DLD

dihydrolipoamide dehydrogenase, the group of Pyruvate dehydrogenase complex

Basic information

Region (hg38): 7:107891161-107931730

Previous symbols: [ "LAD", "GCSL" ]

Links

ENSG00000091140 ∙ NCBI:1738 ∙ OMIM:238331 ∙ HGNC:2898 ∙ Uniprot:P09622 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• pyruvate dehydrogenase E3 deficiency (Definitive), mode of inheritance: AR
• maple syrup urine disease (Definitive), mode of inheritance: AR
• pyruvate dehydrogenase E3 deficiency (Strong), mode of inheritance: AR
• pyruvate dehydrogenase E3 deficiency (Strong), mode of inheritance: AR
• pyruvate dehydrogenase E3 deficiency (Strong), mode of inheritance: AR
• pyruvate dehydrogenase E3 deficiency (Supportive), mode of inheritance: AR
• Leigh syndrome (Definitive), mode of inheritance: AR
• pyruvate dehydrogenase E3 deficiency (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Dihydrolipoyl dehydrogenase deficiency	AR	Biochemical	The potential benefit of long-term medical treatment (eg, with riboflavin, biotin, coenzyme Q and carnitine) has been reported; Biochemical (but not clinical) improvement has been described with high-fat, low-protein diet with MCT oils and sodium dichloroacetate	Biochemical; Neurologic	3769994; 8506365; 8968745; 9298831; 9540846; 9934985; 11687750; 12925875; 14765544; 16770810; 16601893

ClinVar

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

• Pyruvate dehydrogenase E3 deficiency (466 variants)
• not provided (95 variants)
• Leigh syndrome (72 variants)
• Pyruvate dehydrogenase complex deficiency (72 variants)
• not specified (27 variants)
• Inborn genetic diseases (15 variants)
• DLD-Related Disorders (5 variants)
• Maple syrup urine disease (2 variants)
• DLD-related condition (1 variants)
• See cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the DLD 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				136	4	140
missense	2	8	86	3		99
nonsense	12	16				28
start loss						0
frameshift	13	27				40
inframe indel						0
splice donor/acceptor (+/-2bp)	1	19				20
splice region			8	38	2	48
non coding		3	26	83	29	141
Total	28	73	112	222	33

Highest pathogenic variant AF is 0.000178

Variants in DLD

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

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

Position	Type	Phenotype	Significance	ClinVar
7-107891209-C-T		not specified	Likely benign (Nov 15, 2016)
7-107891220-G-A		not specified	Likely benign (Apr 14, 2017)
7-107891241-C-T		Pyruvate dehydrogenase E3 deficiency • Leigh syndrome • Pyruvate dehydrogenase complex deficiency	Uncertain significance (Jan 13, 2018)
7-107891243-G-T		Pyruvate dehydrogenase complex deficiency • Leigh syndrome • Pyruvate dehydrogenase E3 deficiency	Uncertain significance (Jan 12, 2018)
7-107891244-C-G		not specified	Likely benign (Jan 05, 2017)
7-107891253-G-A		Pyruvate dehydrogenase E3 deficiency	Pathogenic (May 18, 2023)
7-107891256-G-A		Pyruvate dehydrogenase E3 deficiency	Likely benign (May 23, 2023)
7-107891256-G-C		Pyruvate dehydrogenase E3 deficiency	Uncertain significance (Dec 18, 2023)
7-107891262-G-A		Pyruvate dehydrogenase E3 deficiency	Pathogenic (Feb 11, 2019)
7-107891263-A-G		Pyruvate dehydrogenase E3 deficiency	Uncertain significance (Sep 10, 2021)
7-107891268-T-C		Pyruvate dehydrogenase E3 deficiency	Likely benign (Jul 13, 2023)
7-107891268-T-TG		Pyruvate dehydrogenase E3 deficiency	Likely pathogenic (May 18, 2022)
7-107891273-A-T		Inborn genetic diseases	Uncertain significance (Jan 18, 2022)
7-107891274-C-G		Pyruvate dehydrogenase E3 deficiency	Pathogenic (Aug 21, 2023)
7-107891274-C-T		Pyruvate dehydrogenase E3 deficiency	Likely benign (Dec 26, 2023)
7-107891275-T-A		Inborn genetic diseases	Uncertain significance (Dec 12, 2023)
7-107891277-C-T		Pyruvate dehydrogenase E3 deficiency	Likely benign (Jul 19, 2022)
7-107891279-C-T		Pyruvate dehydrogenase E3 deficiency	Uncertain significance (Jul 11, 2022)
7-107891280-C-A		Pyruvate dehydrogenase E3 deficiency • Leigh syndrome • Pyruvate dehydrogenase complex deficiency	Conflicting classifications of pathogenicity (Oct 17, 2023)
7-107891280-C-T		Pyruvate dehydrogenase E3 deficiency	Likely benign (May 02, 2023)
7-107891284-G-A		not specified • Leigh syndrome • Pyruvate dehydrogenase complex deficiency • Pyruvate dehydrogenase E3 deficiency	Benign/Likely benign (Jan 29, 2024)
7-107891286-C-T		Pyruvate dehydrogenase E3 deficiency	Likely benign (Jul 29, 2023)
7-107891290-G-A		Pyruvate dehydrogenase E3 deficiency	Likely pathogenic (Aug 09, 2023)
7-107891292-G-C		Pyruvate dehydrogenase E3 deficiency	Uncertain significance (Jun 19, 2021)
7-107891296-G-A		Pyruvate dehydrogenase E3 deficiency	Likely benign (Jul 26, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
DLD	protein_coding	protein_coding	ENST00000205402	14	40761

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00951	0.990	125714	0	33	125747	0.000131

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.10	220	271	0.812	0.0000131	3295
Missense in Polyphen		64	115	0.55653		1451
Synonymous	-0.341	94	89.9	1.05	0.00000448	996
Loss of Function	3.42	9	28.8	0.312	0.00000157	355

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000149	0.000149
Ashkenazi Jewish	0.0000993	0.0000992
East Asian	0.000163	0.000163
Finnish	0.000139	0.000139
European (Non-Finnish)	0.000168	0.000149
Middle Eastern	0.000163	0.000163
South Asian	0.000131	0.000131
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Lipoamide dehydrogenase is a component of the glycine cleavage system as well as an E3 component of three alpha-ketoacid dehydrogenase complexes (pyruvate-, alpha-ketoglutarate-, and branched-chain amino acid-dehydrogenase complex) (PubMed:15712224, PubMed:16442803, PubMed:16770810, PubMed:17404228, PubMed:20160912, PubMed:20385101). The 2-oxoglutarate dehydrogenase complex is mainly active in the mitochondrion (PubMed:29211711). A fraction of the 2-oxoglutarate dehydrogenase complex also localizes in the nucleus and is required for lysine succinylation of histones: associates with KAT2A on chromatin and provides succinyl-CoA to histone succinyltransferase KAT2A (PubMed:29211711). In monomeric form may have additional moonlighting function as serine protease (PubMed:17404228). Involved in the hyperactivation of spermatazoa during capacitation and in the spermatazoal acrosome reaction (By similarity). {ECO:0000250|UniProtKB:Q811C4, ECO:0000269|PubMed:15712224, ECO:0000269|PubMed:16442803, ECO:0000269|PubMed:16770810, ECO:0000269|PubMed:17404228, ECO:0000269|PubMed:20160912, ECO:0000269|PubMed:20385101, ECO:0000269|PubMed:29211711}.
• Disease: DISEASE: Dihydrolipoamide dehydrogenase deficiency (DLDD) [MIM:246900]: An autosomal recessive metabolic disorder characterized biochemically by a combined deficiency of the branched-chain alpha-keto acid dehydrogenase complex (BCKDC), pyruvate dehydrogenase complex (PDC), and alpha-ketoglutarate dehydrogenase complex (KGDC). Clinically, affected individuals have lactic acidosis and neurologic deterioration due to sensitivity of the central nervous system to defects in oxidative metabolism. {ECO:0000269|PubMed:10448086, ECO:0000269|PubMed:11687750, ECO:0000269|PubMed:12925875, ECO:0000269|PubMed:15712224, ECO:0000269|PubMed:16442803, ECO:0000269|PubMed:16770810, ECO:0000269|PubMed:17404228, ECO:0000269|PubMed:20160912, ECO:0000269|PubMed:8506365, ECO:0000269|PubMed:8968745, ECO:0000269|PubMed:9540846, ECO:0000269|PubMed:9934985}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Citrate cycle (TCA cycle) - Homo sapiens (human);Pyruvate metabolism - Homo sapiens (human);Glycolysis / Gluconeogenesis - Homo sapiens (human);Propanoate metabolism - Homo sapiens (human);Glycine, serine and threonine metabolism - Homo sapiens (human);Valine, leucine and isoleucine degradation - Homo sapiens (human);Glyoxylate and dicarboxylate metabolism - Homo sapiens (human);Warburg Effect;Pyruvate Dehydrogenase Complex Deficiency;Lysine Degradation;3-Methylglutaconic Aciduria Type I;Valine, Leucine and Isoleucine Degradation;2-Methyl-3-Hydroxybutryl CoA Dehydrogenase Deficiency;3-Phosphoglycerate dehydrogenase deficiency;Hyperlysinemia I, Familial;Non Ketotic Hyperglycinemia;Ammonia Recycling;Glycine and Serine Metabolism;The oncogenic action of Succinate;The oncogenic action of Fumarate;Primary hyperoxaluria II, PH2;Pyruvate kinase deficiency;2-aminoadipic 2-oxoadipic aciduria;Pyruvate dehydrogenase deficiency (E3);Pyruvate dehydrogenase deficiency (E2);2-ketoglutarate dehydrogenase complex deficiency;Mitochondrial complex II deficiency;Fumarase deficiency;Congenital lactic acidosis;Citric Acid Cycle;Leigh Syndrome;Pyridoxine dependency with seizures;Saccharopinuria/Hyperlysinemia II;Isovaleric Aciduria;3-Methylcrotonyl Coa Carboxylase Deficiency Type I;Propionic Acidemia;Maple Syrup Urine Disease;Glutaminolysis and Cancer;3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency;The oncogenic action of 2-hydroxyglutarate;Isobutyryl-coa dehydrogenase deficiency;3-hydroxyisobutyric aciduria;3-hydroxyisobutyric acid dehydrogenase deficiency;Isovaleric acidemia;Pyruvate Metabolism;Glutaric Aciduria Type I;Methylmalonate Semialdehyde Dehydrogenase Deficiency;The oncogenic action of L-2-hydroxyglutarate in Hydroxygluaricaciduria;The oncogenic action of D-2-hydroxyglutarate in Hydroxygluaricaciduria ;Pyruvate Decarboxylase E1 Component Deficiency (PDHE1 Deficiency);Dimethylglycine Dehydrogenase Deficiency;Hyperglycinemia, non-ketotic;Methylmalonic Aciduria;3-Methylglutaconic Aciduria Type IV;3-Methylglutaconic Aciduria Type III;Hyperlysinemia II or Saccharopinuria;Dimethylglycine Dehydrogenase Deficiency;Sarcosinemia;Threonine and 2-Oxobutanoate Degradation;Beta-Ketothiolase Deficiency;Dihydropyrimidine Dehydrogenase Deficiency (DHPD);Fatty Acid Beta Oxidation;TCA Cycle and Deficiency of Pyruvate Dehydrogenase complex (PDHc);Amino Acid metabolism;Glycolysis and Gluconeogenesis;TCA Cycle;Signal Transduction;Citrate cycle;Branched-chain amino acid catabolism;Glycine degradation;Regulation of pyruvate dehydrogenase (PDH) complex;Pyruvate metabolism;Lysine catabolism;Citric acid cycle (TCA cycle);Pyruvate metabolism and Citric Acid (TCA) cycle;Histidine, lysine, phenylalanine, tyrosine, proline and tryptophan catabolism;Metabolism of amino acids and derivatives;leucine degradation;Glycine Serine metabolism;The citric acid (TCA) cycle and respiratory electron transport;Glycolysis and Gluconeogenesis;Metabolism;pyruvate decarboxylation to acetyl CoA;valine degradation;threonine degradation;Valine, leucine and isoleucine degradation;TCA cycle;isoleucine degradation;Glyoxylate metabolism and glycine degradation;Pyruvate metabolism;Signaling by Retinoic Acid;Signaling by Nuclear Receptors;superpathway of conversion of glucose to acetyl CoA and entry into the TCA cycle;2-oxoisovalerate decarboxylation to isobutanoyl-CoA;2-oxobutanoate degradation;superpathway of methionine degradation;2-oxoglutarate decarboxylation to succinyl-CoA;Glycine, serine, alanine and threonine metabolism;glycine cleavage (Consensus)

Recessive Scores

• pRec: 0.887

Intolerance Scores

• loftool: 0.429
• rvis_EVS: -0.11
• rvis_percentile_EVS: 45.26

Haploinsufficiency Scores

• pHI: 0.239
• hipred: Y
• hipred_score: 0.540
• ghis: 0.576

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.991

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Dld
• Phenotype: embryo phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); growth/size/body region phenotype

Zebrafish Information Network

• Gene name: dldh
• Affected structure: pericardium
• Phenotype tag: abnormal
• Phenotype quality: edematous

Gene ontology

• Biological process: 2-oxoglutarate metabolic process;mitochondrial electron transport, NADH to ubiquinone;proteolysis;gastrulation;aging;lipoate metabolic process;regulation of membrane potential;cell redox homeostasis;sperm capacitation;dihydrolipoamide metabolic process;mitochondrial acetyl-CoA biosynthetic process from pyruvate;histone succinylation
• Cellular component: nucleus;nucleoplasm;mitochondrion;mitochondrial matrix;motile cilium;acrosomal matrix;myelin sheath;oxoglutarate dehydrogenase complex;pyruvate dehydrogenase complex
• Molecular function: dihydrolipoyl dehydrogenase activity;protein binding;electron transfer activity;pyruvate dehydrogenase (NAD+) activity;lipoamide binding;flavin adenine dinucleotide binding;NAD binding