BCKDHB

branched chain keto acid dehydrogenase E1 subunit beta

Basic information

Region (hg38): 6:80106646-80346270

Links

ENSG00000083123 ∙ NCBI:594 ∙ OMIM:248611 ∙ HGNC:987 ∙ Uniprot:P21953 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• maple syrup urine disease type 1B (Definitive), mode of inheritance: AR
• maple syrup urine disease (Definitive), mode of inheritance: AR
• maple syrup urine disease (Strong), mode of inheritance: AR
• classic maple syrup urine disease (Supportive), mode of inheritance: AR
• intermediate maple syrup urine disease (Supportive), mode of inheritance: AR
• intermittent maple syrup urine disease (Supportive), mode of inheritance: AR
• thiamine-responsive maple syrup urine disease (Supportive), mode of inheritance: AR
• maple syrup urine disease type 1B (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Maple syrup urine disease, type Ib	AR	Biochemical	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	Biochemical; Neurologic	2022752; 11509994; 11112664; 14567968; 17922217; 20301495; 22326532

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the BCKDHB gene.

• Maple syrup urine disease (559 variants)
• not provided (131 variants)
• Maple syrup urine disease type 1B (65 variants)
• not specified (30 variants)
• Inborn genetic diseases (19 variants)
• BCKDHB-related condition (3 variants)
• Abnormality of metabolism/homeostasis (1 variants)
• See cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the BCKDHB gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				152		152
missense	12	32	111	2	1	158
nonsense	17	19				36
start loss	1	4				5
frameshift	23	35				58
inframe indel			1			1
splice donor/acceptor (+/-2bp)	9	18				27
splice region		1	6	22	3	32
non coding			33	54	55	142
Total	62	108	145	208	56

Highest pathogenic variant AF is 0.0000263

Variants in BCKDHB

This is a list of pathogenic ClinVar variants found in the BCKDHB region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
6-80106653-C-T		Maple syrup urine disease	Uncertain significance (Jun 14, 2016)
6-80106670-TGAGAATCCCGGTGGTGAGCGGGGATG-T		Maple syrup urine disease	Likely pathogenic (May 08, 2018)
6-80106679-C-T		Maple syrup urine disease	Uncertain significance (Jul 14, 2021)
6-80106694-A-G		Maple syrup urine disease • Maple syrup urine disease type 1B	Pathogenic/Likely pathogenic (Jul 25, 2023)
6-80106694-A-T		Maple syrup urine disease • Maple syrup urine disease type 1B	Pathogenic/Likely pathogenic (Mar 17, 2024)
6-80106695-T-C		Maple syrup urine disease	Pathogenic/Likely pathogenic (Aug 09, 2022)
6-80106696-G-A		Maple syrup urine disease	Pathogenic (Jan 01, 2014)
6-80106695-T-TGGCGGTTGTAGC		Maple syrup urine disease	Uncertain significance (Jun 10, 2022)
6-80106698-C-T		Maple syrup urine disease • Maple syrup urine disease type 1B	Uncertain significance (Jun 19, 2022)
6-80106699-G-A		Maple syrup urine disease	Likely benign (Oct 25, 2019)
6-80106699-G-T		Maple syrup urine disease	Likely benign (Nov 26, 2021)
6-80106702-T-A		Maple syrup urine disease	Likely benign (Jan 07, 2023)
6-80106703-G-A		Maple syrup urine disease • Maple syrup urine disease type 1B	Uncertain significance (Oct 31, 2022)
6-80106703-G-T		Inborn genetic diseases	Uncertain significance (Nov 21, 2022)
6-80106705-A-G		Maple syrup urine disease	Likely benign (Mar 27, 2019)
6-80106706-GCGGCGGCTGC-G		Maple syrup urine disease	Likely pathogenic (May 30, 2023)
6-80106706-G-GC		Maple syrup urine disease	Likely pathogenic (Feb 21, 2023)
6-80106708-G-A		Maple syrup urine disease	Likely benign (Aug 28, 2023)
6-80106708-G-C		Maple syrup urine disease	Likely benign (Oct 17, 2023)
6-80106710-C-T		Maple syrup urine disease • Maple syrup urine disease type 1B • BCKDHB-related disorder	Likely benign (Jan 08, 2024)
6-80106711-G-A		Maple syrup urine disease	Likely benign (Nov 01, 2021)
6-80106711-G-C		Maple syrup urine disease	Likely benign (Apr 04, 2021)
6-80106711-G-T		Maple syrup urine disease	Likely benign (Oct 03, 2022)
6-80106712-G-A		Maple syrup urine disease	Uncertain significance (Aug 30, 2021)
6-80106713-C-CT		Maple syrup urine disease	Pathogenic (Jul 03, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
BCKDHB	protein_coding	protein_coding	ENST00000320393	10	239624

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
4.31e-9	0.584	125675	0	73	125748	0.000290

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.176	226	219	1.03	0.0000108	2534
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00119	0.00118
Ashkenazi Jewish	0.00	0.00
East Asian	0.000165	0.000163
Finnish	0.00	0.00
European (Non-Finnish)	0.000256	0.000255
Middle Eastern	0.000165	0.000163
South Asian	0.000134	0.000131
Other	0.000490	0.000489

dbNSFP

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.
• Pathway: 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;Isovaleric Aciduria;3-Methylcrotonyl Coa Carboxylase Deficiency Type I;Propionic Acidemia;Maple Syrup Urine Disease;3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency;Isobutyryl-coa dehydrogenase deficiency;3-hydroxyisobutyric aciduria;3-hydroxyisobutyric acid dehydrogenase deficiency;Isovaleric acidemia;Methylmalonate Semialdehyde Dehydrogenase Deficiency;Methylmalonic Aciduria;3-Methylglutaconic Aciduria Type IV;3-Methylglutaconic Aciduria Type III;Threonine and 2-Oxobutanoate Degradation;Beta-Ketothiolase Deficiency;miR-targeted genes in epithelium - TarBase;miR-targeted genes in lymphocytes - TarBase;Branched-chain amino acid catabolism;Metabolism of amino acids and derivatives;leucine degradation;Metabolism;valine degradation;threonine degradation;Valine, leucine and isoleucine degradation;isoleucine degradation;Glyoxylate metabolism and glycine degradation;2-oxoisovalerate decarboxylation to isobutanoyl-CoA;2-oxobutanoate degradation;superpathway of methionine degradation (Consensus)

Recessive Scores

• pRec: 0.377

Intolerance Scores

• loftool: 0.231
• rvis_EVS: -0.45
• rvis_percentile_EVS: 24

Haploinsufficiency Scores

• pHI: 0.214
• hipred: N
• hipred_score: 0.204
• ghis: 0.547

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.852

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Bckdhb

Gene ontology

• Biological process: response to nutrient;branched-chain amino acid catabolic process;oxidation-reduction process
• Cellular component: mitochondrion;mitochondrial matrix;mitochondrial alpha-ketoglutarate dehydrogenase complex
• Molecular function: alpha-ketoacid dehydrogenase activity;3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring) activity;protein binding