DLAT

Chr 11AR

dihydrolipoamide S-acetyltransferase

Also known as: DLTA, E2, PBC, PDC-E2, PDCE2

NCBI Gene: 1737 ENSG00000150768 UniProt: P10515 OMIM: 608770

Dihydrolipoamide acetyltransferase (E2 component) transfers acetyl groups from pyruvate to coenzyme A within the mitochondrial pyruvate dehydrogenase complex, which converts pyruvate to acetyl-CoA for energy metabolism. Autosomal recessive mutations cause pyruvate dehydrogenase E2 deficiency, resulting in primary lactic acidosis in infancy and early childhood due to impaired cellular energy production. The pathogenic mechanism involves defective mitochondrial pyruvate metabolism leading to lactate accumulation and metabolic acidosis.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes component E2 of the multi-enzyme pyruvate dehydrogenase complex (PDC). PDC resides in the inner mitochondrial membrane and catalyzes the conversion of pyruvate to acetyl coenzyme A. The protein product of this gene, dihydrolipoamide acetyltransferase, accepts acetyl groups formed by the oxidative decarboxylation of pyruvate and transfers them to coenzyme A. Dihydrolipoamide acetyltransferase is the antigen for antimitochondrial antibodies. These autoantibodies are present in nearly 95% of patients with the autoimmune liver disease primary biliary cirrhosis (PBC). In PBC, activated T lymphocytes attack and destroy epithelial cells in the bile duct where this protein is abnormally distributed and overexpressed. PBC enventually leads to cirrhosis and liver failure. Mutations in this gene are also a cause of pyruvate dehydrogenase E2 deficiency which causes primary lactic acidosis in infancy and early childhood.[provided by RefSeq, Oct 2009]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.861 OMIM phenotype

Clinical Summary— DLAT

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Gene-Disease Validity (ClinGen)

Leigh syndrome · ARModerate

Moderate evidence — consider for supplementary testing

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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

18 unique Pathogenic / Likely Pathogenic· 170 VUS of 405 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — DLAT

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.86LOEUF

pLI 0.000

Z-score 2.14

OE 0.58 (0.39–0.86)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.42Z-score

OE missense 0.94 (0.86–1.03)

338 obs / 360.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.58 (0.39–0.86)

0≤0.351.4

Missense OE?0.94 (0.86–1.03)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 17 / 29.6Missense obs/exp: 338 / 360.3Syn Z: 0.23

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveDLAT-related pyruvate dehydrogenase E2 deficiencyLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6840th %ile

GOF

0.5954th %ile

LOF

0.3940th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

ClinVar Variant Classifications

405 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7

Likely Pathogenic11

VUS170

Likely Benign144

Benign47

Conflicting13

Pathogenic

Likely Pathogenic

170

VUS

144

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	6	0	1	0	7
Likely Pathogenic	8	2	0	1	11
VUS	3	155	10	2	170
Likely Benign	2	21	71	50	144
Benign	0	7	39	1	47
Conflicting	—				13
Total	19	185	121	54	392

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

View in ClinVar →

18 pathogenic / likely-pathogenic (of 26) ClinVar copy-number / structural variants overlap DLAT — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →