BCKDK

Chr 16AR

branched chain keto acid dehydrogenase kinase

Also known as: BCKDKD, BDK

NCBI Gene: 10295 ENSG00000103507 UniProt: O14874 OMIM: 614901

The protein phosphorylates and inactivates the branched-chain alpha-ketoacid dehydrogenase complex in the mitochondrial matrix, regulating the catabolism of valine, leucine, and isoleucine. Mutations cause branched-chain keto acid dehydrogenase kinase deficiency through an autosomal recessive inheritance pattern. The pathogenic mechanism involves dominant-negative effects.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The branched-chain alpha-ketoacid dehydrogenase complex (BCKD) is an important regulator of the valine, leucine, and isoleucine catabolic pathways. The protein encoded by this gene is found in the mitochondrion, where it phosphorylates and inactivates BCKD. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.871 OMIM phenotype

Clinical Summary— BCKDK

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Gene-Disease Validity (ClinGen)

branched-chain keto acid dehydrogenase kinase deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

17 unique Pathogenic / Likely Pathogenic· 93 VUS of 198 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.87LOEUF

pLI 0.000

Z-score 2.00

OE 0.51 (0.31–0.87)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.64Z-score

OE missense 0.73 (0.65–0.82)

209 obs / 287.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.51 (0.31–0.87)

0≤0.351.4

Missense OE?0.73 (0.65–0.82)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 10 / 19.6Missense obs/exp: 209 / 287.1Syn Z: -0.18

This gene — mechanism propensity

0.7325th %ile

GOF

0.6638th %ile

LOF

0.2872th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

198 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic8

Likely Pathogenic9

VUS93

Likely Benign63

Benign6

Conflicting5

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	6	1	1	0	8
Likely Pathogenic	7	2	0	0	9
VUS	0	84	7	2	93
Likely Benign	0	3	25	35	63
Benign	0	0	4	2	6
Conflicting	—				5
Total	13	90	37	39	184

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

14 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap BCKDK — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →