HADHB

protein-coding

hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit beta

Gene summary

This gene encodes the beta subunit of the mitochondrial trifunctional protein, which catalyzes the last three steps of mitochondrial beta-oxidation of long chain fatty acids. The mitochondrial membrane-bound heterocomplex is composed of four alpha and four beta subunits, with the beta subunit catalyzing the 3-ketoacyl-CoA thiolase activity. The encoded protein can also bind RNA and decreases the stability of some mRNAs. The genes of the alpha and beta subunits of the mitochondrial trifunctional protein are located adjacent to each other in the human genome in a head-to-head orientation. Mutations in this gene result in trifunctional protein deficiency. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2013]

MANE transcript

NM_000183.3

Inheritance

ClinVar variants

P:115U:159B:142

Top phenotype

Mitochondrial trifunctional protein deficiency 2

gnomAD constraint

pLI —, LoF o/e 0.72

Max pathogenic AF

—

Genomic locus

chr2:26,243,170-26,290,465

External References & Databases

Ensembl (ENSG00000138029)

Transcript & Mutation Effects

hg38 • Region Span ~47.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial trifunctional protein deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012172

Submitter: Orphanet

mitochondrial trifunctional protein deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012172

Submitter: ClinGen

peripheral neuropathyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0005244

Submitter: LiferaOmics

Genetic evidence – Published: PMID: 24314034 – Reports a patient with early-onset axonal sensorimotor neuropathy due to compound heterozygous HADHB variants (missense and canonical splice; predicted LoF) in trans, with absence of systemic/metabolic features typical of classic mitochondrial trifunctional protein deficiency. Case-level (AR compound heterozygous; evaluate each allele independently: missense = non-LOF, splice = predicted LoF; combined proband score conservatively) = 1.6; segregation = 0; case-control = 0; PMID: 24314034 total = 1.6 PMID: 31130284 – One patient. Case-level (non-LOF missense in AR model; no consanguinity reported) = 0.1; segregation = 0; case-control = 0; PMID: 31130284 total = 0.1 PMID: 30682426 – One Case-level (non-LOF missense in AR model; no consanguinity reported) = 1.0; segregation = 0; case-control = 0; PMID: 30682426 total = 0.1 Published genetic evidence total = 1.8/12 Genetic evidence – Our cases: Family 1 – one proband. Case-level (non-LOF missense in AR model) = 0.1; segregation = 0; case-control = 0; Family 1 total = 0.1 Family 2 – one proband Case-level (non-LOF missense in AR model) = 0.1; segregation = 0; case-control = 0; Family 2 total = 0.1 Our cases total = 1.0/12 Total genetic evidence (published + our cases) 1.8 + 0.2 = 2.0/12 Experimental evidence – Published: None scored for the non-syndromic neuropathy phenotype at this time (no neuropathy-specific functional alteration, model, or rescue evidence meeting ClinGen experimental categories for this phenotype). Experimental evidence total = 0/6 Overall score = 2.0

mitochondrial trifunctional protein deficiency 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0958181

Submitter: PanelApp Australia

mitochondrial trifunctional protein deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012172

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Mitochondrial trifunctional protein deficiency 2AR

Manifestation: Biochemical; Cardiovascular; Gastrointestinal; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Biochemical

Rationale: 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

Comments: Variants are also related to maternal HELLP syndrome and Acute fatty liver of pregnancy

Refs: 8163672; 7738175; 8651282; 9259266; 12754706; 19699128; 21549624; 22000755; 21630065; 24664533; 33744096

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HADHB variants in ClinVar

15 Conditions Cataloged

Mitochondrial trifunctional protein deficiencyTotal: 475

not providedTotal: 113

Mitochondrial trifunctional protein deficiency 2Total: 44

not specifiedTotal: 43

Inborn genetic diseasesTotal: 40

HADHB-related disorderTotal: 27

Mitochondrial trifunctional protein deficiency 1Total: 21

HADHB-related disordersTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000183.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	136 clinvar	4 clinvar	142
missense	5 clinvar	33 clinvar	146 clinvar	2 clinvar		186
nonsense	10 clinvar	6 clinvar				16
start loss	2 clinvar					2
frameshift	14 clinvar	10 clinvar	1 clinvar			25
splice donor/acceptor (+/-2bp)	4 clinvar	31 clinvar	10 clinvar			45
Total	35	80	159	138	4	416

Highest pathogenic variant AF is 0.00018854727

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 133 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000183.3	RefSeq	NP_000174.1	15	MANE Select
ENST00000317799.10	Ensembl	ENSP00000325136.5	15	MANE Select
NM_001281512.2	RefSeq	NP_001268441.1	14	Standard
NM_001281513.2	RefSeq	NP_001268442.1	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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

Biological Process

fatty acid beta-oxidation

Molecular Function

RNA binding
3-hydroxyacyl-CoA dehydrogenase activity
acetyl-CoA C-acyltransferase activity
enoyl-CoA hydratase activity
protein binding

Cellular Component

mitochondrion
mitochondrial envelope
mitochondrial outer membrane
mitochondrial inner membrane
endoplasmic reticulum

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000317799
Coding exons: 15
Length: 47299
Individuals with no LoFs: 125685
Homozygous LoFs: 0
Heterozygous LoFs: 63
Defined: 125748
p: 0.000251

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.649	234	264	0.887	0.0000142	3071
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.00038	0.00038	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00033	0.00033	rare
Finnish	0.00023	0.00023	rare
European (Non-Finnish)	0.00026	0.00025	rare
South Asian	0.00020	0.00020	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec: 0.244

Intolerance Scores

LoFtool: 0.320
RVIS EVS: -0.54
RVIS percentile EVS: 20.54

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.986

Gene Damage Prediction

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