HIBCH

protein-coding

3-hydroxyisobutyryl-CoA hydrolase

Gene summary

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]

MANE transcript

NM_014362.4

Inheritance

ClinVar variants

P:54U:106B:45

Top phenotype

3-hydroxyisobutryl-CoA hydrolase deficiency

gnomAD constraint

pLI —, LoF o/e 0.83

Max pathogenic AF

—

Genomic locus

chr2:190,189,735-190,344,193

External References & Databases

Ensembl (ENSG00000198130)

Transcript & Mutation Effects

hg38 • Region Span ~154.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

3-hydroxyisobutyryl-CoA hydrolase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009603

Submitter: Ambry Genetics

3-hydroxyisobutyryl-CoA hydrolase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009603

Submitter: PanelApp Australia

Leigh syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between HIBCH and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of April 14, 2021. The HIBCH gene encodes 3-hydroxyisobutyryl-CoA hydrolase which is a mitochondrial enzyme with a critical role in valine catabolism and propionate metabolism. In the valine catabolic pathway, HIBCH converts 3-hydroxyisobutyryl-CoA to free 3-hydroxyisobutyrate and 3-hydroxypropionyl-CoA to 3-hydroxypropionate. Methacrylyl-CoA and acryloyl-CoA are the metabolites converted to 3-hydroxyisobutyryl-CoA and 3-hydroxypropionyl-CoA, respectively, by the enzyme short-chain enoyl-CoA hydratase, SCEH, encoded by ECHS1 in the step immediately before HIBCH. ECHS1 variants are also associated with autosomal recessive Leigh syndrome spectrum. The exact disease mechanism has not been fully elucidated, but elevated levels of methacrylyl-CoA and acryloyl-CoA are toxic, postulated to react with exposed thiol groups and thus impair the function of multiple mitochondrial enzymes including components of the pyruvate dehydrogenase complex and the oxidative phosphorylation complexes (PMID: 24299452). The HIBCH gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2007 (PMID: 17160907). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 13 variants in 12 cases from 8 publications (PMIDs: 31523596, 32022391, 24299452, 17160907, 32677093, 26163321, 25251209, 25591832). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by known biochemical function, expression, functional alterations in patient cells, and model organisms (PMIDs: 27977873, 25613900, 27400804, 31127358). In summary, there is definitive evidence to support this gene-disease relationship, including that more than three years have elapsed from the first proposal of the association. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on April 14, 2021 (SOP Version 7).

3-hydroxyisobutyryl-CoA hydrolase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009603

Submitter: Labcorp Genetics (formerly Invitae)

3-hydroxyisobutyryl-CoA hydrolase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009603

Submitter: G2P

3-hydroxyisobutyryl-CoA hydrolase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009603

Submitter: Orphanet

3-hydroxyisobutyryl-CoA hydrolase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009603

Submitter: ClinGen

The relationship between HIBCH and 3-hydroxyisobutyryl-CoA hydrolase deficiency (Autosomal recessive) was evaluated using the ClinGen Clinical Validity Framework as of 09/12/19. Variants in HIBCH were first reported in humans with this disease as early as 2007 (Loupatty et al., PMID: 17160907). At least 12 variants (e.g. missense, frameshift, and splice-site) have been reported in humans. Evidence supporting this gene-disease relationship includes predominantly case-level data with some experimental data. Variants in this gene have been reported in at least 8 probands in 7 publications (24299452, 30847210, 17160907, 26163321, 26026795, 29703962, 27896122). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is homozygous loss of function, with the loss of HIBCH causing Methacrylyl-CoA and its conjugates to build up in the brain and other tissues and disrupt mitochondrial function. This gene-disease association is also supported by two pieces of biochemical function evidence, but with no models or functional evidence being available. In summary, HIBCH is definitively associated with autosomal recessive 3-hydroxyisobutyryl-CoA hydrolase deficiency. Although there is the maximum amount of genetic evidence, further experimental evidence would be valuable to better understand this gene-disease relationship.

3-hydroxyisobutyryl-CoA hydrolase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009603

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

3-hydroxyisobutryl-CoA hydrolase deficiencyAR

Manifestation: Biochemical;Neurologic

Intervention: Biochemical

Rationale: Dietary measures (eg, low-protein, high carbohydrate) especially in ketosis, as well as medical treatment (eg, carnitine) may be beneficial)

Refs: 7122152; 17160907; 24299452; 26026795; 26163321

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HIBCH variants in ClinVar

9 Conditions Cataloged

3-hydroxyisobutyryl-CoA hydrolase deficiencyTotal: 183

not providedTotal: 69

Inborn genetic diseasesTotal: 43

not specifiedTotal: 41

HIBCH-related disorderTotal: 13

HIBCH-related disordersTotal: 8

See casesTotal: 5

Mitochondrial diseaseTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014362.4. 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			7 clinvar	35 clinvar		42
missense	2 clinvar	19 clinvar	88 clinvar	8 clinvar	2 clinvar	119
nonsense	4 clinvar	5 clinvar	2 clinvar			11
start loss			2 clinvar			2
frameshift	1 clinvar	12 clinvar	1 clinvar			14
splice donor/acceptor (+/-2bp)	1 clinvar	10 clinvar	6 clinvar			17
Total	8	46	106	43	2	205

Highest pathogenic variant AF is 0.00004491006

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 59 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014362.4	RefSeq	NP_055177.2	14	MANE Select
ENST00000359678.10	Ensembl	ENSP00000352706.5	14	MANE Select
NM_198047.3	RefSeq	NP_932164.1	13	Standard
ENST00000392332.7	Ensembl	ENSP00000376144.3	13	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

beta-Alanine metabolism - Homo sapiens (human)
Propanoate metabolism - Homo sapiens (human)
Valine, leucine and isoleucine degradation - Homo sapiens (human)
3-Methylglutaconic Aciduria Type I
Valine, Leucine and Isoleucine Degradation

Biological Process

valine catabolic process
fatty acid beta-oxidation
branched-chain amino acid catabolic process

Molecular Function

3-hydroxyisobutyryl-CoA hydrolase activity

Cellular Component

mitochondrion
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000359678
Coding exons: 14
Length: 154459
Individuals with no LoFs: 125692
Homozygous LoFs: 0
Heterozygous LoFs: 53
Defined: 125745
p: 0.000211

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.293	188	200	0.942	0.00000934	2535
Missense (PolyPhen)		48	61.907	0.77536		746
Synonymous	0.463	62	66.8	0.928	0.00000323	693
Loss of Function	0.808	22	26.5	0.831	0.00000135	313

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00050	0.00049	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.00011	0.00011	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00022	0.00022	rare
South Asian	0.00033	0.00033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Hydrolyzes 3-hydroxyisobutyryl-CoA (HIBYL-CoA), a saline catabolite. Has high activity toward isobutyryl-CoA. Could be an isobutyryl-CoA dehydrogenase that functions in valine catabolism. Also hydrolyzes 3-hydroxypropanoyl-CoA. {ECO:0000269|PubMed:8824301}.;

Recessive Scores

pRec: 0.180

Intolerance Scores

LoFtool: 0.955
RVIS EVS: 0.75
RVIS percentile EVS: 86.57

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.992

Gene Damage Prediction

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