PubMed:9259266}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: 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;Valproic acid pathway;Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways;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;Fatty acid metabolism;Acyl chain remodeling of CL;Propanoate metabolism;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;fatty acid β-oxidation (peroxisome);Beta oxidation of palmitoyl-CoA to myristoyl-CoA;fatty acid β-oxidation;Beta oxidation of lauroyl-CoA to decanoyl-CoA-CoA;Glycerophospholipid biosynthesis;Phospholipid metabolism;Valine Leucine Isoleucine degradation (Consensus)

Recessive Scores

• pRec: 0.244

Intolerance Scores

• loftool: 0.320
• rvis_EVS: -0.54
• rvis_percentile_EVS: 20.54

Haploinsufficiency Scores

• pHI: 0.0958
• hipred: N
• hipred_score: 0.229
• ghis: 0.579

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.986

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Hadhb
• Phenotype: muscle phenotype; homeostasis/metabolism phenotype; growth/size/body region phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); liver/biliary system 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); 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)

Gene ontology

• Biological process: fatty acid beta-oxidation
• Cellular component: mitochondrion;mitochondrial envelope;mitochondrial outer membrane;mitochondrial inner membrane;endoplasmic reticulum;mitochondrial nucleoid
• Molecular function: RNA binding;3-hydroxyacyl-CoA dehydrogenase activity;acetyl-CoA C-acyltransferase activity;enoyl-CoA hydratase activity;protein binding;long-chain-enoyl-CoA hydratase activity;long-chain-3-hydroxyacyl-CoA dehydrogenase activity