HIBADH

protein-coding

3-hydroxyisobutyrate dehydrogenase

Gene summary

This gene encodes a mitochondrial 3-hydroxyisobutyrate dehydrogenase enzyme. The encoded protein plays a critical role in the catabolism of L-valine by catalyzing the oxidation of 3-hydroxyisobutyrate to methylmalonate semialdehyde. [provided by RefSeq, Nov 2011]

MANE transcript

NM_152740.4

Inheritance

ClinVar variants

U:52B:2

Top phenotype

HIBADH-related disorder

gnomAD constraint

pLI —, LoF o/e 0.42

Max pathogenic AF

—

Genomic locus

chr7:27,525,442-27,662,883

External References & Databases

Ensembl (ENSG00000106049)

Transcript & Mutation Effects

hg38 • Region Span ~137.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

3-hydroxyisobutyric aciduriaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0009371

Submitter: PanelApp Australia

3-hydroxyisobutyric aciduriaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0009371

Submitter: ClinGen

*HIBADH* was first reported in relation to autosomal recessive 3-Hydroxyisobutyrate dehydrogenase deficiency and 3-hydroxyisobutyric aciduria in 2021 by Meyer et al., PMID:34176136. At least three unique variants (missense and frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes both case-level data and experimental data. Variants in this gene have been reported in at least 3 probands in 2 publications (PMIDs:34176136, 35174513). Patient symptoms ranged from delayed psychomotor and speech development to apparently asymptomatic. No supporting segregation information is available. The disease mechanism appears to be biallelic loss-of-function, with a deficiency in HIBADH leading to an increase in 3-hydroxyisobutyric acid, a metabolite produced from the multi-step catabolism of Valine and potentially the phenotypes seen in conjunction with the biochemical abnormality. This gene-disease relationship is supported by the biochemical function of 3-Hydroxyisobutyrate dehydrogenase, an enzyme responsible for the conversion of 3-hydroxyisobutyrate to methylmalonate semialdehyde. Biallelic variants in *ALDH6A1* encoding for methylmalonate semialdehyde dehydrogenase (MMSDH) are also associated with 3-hydroxyisobutyric aciduria, with patients presenting with phenotypes ranging from severe developmental delay to virtually asymptomatic (Limited Classification 10/14/2022). In summary, there is limited evidence to support this gene-disease relationship. In affected individuals, a low valine diet may improve phenotypes such as developmental delay, however there is insufficient evidence at this time to determine if the clinicla phenotypes observed in these patients are related to the 3-Hydroxyisobutyrate dehydrogenase deficiency. Although more evidence, genetic and experimental, is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. A classification of limited was approved by the ClinGen Aminoacidopathy GCEP on 3/24/2023 (SOP Version 9).

inborn organic aciduriaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0000688

Submitter: Ambry Genetics

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HIBADH variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 41

not providedTotal: 3

HIBADH-related disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_152740.4. 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			2 clinvar			2
missense			43 clinvar	2 clinvar		45
nonsense						0
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)			5 clinvar			5
Total	0	0	52	2	0	54

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 76 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_152740.4	RefSeq	NP_689953.1	8	MANE Select
ENST00000265395.7	Ensembl	ENSP00000265395.2	8	MANE Select
NM_001430749.1	RefSeq	NP_001417678.1	6	Standard
ENST00000425715.1	Ensembl	ENSP00000390205.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Valine, leucine and isoleucine degradation - Homo sapiens (human)
3-Methylglutaconic Aciduria Type I
Valine, Leucine and Isoleucine Degradation
2-Methyl-3-Hydroxybutryl CoA Dehydrogenase Deficiency
Isovaleric Aciduria

Biological Process

valine catabolic process
branched-chain amino acid catabolic process
oxidation-reduction process

Molecular Function

3-hydroxyisobutyrate dehydrogenase activity
oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor
NADP binding
NAD binding

Cellular Component

mitochondrion
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000265395
Coding exons: 8
Length: 137554
Individuals with no LoFs: 125729
Homozygous LoFs: 0
Heterozygous LoFs: 17
Defined: 125746
p: 0.0000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.131	167	172	0.972	0.00000833	2156
Missense (PolyPhen)		46	65.601	0.70121		779
Synonymous	-0.499	67	62.0	1.08	0.00000321	681
Loss of Function	2.02	6	14.2	0.422	6.94e-7	195

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000054	0.000053	rare
South Asian	0.00013	0.00013	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Recessive Scores

pRec: 0.290

Intolerance Scores

LoFtool: 0.572
RVIS EVS: -0.43
RVIS percentile EVS: 25.15

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.997

Gene Damage Prediction

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