BCKDHA

branched chain keto acid dehydrogenase E1 subunit alpha

Basic information

Region (hg38): 19:41397808-41425002

Previous symbols: [ "OVD1A" ]

Links

ENSG00000248098 ∙ NCBI:593 ∙ OMIM:608348 ∙ HGNC:986 ∙ Uniprot:P12694 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• maple syrup urine disease type 1A (Definitive), mode of inheritance: AR
• maple syrup urine disease (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 1A (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Maple syrup urine disease, type Ia	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	8037208; 7883996; 7672509; 11112664; 12042535; 14567968; 14742428; 17922217; 18378174; 20301313; 20301495; 20061171; 22326532

ClinVar

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

• Maple syrup urine disease (51 variants)
• not provided (16 variants)
• Maple syrup urine disease type 1A (11 variants)
• Inborn genetic diseases (2 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the BCKDHA 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			2	193	5	200
missense	8	37	101	9		155
nonsense	19	22				41
start loss		1				1
frameshift	24	28	1			53
inframe indel		1	4			5
splice donor/acceptor (+/-2bp)	4	17			1	22
splice region		1	3	36	4	44
non coding		1	17	113	17	148
Total	55	107	125	315	23

Highest pathogenic variant AF is 0.0000792

Variants in BCKDHA

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

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

Position	Type	Phenotype	Significance	ClinVar
19-41397824-C-CAAGATGGCGGTAGCGGACGGGCGAGGTGGCTCACGCCTGAAATCCCAGCACTATGGGAGGCCGAGGCGGGCGGATCACGAGGTCAGGANNNNNNNNNNAAAAAAAAAAAAAAAAAAAA		Maple syrup urine disease	Pathogenic (May 18, 2022)
19-41397830-G-A		Maple syrup urine disease	Likely pathogenic (Jan 15, 2018)
19-41397833-G-A		Maple syrup urine disease	Likely benign (Nov 20, 2021)
19-41397839-G-A		Maple syrup urine disease	Likely benign (Apr 11, 2023)
19-41397839-G-C		Maple syrup urine disease	Likely benign (Oct 03, 2021)
19-41397840-AT-A		Maple syrup urine disease	Pathogenic/Likely pathogenic (Jan 31, 2024)
19-41397841-T-C		Inborn genetic diseases	Uncertain significance (May 10, 2023)
19-41397842-C-A		Maple syrup urine disease	Likely benign (Jan 28, 2024)
19-41397842-C-T		not specified • Maple syrup urine disease • Maple syrup urine disease type 1A • Inborn genetic diseases	Benign/Likely benign (Jan 28, 2024)
19-41397848-A-C		Inborn genetic diseases • Maple syrup urine disease	Likely benign (Jan 25, 2024)
19-41397848-A-G		Inborn genetic diseases • Maple syrup urine disease	Likely benign (Aug 14, 2023)
19-41397849-G-C		Inborn genetic diseases	Uncertain significance (Nov 02, 2021)
19-41397851-G-A		Maple syrup urine disease	Likely benign (Mar 11, 2019)
19-41397854-G-A		Maple syrup urine disease	Likely benign (Oct 31, 2022)
19-41397855-G-T		Maple syrup urine disease	Uncertain significance (Aug 27, 2021)
19-41397857-C-G		Maple syrup urine disease	Likely benign (Nov 04, 2020)
19-41397857-C-T		Maple syrup urine disease	Likely benign (Apr 24, 2023)
19-41397859-G-A		Maple syrup urine disease	Likely pathogenic (Oct 28, 2023)
19-41397860-G-A		Maple syrup urine disease	Pathogenic (Jun 25, 2021)
19-41397861-C-A		not specified • Maple syrup urine disease • Maple syrup urine disease type 1A	Benign/Likely benign (Feb 01, 2024)
19-41397862-G-A		Maple syrup urine disease	Uncertain significance (Jul 06, 2022)
19-41397862-G-C		Maple syrup urine disease • Inborn genetic diseases	Conflicting classifications of pathogenicity (Mar 06, 2024)
19-41397865-TA-T		Maple syrup urine disease	Pathogenic (Aug 09, 2022)
19-41397866-A-G		Maple syrup urine disease	Likely benign (Feb 05, 2023)
19-41397869-C-T		Maple syrup urine disease	Likely benign (Dec 18, 2020)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
BCKDHA	protein_coding	protein_coding	ENST00000269980	9	46696

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
9.82e-9	0.758	125702	0	46	125748	0.000183

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.684	256	289	0.887	0.0000198	2908
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000388	0.000388
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.0000929	0.0000924
European (Non-Finnish)	0.000177	0.000176
Middle Eastern	0.0000544	0.0000544
South Asian	0.000371	0.000359
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).
• 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.
• 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;Lipid Metabolism Pathway;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: 0.109

Intolerance Scores

• loftool: 0.204
• rvis_EVS: -1.02
• rvis_percentile_EVS: 8.04

Haploinsufficiency Scores

• hipred: N
• hipred_score: 0.165
• ghis: 0.498

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.972

Mouse Genome Informatics

• Gene name: Bckdha

Gene ontology

• Biological process: 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;carboxy-lyase activity;metal ion binding