HADH

hydroxyacyl-CoA dehydrogenase

Basic information

Region (hg38): 4:107989713-108035241

Previous symbols: [ "HADHSC" ]

Links

ENSG00000138796 ∙ NCBI:3033 ∙ OMIM:601609 ∙ HGNC:4799 ∙ Uniprot:Q16836 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hyperinsulinism due to short chain 3-hydroxylacyl-CoA dehydrogenase deficiency (Supportive), mode of inheritance: AR
• hyperinsulinism due to short chain 3-hydroxylacyl-CoA dehydrogenase deficiency (Definitive), mode of inheritance: AR
• 3-hydroxyacyl-CoA dehydrogenase deficiency (Definitive), mode of inheritance: AR
• hyperinsulinism due to short chain 3-hydroxylacyl-CoA dehydrogenase deficiency (Strong), mode of inheritance: AR
• hyperinsulinemic hypoglycemia, familial, 4 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
3-hydroxyacyl-CoA dehydrogenase deficiency; Hyperinsulinemic hypoglycemia, familial, 4	AR	Cardiovascular; Endocrine; Gastrointestinal	Individuals may present with hypoglycemic seizures, which can lead to neurologic sequelae, and measures to treat/prevent hypoglycemia (eg, with diazoxide) can be effective; In the longer-term, medical and/or surgical treatment (eg, with pancreatectomy, glucagon) may help prevent severe sequelae; In 3-hydroxyacyl-CoA dehydrogenase deficiency, surveillance for cardiovascular manifestations (eg, cardiomyopathy) may allow prompt management; Liver transplant has been described	Biochemical; Endocrine; Gastrointestinal	4193973; 904979; 1835339; 10347277; 10931422; 11489939; 12400064; 14693719; 15870679; 16725361; 19417036; 19318379; 20301549; 21347589; 23273570

ClinVar

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

• Deficiency of 3-hydroxyacyl-CoA dehydrogenase (191 variants)
• Hyperinsulinemic hypoglycemia (71 variants)
• Hyperinsulinemic hypoglycemia, familial, 4 (55 variants)
• not provided (51 variants)
• not specified (14 variants)
• Inborn genetic diseases (13 variants)
• Monogenic diabetes (9 variants)
• Hyperinsulinism, Dominant/Recessive (4 variants)
• Deficiency of 3-hydroxyacyl-CoA dehydrogenase;Hyperinsulinemic hypoglycemia, familial, 4 (4 variants)
• Abnormal brain morphology (1 variants)
• Hyperinsulinemic hypoglycemia, familial, 1 (1 variants)
• Hyperinsulinemic hypoglycemia, familial, 4;Deficiency of 3-hydroxyacyl-CoA dehydrogenase (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HADH 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				34		34
missense		4	48	3	1	56
nonsense		2	1			3
start loss						0
frameshift	2	3				5
inframe indel			2			2
splice donor/acceptor (+/-2bp)	1	5				6
splice region		1	1	7	1	10
non coding			5	43	19	67
Total	3	14	56	80	20

Highest pathogenic variant AF is 0.000112

Variants in HADH

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

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

Position	Type	Phenotype	Significance	ClinVar
4-107989730-A-G		Deficiency of 3-hydroxyacyl-CoA dehydrogenase • Hyperinsulinemic hypoglycemia, familial, 4 • Hyperinsulinemic hypoglycemia	Conflicting classifications of pathogenicity (Apr 27, 2017)
4-107989738-A-C		Deficiency of 3-hydroxyacyl-CoA dehydrogenase • Hyperinsulinemic hypoglycemia, familial, 4	Uncertain significance (Jan 13, 2018)
4-107989738-A-G		Hyperinsulinemic hypoglycemia, familial, 4 • Deficiency of 3-hydroxyacyl-CoA dehydrogenase	Uncertain significance (Jan 13, 2018)
4-107989738-A-T		Hyperinsulinemic hypoglycemia	Likely benign (-)
4-107989740-G-A		Hyperinsulinemic hypoglycemia, familial, 4 • Deficiency of 3-hydroxyacyl-CoA dehydrogenase	Benign/Likely benign (Sep 22, 2018)
4-107989740-G-T		Hyperinsulinemic hypoglycemia	Likely benign (-)
4-107989817-CG-C		Hyperinsulinism, Dominant/Recessive • Deficiency of 3-hydroxyacyl-CoA dehydrogenase • Hyperinsulinemic hypoglycemia, familial, 4;Deficiency of 3-hydroxyacyl-CoA dehydrogenase • Hyperinsulinemic hypoglycemia	Uncertain significance/Uncertain risk allele (Jan 12, 2022)
4-107989821-C-T			Likely benign (Oct 01, 2023)
4-107989827-G-A			Likely benign (Oct 01, 2022)
4-107989831-G-A		Deficiency of 3-hydroxyacyl-CoA dehydrogenase • Hyperinsulinemic hypoglycemia, familial, 4 • Hyperinsulinemic hypoglycemia	Conflicting classifications of pathogenicity (Oct 01, 2022)
4-107989847-G-T		Hyperinsulinemic hypoglycemia, familial, 4 • Deficiency of 3-hydroxyacyl-CoA dehydrogenase • Hyperinsulinemic hypoglycemia	Conflicting classifications of pathogenicity (Jan 13, 2018)
4-107989862-C-T		Hyperinsulinemic hypoglycemia, familial, 4 • Deficiency of 3-hydroxyacyl-CoA dehydrogenase • Hyperinsulinemic hypoglycemia	Benign/Likely benign (Jan 12, 2018)
4-107989868-G-A		Hyperinsulinemic hypoglycemia, familial, 4 • Deficiency of 3-hydroxyacyl-CoA dehydrogenase • Hyperinsulinemic hypoglycemia	Benign/Likely benign (Nov 08, 2018)
4-107989877-C-A		Deficiency of 3-hydroxyacyl-CoA dehydrogenase • Hyperinsulinemic hypoglycemia, familial, 4 • Hyperinsulinemic hypoglycemia	Conflicting classifications of pathogenicity (Jan 13, 2018)
4-107989881-TC-T		Hyperinsulinism, Dominant/Recessive • Deficiency of 3-hydroxyacyl-CoA dehydrogenase • not specified • Hyperinsulinemic hypoglycemia	Uncertain significance/Uncertain risk allele (May 04, 2022)
4-107989895-T-C		Hyperinsulinemic hypoglycemia, familial, 4 • Deficiency of 3-hydroxyacyl-CoA dehydrogenase • Hyperinsulinemic hypoglycemia	Benign/Likely benign (Jan 13, 2018)
4-107989897-C-T		Deficiency of 3-hydroxyacyl-CoA dehydrogenase • Hyperinsulinemic hypoglycemia, familial, 4 • Hyperinsulinemic hypoglycemia	Conflicting classifications of pathogenicity (Jan 13, 2018)
4-107989899-C-T		Deficiency of 3-hydroxyacyl-CoA dehydrogenase • Hyperinsulinemic hypoglycemia, familial, 4 • Hyperinsulinemic hypoglycemia	Conflicting classifications of pathogenicity (Jan 12, 2018)
4-107989926-CCA-C		HADH-related disorder	Likely benign (Oct 25, 2021)
4-107989940-T-C		Deficiency of 3-hydroxyacyl-CoA dehydrogenase	Uncertain significance (Sep 27, 2021)
4-107989947-C-T		HADH-related disorder	Likely benign (Sep 10, 2021)
4-107989950-G-A		Deficiency of 3-hydroxyacyl-CoA dehydrogenase	Likely benign (Jan 09, 2024)
4-107989953-G-A		Hyperinsulinemic hypoglycemia, familial, 4 • Deficiency of 3-hydroxyacyl-CoA dehydrogenase • Hyperinsulinemic hypoglycemia	Conflicting classifications of pathogenicity (Jan 13, 2018)
4-107989960-C-T		Inborn genetic diseases	Uncertain significance (Feb 01, 2023)
4-107989964-C-T		Deficiency of 3-hydroxyacyl-CoA dehydrogenase	Uncertain significance (Feb 14, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HADH	protein_coding	protein_coding	ENST00000603302	9	45462

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0000656	0.912	125728	0	20	125748	0.0000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.528	163	183	0.890	0.00000981	2175
Missense in Polyphen		40	61.125	0.6544		739
Synonymous	-0.350	79	75.1	1.05	0.00000465	648
Loss of Function	1.57	9	15.7	0.572	8.57e-7	184

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000440	0.000423
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.0000703	0.0000703
Middle Eastern	0.0000544	0.0000544
South Asian	0.0000329	0.0000327
Other	0.000176	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Plays an essential role in the mitochondrial beta- oxidation of short chain fatty acids. Exerts it highest activity toward 3-hydroxybutyryl-CoA.
• Disease: DISEASE: 3-alpha-hydroxyacyl-CoA dehydrogenase deficiency (HADH deficiency) [MIM:231530]: An autosomal recessive, metabolic disorder with various clinical presentations including hypoglycemia, hepatoencephalopathy, myopathy or cardiomyopathy, and in some cases sudden death. {ECO:0000269|Ref.13}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Familial hyperinsulinemic hypoglycemia 4 (HHF4) [MIM:609975]: Most common cause of persistent hypoglycemia in infancy. Unless early and aggressive intervention is undertaken, brain damage from recurrent episodes of hypoglycemia may occur. HHF4 should be easily recognizable by analysis of acylcarnitine species and that this disorder responds well to treatment with diazoxide. It provides the first 'experiment of nature' that links impaired fatty acid oxidation to hyperinsulinism and that provides support for the concept that a lipid signaling pathway is implicated in the control of insulin secretion. {ECO:0000269|PubMed:11489939}. 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);Lysine degradation - Homo sapiens (human);Fatty acid degradation - Homo sapiens (human);Fatty acid elongation - Homo sapiens (human);Valine, leucine and isoleucine degradation - Homo sapiens (human);Lysine Degradation;Hyperlysinemia I, Familial;2-aminoadipic 2-oxoadipic aciduria;Pyridoxine dependency with seizures;Saccharopinuria/Hyperlysinemia II;Glutaric Aciduria Type I;Mitochondrial Beta-Oxidation of Short Chain Saturated Fatty Acids;Mitochondrial Beta-Oxidation of Medium Chain Saturated Fatty Acids;Mitochondrial Beta-Oxidation of Long Chain Saturated Fatty Acids;Short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (SCHAD);Hyperlysinemia II or Saccharopinuria;Butyrate Metabolism;Fatty Acid Beta Oxidation;Fatty Acid Biosynthesis;Mitochondrial LC-Fatty Acid Beta-Oxidation;Amino Acid metabolism;Liver steatosis AOP;Tryptophan metabolism;Butanoate metabolism;Metabolism of lipids;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;Beta oxidation of butanoyl-CoA to acetyl-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;Mono-unsaturated fatty acid beta-oxidation;Omega-6 fatty acid metabolism;Valine, leucine and isoleucine degradation;Dimethyl-branched-chain fatty acid mitochondrial beta-oxidation;Di-unsaturated fatty acid beta-oxidation;Vitamin E metabolism;fatty acid β-oxidation (peroxisome);fatty acid β-oxidation;Tryptophan degradation;Beta oxidation of lauroyl-CoA to decanoyl-CoA-CoA;Valine Leucine Isoleucine degradation;FOXA2 and FOXA3 transcription factor networks (Consensus)

Recessive Scores

• pRec: 0.314

Intolerance Scores

• loftool: 0.312
• rvis_EVS: 0.82
• rvis_percentile_EVS: 87.95

Haploinsufficiency Scores

• pHI: 0.0766
• hipred: N
• hipred_score: 0.352
• ghis: 0.431

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.896

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Hadh
• Phenotype: renal/urinary system 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); endocrine/exocrine gland phenotype; cellular phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: fatty acid beta-oxidation;response to activity;response to insulin;response to drug;negative regulation of insulin secretion;positive regulation of cold-induced thermogenesis
• Cellular component: nucleoplasm;cytoplasm;mitochondrion;mitochondrial matrix
• Molecular function: 3-hydroxyacyl-CoA dehydrogenase activity;NAD+ binding