maple syrup urine disease type 1B

Summary

maple syrup urine disease type 1B (MONDO:0023692) is a disease caused by BCKDHB (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: BCKDHB (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 186

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	maple syrup urine disease type 1B
Mondo ID	MONDO:0023692
OMIM	620698
DOID	DOID:0061206
UMLS	C2930990
MedGen	443951
GARD	0008597
Is cancer (heuristic)	no

Also known as: maple syrup urine disease type 1B · MSUD due to deficiency of E1-beta subunit of branched-chain alpha-keto acid dehydrogenase complex · MSUD type 3 (formerly) · MSUD type IB

Data availability: 186 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › inborn organic aciduria › maple syrup urine disease › maple syrup urine disease type 1B

Related subtypes (8): pyruvate dehydrogenase E3 deficiency, maple syrup urine disease, mild variant, classic maple syrup urine disease, intermediate maple syrup urine disease, intermittent maple syrup urine disease, thiamine-responsive maple syrup urine disease, maple syrup urine disease type 1A, maple syrup urine disease type 2

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

186 retrieved; paginated sample, class counts are floors:

50 uncertain significance, 44 pathogenic/likely pathogenic, 40 likely pathogenic, 22 pathogenic, 14 conflicting classifications of pathogenicity, 12 likely benign, 2 benign, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
11937	NM_183050.4(BCKDHB):c.548G>C (p.Arg183Pro)	BCKDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11939	NM_183050.4(BCKDHB):c.356T>G (p.Val119Gly)	BCKDHB	Pathogenic	no assertion criteria provided
11941	BCKDHB, 8-BP INS, NT1109	BCKDHB	Pathogenic	no assertion criteria provided
1407094	NM_183050.4(BCKDHB):c.392G>T (p.Gly131Val)	BCKDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452370	NM_183050.4(BCKDHB):c.21dup (p.Ala8fs)	BCKDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1487606	NM_183050.4(BCKDHB):c.641T>A (p.Ile214Lys)	BCKDHB	Pathogenic	criteria provided, multiple submitters, no conflicts
1487625	NM_183050.4(BCKDHB):c.1037A>G (p.Gln346Arg)	BCKDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685567	NM_183050.4(BCKDHB):c.1039-2A>G	BCKDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
189101	NM_183050.4(BCKDHB):c.93_103dup (p.Phe35fs)	BCKDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2006724	NM_183050.4(BCKDHB):c.585T>A (p.Tyr195Ter)	BCKDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2136445	NM_183050.4(BCKDHB):c.662_663del (p.Ala221fs)	BCKDHB	Pathogenic	criteria provided, multiple submitters, no conflicts
224057	NM_183050.4(BCKDHB):c.3G>A (p.Met1Ile)	BCKDHB	Pathogenic	criteria provided, multiple submitters, no conflicts
224059	NM_183050.4(BCKDHB):c.1065del (p.Pro356fs)	BCKDHB	Pathogenic	criteria provided, multiple submitters, no conflicts
224061	NM_183050.4(BCKDHB):c.964A>G (p.Thr322Ala)	BCKDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2442395	NM_183050.4(BCKDHB):c.580C>T (p.Leu194Phe)	BCKDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2680128	NM_183050.4(BCKDHB):c.818C>T (p.Thr273Ile)	BCKDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2680131	NM_183050.4(BCKDHB):c.550del (p.Ser184fs)	BCKDHB	Pathogenic	criteria provided, multiple submitters, no conflicts
2798713	NM_183050.4(BCKDHB):c.756_759del (p.Ile253fs)	BCKDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2982268	NM_183050.4(BCKDHB):c.75del (p.Leu26fs)	BCKDHB	Pathogenic	criteria provided, multiple submitters, no conflicts
370823	NM_183050.4(BCKDHB):c.79_89del (p.Pro27fs)	BCKDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
370827	NM_183050.4(BCKDHB):c.487G>T (p.Glu163Ter)	BCKDHB	Pathogenic	criteria provided, multiple submitters, no conflicts
370949	NM_183050.4(BCKDHB):c.410C>T (p.Ala137Val)	BCKDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3768264	NC_000006.11:g.(80878748_80880998)_(80881108_80910650)del	BCKDHB	Pathogenic	criteria provided, single submitter
4081599	NM_183050.4(BCKDHB):c.693dup (p.Lys232Ter)	BCKDHB	Pathogenic	criteria provided, single submitter
457148	NM_183050.4(BCKDHB):c.348del (p.Asp117fs)	BCKDHB	Pathogenic	criteria provided, multiple submitters, no conflicts
457149	NM_183050.4(BCKDHB):c.503G>A (p.Arg168His)	BCKDHB	Pathogenic	criteria provided, multiple submitters, no conflicts
496569	NM_183050.4(BCKDHB):c.403G>A (p.Gly135Arg)	BCKDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
527129	NM_183050.4(BCKDHB):c.152del (p.Val51fs)	BCKDHB	Pathogenic	criteria provided, multiple submitters, no conflicts
527130	NM_183050.4(BCKDHB):c.714dup (p.Glu239Ter)	BCKDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
527135	NM_183050.4(BCKDHB):c.548G>A (p.Arg183Gln)	BCKDHB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
BCKDHB	Definitive	Autosomal recessive	maple syrup urine disease type 1B	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BCKDHB	Orphanet:268145	Classic maple syrup urine disease
BCKDHB	Orphanet:268162	Intermediate maple syrup urine disease
BCKDHB	Orphanet:268173	Intermittent maple syrup urine disease

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BCKDHB	HGNC:987	ENSG00000083123	P21953	2-oxoisovalerate dehydrogenase subunit beta, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BCKDHB	2-oxoisovalerate dehydrogenase subunit beta, mitochondrial	Together with BCKDHA forms the heterotetrameric E1 subunit of the mitochondrial branched-chain alpha-ketoacid dehydrogenase (BCKD) complex.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BCKDHB	Other/Unknown	no		Transketolase-like_Pyr-bd, Transketo_C/PFOR_II, THDP-binding

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	1
rectum	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BCKDHB	247	ubiquitous	marker	right lobe of liver, rectum, liver

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BCKDHB	2,616

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BCKDHB	P21953	24

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Loss-of-function mutations in BCKDHA or BCKDHB cause MSUD	1	3806.7×	5e-04	BCKDHB
BCKDH synthesizes BCAA-CoA from KIC, KMVA, KIV	1	2855.0×	5e-04	BCKDHB
Loss-of-function mutations in DBT cause MSUD2	1	2855.0×	5e-04	BCKDHB
Loss-of-function mutations in DLD cause MSUD3/DLDD	1	2855.0×	5e-04	BCKDHB
Branched-chain ketoacid dehydrogenase kinase deficiency	1	2284.0×	5e-04	BCKDHB
H139Hfs13* PPM1K causes a mild variant of MSUD	1	2284.0×	5e-04	BCKDHB
Branched-chain amino acid catabolism	1	475.8×	0.002	BCKDHB

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
branched-chain alpha-keto acid decarboxylation to branched-chain acyl-CoA	1	4213.0×	7e-04	BCKDHB
branched-chain amino acid catabolic process	1	1053.2×	0.001	BCKDHB
response to nutrient	1	295.6×	0.003	BCKDHB

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BCKDHB	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
BCKDHB	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	BCKDHB

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
BCKDHB	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.