BCKDHA

protein-coding

branched chain keto acid dehydrogenase E1 subunit alpha

Gene summary

The branched-chain alpha-keto acid (BCAA) dehydrogenase (BCKD) complex is an innter mitochondrial enzyme complex that catalyzes the second major step in the catabolism of the branched-chain amino acids leucine, isoleucine, and valine. The BCKD complex consists of three catalytic components: a heterotetrameric (alpha2-beta2) branched-chain alpha-keto acid decarboxylase (E1), a dihydrolipoyl transacylase (E2), and a dihydrolipoamide dehydrogenase (E3). This gene encodes the alpha subunit of the decarboxylase (E1) component. Mutations in this gene result in maple syrup urine disease, type IA. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]

Previous symbols:

OVD1A

MANE transcript

NM_000709.4

Inheritance

ClinVar variants

P:215U:154B:246

Top phenotype

Maple syrup urine disease, type Ia

gnomAD constraint

pLI —, LoF o/e 0.68

Max pathogenic AF

—

Genomic locus

chr19:41,397,808-41,425,002

External References & Databases

Ensembl (ENSG00000248098)

Transcript & Mutation Effects

hg38 • Region Span ~27.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intermediate maple syrup urine diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017052

Submitter: Orphanet

maple syrup urine disease type 1ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0023691

Submitter: Myriad Women's Health

maple syrup urine disease type 1ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0023691

Submitter: ClinGen

The relationship between BCKDHA and maple syrup urine disease (autosomal recessive) was evaluated using the ClinGen Clinical Validity Framework as of August, 2018. Variants in BCKDHA were first reported in humans with this disease as early as 1989 (Zhang et al., PMID: 2703538). At least 11 variants (missense, nonsense, frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level and experimental data. Variants in this gene account for ~45% of MSUD cases (Strauss et al., 2013; PMID: 20301495). More cases are available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. BCKDHA encodes the E1 alpha subunit of the BCKAD complex and variants in the gene result in reduced activity of the complex. This gene-disease association is supported by in vitro studies and animal models. This classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel on 9/14/18 (SOP Version 5).

maple syrup urine diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009563

Submitter: Ambry Genetics

maple syrup urine diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009563

Submitter: Natera

maple syrup urine disease type 1ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0023691

Submitter: G2P

intermittent maple syrup urine diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017053

Submitter: Orphanet

maple syrup urine diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009563

Submitter: Labcorp Genetics (formerly Invitae)

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

Clinical Genomic Database (CGD)

Maple syrup urine disease, type IaAR

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: 8037208; 7883996; 7672509; 11112664; 12042535; 14567968; 14742428; 17922217; 18378174; 20301313; 20301495; 20061171; 22326532

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to BCKDHA variants in ClinVar

8 Conditions Cataloged

Maple syrup urine diseaseTotal: 649

Maple syrup urine disease type 1ATotal: 230

not providedTotal: 109

Inborn genetic diseasesTotal: 106

not specifiedTotal: 65

BCKDHA-related disorderTotal: 36

Intellectual disabilityTotal: 1

Likely inborn error of metabolismTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000709.4. 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			7 clinvar	227 clinvar	3 clinvar	237
missense	7 clinvar	64 clinvar	142 clinvar	16 clinvar		229
nonsense	19 clinvar	26 clinvar				45
start loss		1 clinvar				1
frameshift	35 clinvar	41 clinvar	1 clinvar			77
splice donor/acceptor (+/-2bp)	3 clinvar	19 clinvar	4 clinvar			26
Total	64	151	154	243	3	615

Highest pathogenic variant AF is 0.00011028624

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 39 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000709.4	RefSeq	NP_000700.1	9	MANE Select
ENST00000269980.7	Ensembl	ENSP00000269980.2	9	MANE Select
NM_001164783.2	RefSeq	NP_001158255.1	9	Standard
ENST00000457836.6	Ensembl	ENSP00000416000.2	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

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
carboxy-lyase activity
metal ion binding

Cellular Component

mitochondrion
mitochondrial matrix
mitochondrial alpha-ketoglutarate dehydrogenase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000269980
Coding exons: 9
Length: 46696
Individuals with no LoFs: 125702
Homozygous LoFs: 0
Heterozygous LoFs: 46
Defined: 125748
p: 0.000183

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.684	256	289	0.887	0.0000198	2908
Missense (PolyPhen)		80	110.09	0.72668		1050
Synonymous	0.0715	120	121	0.992	0.00000903	870
Loss of Function	1.44	16	23.5	0.680	0.00000131	238

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.00020	0.00020	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00018	0.00018	rare
South Asian	0.00037	0.00036	rare
Other	0.00033	0.00033	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 1A (MSUD1A) [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:1867199, ECO:0000269|PubMed:1885764, ECO:0000269|PubMed:2060625, ECO:0000269|PubMed:21844576, ECO:0000269|PubMed:2241958, ECO:0000269|PubMed:2703538, ECO:0000269|PubMed:7883996, ECO:0000269|PubMed:8037208, ECO:0000269|PubMed:8161368}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.109

Intolerance Scores

LoFtool: 0.204
RVIS EVS: -1.02
RVIS percentile EVS: 8.04

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.972