HIBCH

Chr 2AR

3-hydroxyisobutyryl-CoA hydrolase

Also known as: HIBYLCOAH

NCBI Gene: 26275 ENSG00000198130 UniProt: Q6NVY1 OMIM: 610690

The protein functions as a mitochondrial enzyme that hydrolyzes both 3-hydroxyisobutyryl-CoA and beta-hydroxypropionyl-CoA in the valine catabolic pathway. Mutations cause 3-hydroxyisobutyryl-CoA hydrolase deficiency, an autosomal recessive disorder of branched-chain amino acid metabolism. Disease results from loss of enzyme function leading to accumulation of toxic metabolites.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

3-hydroxyisobutryl-CoA hydrolase deficiencyMIM #250620

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.19

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — HIBCH

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

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?

0.29Z-score

OE missense 0.94 (0.83–1.06)

188 obs / 199.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.83 (0.59–1.19)

0≤0.351.4

Missense OE?0.94 (0.83–1.06)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 22 / 26.5Missense obs/exp: 188 / 199.7Syn Z: 0.46

Background carrier burden — how many people carry a rare variant somewhere in HIBCH?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 140

564 rare PASS variants

Rare truncating (LoF)

1 in 770

125 rare PASS variants

Rare synonymous (reference)

1 in 240

198 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for HIBCH. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 130	1 in 770
South Asian	~43k	1 in 68	1 in 810
Remaining (unassigned)	~30k	1 in 130	1 in 1,400
European (Finnish)	~27k	1 in 280	1 in 780
Admixed American	~22k	1 in 110	1 in 2,800
African / African American	~21k	1 in 100	1 in 670
East Asian	~20k	1 in 160	1 in 400
Ashkenazi Jewish	~13k	1 in 1,200	1 in 1,100
Middle Eastern	~2,884	1 in 180	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 9 of 14 coding exons well covered in gnomAD exomes; exons 5, 9, 10, 11, 14 marginal. Genomes: all 14.? see exons ↓