DBT

dihydrolipoamide branched chain transacylase E2

Basic information

Region (hg38): 1:100186918-100249834

Links

ENSG00000137992 ∙ NCBI:1629 ∙ OMIM:248610 ∙ HGNC:2698 ∙ Uniprot:P11182 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• maple syrup urine disease type 2 (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 (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Maple syrup urine disease, type II	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	1847055; 1990841; 9621512; 11112664; 14517957; 14567968; 16786533; 20301495; 20946191; 22727569; 23313820

ClinVar

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

• Maple syrup urine disease (620 variants)
• not provided (111 variants)
• not specified (37 variants)
• Inborn genetic diseases (10 variants)
• Maple syrup urine disease type 2 (9 variants)
• DBT-related condition (3 variants)
• See cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the DBT 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			1	131		132
missense	6	13	83	11	2	115
nonsense	8	18				26
start loss						0
frameshift	28	24				52
inframe indel			6	1		7
splice donor/acceptor (+/-2bp)	5	17	1			23
splice region	1		7	25	3	36
non coding			112	104	54	270
Total	47	72	203	247	56

Highest pathogenic variant AF is 0.000243

Variants in DBT

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

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

Position	Type	Phenotype	Significance	ClinVar
1-100187025-A-G		Maple syrup urine disease	Uncertain significance (Jan 13, 2018)
1-100187027-G-A		Maple syrup urine disease	Uncertain significance (Jan 12, 2018)
1-100187098-AGTGG-A		Maple syrup urine disease	Uncertain significance (Jun 14, 2016)
1-100187132-T-C		Maple syrup urine disease	Uncertain significance (Jan 12, 2018)
1-100187150-T-C		Maple syrup urine disease	Uncertain significance (Jan 13, 2018)
1-100187173-G-A		Maple syrup urine disease	Benign (Apr 11, 2023)
1-100187197-G-A		Maple syrup urine disease	Uncertain significance (Jan 12, 2018)
1-100187271-A-AC		Maple syrup urine disease	Likely benign (Jun 14, 2016)
1-100187278-A-G		Maple syrup urine disease	Benign (Jan 12, 2018)
1-100187311-T-C		Maple syrup urine disease	Benign (Jan 12, 2018)
1-100187355-T-A		Maple syrup urine disease	Uncertain significance (Jan 13, 2018)
1-100187425-A-G		Maple syrup urine disease	Uncertain significance (Jan 13, 2018)
1-100187521-T-G		Maple syrup urine disease	Uncertain significance (Jan 13, 2018)
1-100187585-T-C		Maple syrup urine disease	Uncertain significance (Jan 13, 2018)
1-100187592-A-G		Maple syrup urine disease	Uncertain significance (Jan 13, 2018)
1-100187613-G-C		Maple syrup urine disease	Uncertain significance (Jan 12, 2018)
1-100187648-C-T		Maple syrup urine disease	Likely benign (Apr 27, 2017)
1-100187700-AT-A			Likely benign (Mar 03, 2020)
1-100187700-A-AT		Maple syrup urine disease	Conflicting classifications of pathogenicity (Mar 17, 2021)
1-100187702-T-TA		Maple syrup urine disease	Uncertain significance (Jun 14, 2016)
1-100187703-T-A		Maple syrup urine disease	Likely benign (Apr 11, 2023)
1-100187784-A-G		Maple syrup urine disease	Uncertain significance (Jan 13, 2018)
1-100187870-T-G		Maple syrup urine disease	Uncertain significance (Jan 13, 2018)
1-100187980-T-C		Maple syrup urine disease	Uncertain significance (Jan 12, 2018)
1-100188029-C-A		Maple syrup urine disease	Uncertain significance (Jan 12, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
DBT	protein_coding	protein_coding	ENST00000370132	11	62916

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0000105	0.988	125703	0	45	125748	0.000179

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.991	215	260	0.827	0.0000131	3150
Missense in Polyphen		55	71.116	0.77338		831
Synonymous	0.275	83	86.3	0.962	0.00000420	940
Loss of Function	2.25	12	23.8	0.503	0.00000126	300

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00108	0.00108
Ashkenazi Jewish	0.00	0.00
East Asian	0.000163	0.000163
Finnish	0.0000468	0.0000462
European (Non-Finnish)	0.000115	0.000114
Middle Eastern	0.000163	0.000163
South Asian	0.000264	0.000261
Other	0.000326	0.000326

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). Within this complex, the catalytic function of this enzyme is to accept, and to transfer to coenzyme A, acyl groups that are generated by the branched-chain alpha-keto acid decarboxylase component.
• Disease: DISEASE: Note=Patients with primary biliary cirrhosis (PBC) show autoantibodies against the E2 component of branched-chain alpha- keto acid dehydrogenase complex. PBC is a chronic, progressive cholestatic liver disease characterized by the presence of antimitochondrial autoantibodies in patients serum. It manifests with inflammatory obliteration of intra-hepatic bile duct, leading to liver cell damage and cirrhosis. {ECO:0000269|PubMed:2908870, ECO:0000269|PubMed:7543435, ECO:0000269|PubMed:9141421}.; DISEASE: Maple syrup urine disease 2 (MSUD2) [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:1847055, ECO:0000269|PubMed:9621512}. 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;Branched-chain amino acid catabolism;Metabolism of amino acids and derivatives;leucine degradation;Metabolism;AndrogenReceptor;valine degradation;threonine 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: 0.321

Intolerance Scores

• rvis_EVS: 0.82
• rvis_percentile_EVS: 87.95

Haploinsufficiency Scores

• pHI: 0.391
• hipred: N
• hipred_score: 0.429
• ghis: 0.468

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.979

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Dbt
• Phenotype: nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); renal/urinary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); homeostasis/metabolism phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: dbt
• Affected structure: whole organism
• Phenotype tag: abnormal
• Phenotype quality: movement behavioral quality

Gene ontology

• Cellular component: cytoplasm;mitochondrion;mitochondrial matrix;mitochondrial alpha-ketoglutarate dehydrogenase complex;mitochondrial nucleoid
• Molecular function: acetyltransferase activity;lipoic acid binding;ubiquitin protein ligase binding;dihydrolipoyllysine-residue (2-methylpropanoyl)transferase activity