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…

LOFmechanismARLOEUF 1.191 OMIM phenotype

Clinical Summary— HIBCH

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Gene-Disease Validity (ClinGen)

Leigh syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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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

44 unique Pathogenic / Likely Pathogenic· 92 VUS of 293 total submissions

Explore recent and relevant literature in Research Assistant →

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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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveHIBCH-related 3-hydroxyisobutryl-CoA hydrolase deficiencyLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.7227th %ile

GOF

0.5367th %ile

LOF

0.2872th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

293 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic10

Likely Pathogenic34

VUS92

Likely Benign93

Benign33

Conflicting11

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	6	1	3	0	10
Likely Pathogenic	16	16	2	0	34
VUS	3	80	4	5	92
Likely Benign	0	5	57	31	93
Benign	0	4	29	0	33
Conflicting	—				11
Total	25	106	95	36	273

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

View in ClinVar →

28 pathogenic / likely-pathogenic (of 30) ClinVar copy-number / structural variants overlap HIBCH — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →