BCKDHB

protein-coding

branched chain keto acid dehydrogenase E1 subunit beta

Gene summary

This gene encodes the E1 beta subunit of branched-chain keto acid dehydrogenase, which is a multienzyme complex associated with the inner membrane of mitochondria. This enzyme complex functions in the catabolism of branched-chain amino acids. Mutations in this gene have been associated with maple syrup urine disease (MSUD), type 1B, a disease characterized by a maple syrup odor to the urine in addition to mental and physical retardation and feeding problems. Alternative splicing at this locus results in multiple transcript variants. [provided by RefSeq, Jan 2016]

MANE transcript

NM_183050.4

Inheritance

ClinVar variants

P:269U:170B:198

Top phenotype

Maple syrup urine disease, type Ib

gnomAD constraint

pLI —, LoF o/e 0.73

Max pathogenic AF

—

Genomic locus

chr6:80,106,647-80,346,270

External References & Databases

Ensembl (ENSG00000083123)

Transcript & Mutation Effects

hg38 • Region Span ~239.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

maple syrup urine disease type 1ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0023691

Submitter: PanelApp Australia

classic maple syrup urine diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017051

Submitter: Orphanet

maple syrup urine disease type 1BDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0023692

Submitter: Myriad Women's Health

maple syrup urine diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009563

Submitter: Natera

maple syrup urine disease type 1BDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0023692

Submitter: G2P

maple syrup urine diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009563

Submitter: Labcorp Genetics (formerly Invitae)

intermittent maple syrup urine diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017053

Submitter: Orphanet

intermediate maple syrup urine diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017052

Submitter: Orphanet

maple syrup urine disease type 1BDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0023692

Submitter: ClinGen

The relationship between BCKDHB and maple syrup urine disease (autosomal recessive) was evaluated using the ClinGen Clinical Validity Framework as of September, 2018. Variants in BCKDHB were first reported in humans with this disease as early as 1991 (Nobukuni et al., PMID 2022752). At least 15 variants ( missense, nonsense, frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data. Approximately 35% of maple syrup urine disease cases can be attributed to pathogenic variants in BCKDHB (Strauss et al., 2006, PMID 20301495). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is supported by biochemical and in vitro assays. In summary, BCKDHB is definitively associated with autosomal recessive maple syrup urine disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Clinical Genomic Database (CGD)

Maple syrup urine disease, type IbAR

Manifestation: Biochemical; Neurologic

Intervention: Biochemical

Rationale: Dietary measures (eg, leucine restriction, high-calorie branched chain amino acid-free formulas, isoleucine and valine supplementation) combined with careful surveillance can be beneficial to prevent decompensation and minimize disease sequelae; specific treatment in times of metabolic decompensation can reduce morbidity and mortaility; Liver transplantation is effective for classic MSUD; Specific monitoring is indicated in pregnancy

Refs: 2022752; 11509994; 11112664; 14567968; 17922217; 20301495; 22326532

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to BCKDHB variants in ClinVar

9 Conditions Cataloged

Maple syrup urine diseaseTotal: 584

Maple syrup urine disease type 1BTotal: 221

not providedTotal: 115

Maple syrup urine disease type 1ATotal: 88

Inborn genetic diseasesTotal: 51

not specifiedTotal: 42

BCKDHB-related disorderTotal: 28

Abnormality of metabolism/homeostasisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_183050.4. 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			3 clinvar	191 clinvar		194
missense	10 clinvar	72 clinvar	164 clinvar	7 clinvar		253
nonsense	18 clinvar	23 clinvar				41
start loss	2 clinvar	4 clinvar				6
frameshift	57 clinvar	47 clinvar				104
splice donor/acceptor (+/-2bp)	9 clinvar	27 clinvar	3 clinvar			39
Total	96	173	170	198	0	637

Highest pathogenic variant AF is 0.00029477978

Loading ClinVar variants...

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_183050.4	RefSeq	NP_898871.1	10	MANE Select
ENST00000320393.9	Ensembl	ENSP00000318351.5	10	MANE Select
NM_000056.5	RefSeq	NP_000047.1	10	Standard
NM_001318975.1	RefSeq	NP_001305904.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Propanoate metabolism - Homo sapiens (human)
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

Biological Process

response to nutrient
branched-chain amino acid catabolic process
oxidation-reduction process

Molecular Function

alpha-ketoacid dehydrogenase activity
3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring) activity
protein binding

Cellular Component

mitochondrion
mitochondrial matrix
mitochondrial alpha-ketoglutarate dehydrogenase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000320393
Coding exons: 10
Length: 239624
Individuals with no LoFs: 125675
Homozygous LoFs: 0
Heterozygous LoFs: 73
Defined: 125748
p: 0.000290

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.176	226	219	1.03	0.0000108	2534
Missense (PolyPhen)		71	77.769	0.91296		913
Synonymous	-0.774	88	79.2	1.11	0.00000399	780
Loss of Function	1.19	16	22.0	0.726	0.00000119	238

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00038	0.00037	rare
Latino/Admixed American	0.00081	0.00081	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00017	0.00016	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00026	0.00025	rare
South Asian	0.00013	0.00013	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: The branched-chain alpha-keto dehydrogenase complex catalyzes the overall conversion of alpha-keto acids to acyl-CoA and CO(2). It contains multiple copies of three enzymatic components: branched-chain alpha-keto acid decarboxylase (E1), lipoamide acyltransferase (E2) and lipoamide dehydrogenase (E3).;
Disease: DISEASE: Maple syrup urine disease 1B (MSUD1B) [MIM:248600]: A metabolic disorder due to an enzyme defect in the catabolic pathway of the branched-chain amino acids leucine, isoleucine, and valine. Accumulation of these 3 amino acids and their corresponding keto acids leads to encephalopathy and progressive neurodegeneration. Clinical features include mental and physical retardation, feeding problems, and a maple syrup odor to the urine. The keto acids of the branched-chain amino acids are present in the urine. If untreated, maple syrup urine disease can lead to seizures, coma, and death. The disease is often classified by its pattern of signs and symptoms. The most common and severe form of the disease is the classic type, which becomes apparent soon after birth. Variant forms of the disorder become apparent later in infancy or childhood and are typically milder, but they still involve developmental delay and other medical problems if not treated. {ECO:0000269|PubMed:11509994, ECO:0000269|PubMed:22326532, ECO:0000269|PubMed:8161368}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.377

Intolerance Scores

LoFtool: 0.231
RVIS EVS: -0.45
RVIS percentile EVS: 24

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.852

Gene Damage Prediction

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