HIBCH

Chr 2AR

3-hydroxyisobutyryl-CoA hydrolase

Also known as: HIBYLCOAH

NCBI Gene: 26275ENSG00000198130UniProt: Q6NVY1

This gene encodes the enzyme responsible for hydrolysis of both HIBYL-CoA and beta-hydroxypropionyl-CoA. Mutations in this gene have been associated with 3-hyroxyisobutyryl-CoA hydrolase deficiency. Alternative splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

Primary Disease Associations & Inheritance

3-hydroxyisobutryl-CoA hydrolase deficiencyMIM #250620
AR
322
ClinVar variants
52
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— HIBCH
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
52 Pathogenic / Likely Pathogenic· 94 VUS of 322 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.19LOEUF
pLI 0.000
Z-score 0.81
OE 0.83 (0.59–1.19)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.29Z-score
OE missense 0.94 (0.83–1.06)
188 obs / 199.7 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.83 (0.59–1.19)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.94 (0.83–1.06)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.93
0≤1.21.6
LoF obs/exp: 22 / 26.5Missense obs/exp: 188 / 199.7Syn Z: 0.46

ClinVar Variant Classifications

322 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic22
Likely Pathogenic30
VUS94
Likely Benign93
Benign33
Conflicting8
22
Pathogenic
30
Likely Pathogenic
94
VUS
93
Likely Benign
33
Benign
8
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
0
21
0
22
Likely Pathogenic
11
12
7
0
30
VUS
2
80
7
5
94
Likely Benign
0
5
57
31
93
Benign
0
4
29
0
33
Conflicting
—8
Total1410112136280

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

View in ClinVar →

Protein Context — Lollipop Plot

HIBCH · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

HIBCH-related 3-hydroxyisobutryl-CoA hydrolase deficiency

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

3-hydroxyisobutryl-CoA hydrolase deficiency

MIM #250620

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders.
Reuter MS et al.·JAMA Psychiatry
2017
Delineating the neurological phenotype in children with defects in the ECHS1 or HIBCH gene.
Marti-Sanchez L et al.·J Inherit Metab Dis
2021
Mitochondrial dysfunction and onset of type 2 diabetes along with its complications: a multi-omics Mendelian randomization and colocalization study.
Li Y et al.·Front Endocrinol (Lausanne)
2024
Truncating mutations of HIBCH tend to cause severe phenotypes in cases with HIBCH deficiency: a case report and brief literature review.
Tan H et al.·J Hum Genet
2018Case report
Movement disorders in valine métabolism diseases caused by HIBCH and ECHS1 deficiencies.
François-Heude MC et al.·Eur J Neurol
2022
A movement disorder with dystonia and ataxia caused by a mutation in the HIBCH gene.
Schottmann G et al.·Mov Disord
2016
Systematic Mendelian randomization of the human plasma proteome to identify therapeutic targets linking aging and frailty to perioperative delirium.
Tang J et al.·J Affect Disord
2025
Successful diagnosis of HIBCH deficiency from exome sequencing and positive retrospective analysis of newborn screening cards in two siblings presenting with Leigh's disease.
Stiles AR et al.·Mol Genet Metab
2015Case report
A Common Polymorphism in HIBCH Influences Methylmalonic Acid Concentrations in Blood Independently of Cobalamin.
Molloy AM et al.·Am J Hum Genet
2016
Paroxysmal Dyskinesias Revealing 3-Hydroxy-Isobutyryl-CoA Hydrolase (HIBCH) Deficiency.
Spitz MA et al.·Neuropediatrics
2021
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Lethal neonatal acidosis: Multiomic investigation of a novel HIBCH variant as the underlying cause.
Patel S et al.·Mol Genet Metab Rep
2025🔓 Open Access
Ectopic protein lysine methacrylation contributes to defects caused by loss of HIBCH or ECHS1.
Li Y et al.·Cell Rep
2025
Identification of HIBCH and MGME1 as Mitochondrial Dynamics-Related Biomarkers in Alzheimer's Disease Via Integrated Bioinformatics Analysis.
Li H et al.·IET Syst Biol
2025🔓 Open Access
Novel lipid metabolism factor HIBCH inhibitor synergizes with doxorubicin to suppress osteosarcoma growth and impacts clinical prognosis in osteosarcoma patients.
Yuan X et al.·J Bone Oncol
2024🔓 Open AccessCohort
Two genetic variants in the HIBCH and FTCDNL1 genes are associated with susceptibility to developmental dysplasia of the hips among the Han Chinese population of Southwest China.
Meng XH et al.·J Orthop Surg Res
2024🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools