DLD

dihydrolipoamide dehydrogenase, the group of Pyruvate dehydrogenase complex

Basic information

Region (hg38): 7:107891162-107931730

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

Links

ENSG00000091140NCBI:1738OMIM:238331HGNC:2898Uniprot:P09622AlphaFoldGenCCjaxSfariGnomADPubmedClinVar

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

ConditionInheritanceIntervention CategoriesIntervention/Rationale Manifestation CategoriesReferences
Dihydrolipoyl dehydrogenase deficiencyARBiochemicalThe 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 dichloroacetateBiochemical; Neurologic3769994; 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 (32 variants)
  • not provided (2 variants)
  • DLD-related disorder (1 variants)
  • Inborn genetic diseases (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
160
clinvar
4
clinvar
164
missense
2
clinvar
9
clinvar
93
clinvar
3
clinvar
107
nonsense
15
clinvar
16
clinvar
1
clinvar
32
start loss
1
clinvar
1
frameshift
13
clinvar
28
clinvar
41
inframe indel
0
splice donor/acceptor (+/-2bp)
1
clinvar
21
clinvar
22
splice region
1
8
45
3
57
non coding
3
clinvar
25
clinvar
124
clinvar
29
clinvar
181
Total 32 77 119 287 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)377771
7-107891220-G-A not specified Likely benign (Apr 14, 2017)510914
7-107891241-C-T Pyruvate dehydrogenase E3 deficiency • Leigh syndrome • Pyruvate dehydrogenase complex deficiency Uncertain significance (Jan 13, 2018)909173
7-107891243-G-T Pyruvate dehydrogenase complex deficiency • Leigh syndrome • Pyruvate dehydrogenase E3 deficiency Uncertain significance (Jan 12, 2018)358563
7-107891244-C-G not specified Likely benign (Jan 05, 2017)392114
7-107891253-G-A Pyruvate dehydrogenase E3 deficiency Pathogenic (May 18, 2023)2865401
7-107891256-G-A Pyruvate dehydrogenase E3 deficiency Likely benign (May 23, 2023)1540218
7-107891256-G-C Pyruvate dehydrogenase E3 deficiency Uncertain significance (Dec 18, 2023)2140178
7-107891262-G-A Pyruvate dehydrogenase E3 deficiency Pathogenic (Feb 11, 2019)572549
7-107891263-A-G Pyruvate dehydrogenase E3 deficiency Uncertain significance (Sep 10, 2021)2442023
7-107891268-T-C Pyruvate dehydrogenase E3 deficiency Likely benign (Jul 13, 2023)1119924
7-107891268-T-TG Pyruvate dehydrogenase E3 deficiency Likely pathogenic (May 18, 2022)1726142
7-107891273-A-T Inborn genetic diseases Uncertain significance (Jan 18, 2022)2359320
7-107891274-C-G Pyruvate dehydrogenase E3 deficiency Pathogenic (Aug 21, 2023)1392784
7-107891274-C-T Pyruvate dehydrogenase E3 deficiency Likely benign (Dec 26, 2023)1115179
7-107891275-T-A Inborn genetic diseases Uncertain significance (Dec 12, 2023)3082700
7-107891277-C-T Pyruvate dehydrogenase E3 deficiency Likely benign (Jul 19, 2022)1951524
7-107891279-C-T Pyruvate dehydrogenase E3 deficiency Uncertain significance (Jul 11, 2022)2149368
7-107891280-C-A Pyruvate dehydrogenase E3 deficiency • Leigh syndrome • Pyruvate dehydrogenase complex deficiency Conflicting classifications of pathogenicity (Oct 17, 2023)911148
7-107891280-C-T Pyruvate dehydrogenase E3 deficiency Likely benign (May 02, 2023)1126433
7-107891284-G-A not specified • Pyruvate dehydrogenase complex deficiency • Leigh syndrome • Pyruvate dehydrogenase E3 deficiency Benign/Likely benign (Jan 29, 2024)137103
7-107891286-C-T Pyruvate dehydrogenase E3 deficiency Likely benign (Jul 29, 2023)732787
7-107891290-G-A Pyruvate dehydrogenase E3 deficiency Likely pathogenic (Aug 09, 2023)371615
7-107891292-G-C Pyruvate dehydrogenase E3 deficiency Uncertain significance (Jun 19, 2021)1483123
7-107891296-G-A Pyruvate dehydrogenase E3 deficiency Likely benign (Jul 26, 2023)2747286

GnomAD

Source: gnomAD

GeneTypeBio TypeTranscript Coding Exons Length
DLDprotein_codingprotein_codingENST00000205402 1440761
pLI Probability
LOF Intolerant
pRec Probability
LOF Recessive
Individuals with
no LOFs
Individuals with
Homozygous LOFs
Individuals with
Heterozygous LOFs
Defined p
0.009510.9901257140331257470.000131
Z-Score Observed Expected Observed/Expected Mutation Rate Total Possible in Transcript
Missense1.102202710.8120.00001313295
Missense in Polyphen641150.556531451
Synonymous-0.3419489.91.050.00000448996
Loss of Function3.42928.80.3120.00000157355

LoF frequencies by population

EthnicitySum of pLOFs p
African & African-American0.0001490.000149
Ashkenazi Jewish0.00009930.0000992
East Asian0.0001630.000163
Finnish0.0001390.000139
European (Non-Finnish)0.0001680.000149
Middle Eastern0.0001630.000163
South Asian0.0001310.000131
Other0.0001630.000163

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

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium

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