Hypervalinemia and hyperleucine-isoleucinemia

Summary

Hypervalinemia and hyperleucine-isoleucinemia (MONDO:0100058) is a disease caused by BCAT2 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: BCAT2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 10

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypervalinemia and hyperleucine-isoleucinemia
Mondo ID	MONDO:0100058
OMIM	618850
DOID	DOID:0060950
UMLS	C5394277
MedGen	1719306
GARD	0026028
Is cancer (heuristic)	no

Also known as: branched-chain aminotransferase deficiency · HVLI · hypervalinemia and hyperleucine-isoleucinemia · hypervalinemia or hyperleucine-isoleucinemia

Data availability: 10 ClinVar variants · 4 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 disorder of branched-chain amino acid metabolism › hypervalinemia and hyperleucine-isoleucinemia

Related subtypes (6): 3-hydroxyisobutyric aciduria, maple syrup urine disease, 3-hydroxyisobutyryl-CoA hydrolase deficiency, holocarboxylase synthetase deficiency, methylmalonate semialdehyde dehydrogenase deficiency, branched-chain keto acid dehydrogenase kinase deficiency

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

10 retrieved; paginated sample, class counts are floors:

6 pathogenic, 3 uncertain significance, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1980342	NM_001190.4(BCAT2):c.600C>A (p.Tyr200Ter)	BCAT2	Pathogenic	criteria provided, single submitter
2898513	NM_001190.4(BCAT2):c.898_899del (p.Leu301fs)	BCAT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3338118	NM_001190.4(BCAT2):c.545T>G (p.Val182Gly)	BCAT2	Pathogenic	no assertion criteria provided
3338121	NM_001190.4(BCAT2):c.136_147del (p.His46_Pro49del)	BCAT2	Pathogenic	no assertion criteria provided
3338122	BCAT2, INS/DEL, NT1154	BCAT2	Pathogenic	no assertion criteria provided
869184	NM_001190.4(BCAT2):c.509G>A (p.Arg170Gln)	BCAT2	Pathogenic	no assertion criteria provided
869185	NM_001190.4(BCAT2):c.790G>A (p.Glu264Lys)	BCAT2	Pathogenic	no assertion criteria provided
1918210	NM_001190.4(BCAT2):c.1021G>A (p.Ala341Thr)	BCAT2	Uncertain significance	criteria provided, single submitter
3893000	NM_001190.4(BCAT2):c.31dup (p.Ala11fs)	BCAT2	Uncertain significance	criteria provided, single submitter
3897949	NM_001190.4(BCAT2):c.616G>C (p.Val206Leu)	BCAT2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 0 · 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
BCAT2	Strong	Autosomal recessive	hypervalinemia and hyperleucine-isoleucinemia	4

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
BCAT2	HGNC:977	ENSG00000105552	O15382	Branched-chain-amino-acid aminotransferase, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BCAT2	Branched-chain-amino-acid aminotransferase, mitochondrial	Catalyzes the first reaction in the catabolism of the essential branched chain amino acids leucine, isoleucine, and valine.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BCAT2	Enzyme (other)	yes	2.6.1.42	Aminotrans_IV, B_amino_transII, Aminotrans_IV_CS

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
left adrenal gland	1
right adrenal gland	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BCAT2	269	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, left adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BCAT2	2,799

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BCAT2	O15382	30

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Branched-chain amino acid catabolism	1	475.8×	0.006	BCAT2
Metabolism of amino acids and derivatives	1	67.6×	0.022	BCAT2
Metabolism	1	11.6×	0.086	BCAT2

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 amino acid biosynthetic process	1	5617.3×	6e-04	BCAT2
L-leucine biosynthetic process	1	5617.3×	6e-04	BCAT2
L-valine biosynthetic process	1	4213.0×	6e-04	BCAT2
regulation of hormone levels	1	3370.4×	6e-04	BCAT2
L-isoleucine catabolic process	1	2808.7×	6e-04	BCAT2
branched-chain amino acid catabolic process	1	1053.2×	0.001	BCAT2
brown fat cell differentiation	1	432.1×	0.003	BCAT2
cellular response to leukemia inhibitory factor	1	159.0×	0.007	BCAT2
lipid metabolic process	1	91.6×	0.011	BCAT2

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
BCAT2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
BCAT2	9	Binding:9

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BCAT2	2.6.1.42	branched-chain-amino-acid transaminase

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	1	BCAT2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
BCAT2	9	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.