HADHB

Chr 2AR

hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit beta

Also known as: ECHB, MSTP029, MTPB, MTPD, MTPD2, TP-BETA

NCBI Gene: 3032 ENSG00000138029 UniProt: P55084 OMIM: 143450

The beta subunit of mitochondrial trifunctional protein catalyzes 3-ketoacyl-CoA thiolase activity in the final three steps of long-chain fatty acid beta-oxidation and also functions as an RNA-binding protein that destabilizes certain mRNAs. Autosomal recessive mutations cause mitochondrial trifunctional protein deficiency, a disorder of fatty acid oxidation. The pathogenic mechanism involves dominant-negative effects where mutant protein disrupts normal enzyme function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 1.041 OMIM phenotype

Clinical Summary— HADHB

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Gene-Disease Validity (ClinGen)

mitochondrial trifunctional protein deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

111 unique Pathogenic / Likely Pathogenic· 164 VUS of 651 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — HADHB

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.04LOEUF

pLI 0.000

Z-score 1.39

OE 0.72 (0.51–1.04)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.65Z-score

OE missense 0.89 (0.80–0.99)

234 obs / 263.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.72 (0.51–1.04)

0≤0.351.4

Missense OE?0.89 (0.80–0.99)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 21 / 29.1Missense obs/exp: 234 / 263.7Syn Z: 0.39

This gene — mechanism propensity

0.73top 25%

GOF

0.6051th %ile

LOF

0.4135th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

LOF63% of P/LP variants are LoF

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

651 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic46

Likely Pathogenic65

VUS164

Likely Benign292

Benign36

Conflicting20

Pathogenic

Likely Pathogenic

164

VUS

292

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	28	6	12	0	46
Likely Pathogenic	42	19	4	0	65
VUS	2	140	21	1	164
Likely Benign	0	2	156	134	292
Benign	0	2	30	4	36
Conflicting	—				20
Total	72	169	223	139	623

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

17 pathogenic / likely-pathogenic (of 26) ClinVar copy-number / structural variants overlap HADHB — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →