DLD
Basic information
Region (hg38): 7:107891162-107931730
Previous symbols: [ "LAD", "GCSL" ]
Links
Phenotypes
GenCC
Source:
- 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:
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
- 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 | 164 | ||||
missense | 93 | 107 | ||||
nonsense | 15 | 16 | 32 | |||
start loss | 1 | |||||
frameshift | 13 | 28 | 41 | |||
inframe indel | 0 | |||||
splice donor/acceptor (+/-2bp) | 21 | 22 | ||||
splice region | 1 | 8 | 45 | 3 | 57 | |
non coding | 25 | 124 | 29 | 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) | ||
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 • Pyruvate dehydrogenase complex deficiency • Leigh syndrome • 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:
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:
- 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