DHTKD1

dehydrogenase E1 and transketolase domain containing 1, the group of Oxoglutarate dehydrogenase family

Basic information

Region (hg38): 10:12068954-12123221

Links

ENSG00000181192NCBI:55526OMIM:614984HGNC:23537Uniprot:Q96HY7AlphaFoldGenCCjaxSfariGnomADPubmedClinVar

Phenotypes

GenCC

Source: genCC

  • 2-aminoadipic 2-oxoadipic aciduria (Strong), mode of inheritance: AR
  • Charcot-Marie-Tooth disease axonal type 2Q (Supportive), mode of inheritance: AD
  • 2-aminoadipic 2-oxoadipic aciduria (Strong), mode of inheritance: AR
  • Charcot-Marie-Tooth disease axonal type 2Q (Strong), mode of inheritance: AD
  • 2-aminoadipic 2-oxoadipic aciduria (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

ConditionInheritanceIntervention CategoriesIntervention/Rationale Manifestation CategoriesReferences
Charcot-Marie-Tooth disease, axonal, type 2Q; Alpha-aminoadipic and alpha-ketoadipic aciduriaAD/ARGeneralGenetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testingBiochemical; Musculoskeletal; Neurologic23141293; 23141294
In Alpha-aminoadipic and alpha-ketoadipic aciduria, dietary management (with protein restriction) has been reported, but it is not clear whether this was beneficial

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the DHTKD1 gene.

  • 2-aminoadipic_2-oxoadipic_aciduria (807 variants)
  • Inborn_genetic_diseases (158 variants)
  • not_provided (116 variants)
  • DHTKD1-related_disorder (26 variants)
  • Charcot-Marie-Tooth_disease_axonal_type_2Q (26 variants)
  • not_specified (26 variants)
  • Charcot-Marie-Tooth_disease_type_2A2 (4 variants)
  • Tip-toe_gait (4 variants)
  • Peripheral_neuropathy (1 variants)
  • Nephrotic_syndrome (1 variants)
  • Abnormality_of_neuronal_migration (1 variants)
  • Inborn_disorder_of_lysine_and_hydroxylysine_metabolism (1 variants)
  • Distal_amyotrophy (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the DHTKD1 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000018706.7. Only rare variants are included in the table.

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.

EffectPLPVUSLBBSum
synonymous
6
clinvar
184
clinvar
6
clinvar
196
missense
4
clinvar
478
clinvar
17
clinvar
499
nonsense
13
clinvar
8
clinvar
21
start loss
1
1
2
frameshift
14
clinvar
6
clinvar
2
clinvar
22
splice donor/acceptor (+/-2bp)
13
clinvar
6
clinvar
1
clinvar
20
Total 27 32 493 201 7

Highest pathogenic variant AF is 0.0026642366

Loading clinvar variants...

GnomAD

Source: gnomAD

GeneTypeBio TypeTranscript Coding Exons Length
DHTKD1protein_codingprotein_codingENST00000263035 1754254
pLI Probability
LOF Intolerant
pRec Probability
LOF Recessive
Individuals with
no LOFs
Individuals with
Homozygous LOFs
Individuals with
Heterozygous LOFs
Defined p
2.79e-300.000095112558801601257480.000636
Z-Score Observed Expected Observed/Expected Mutation Rate Total Possible in Transcript
Missense-0.1165395311.010.00002946007
Missense in Polyphen175188.670.927562120
Synonymous-1.162382161.100.00001331811
Loss of Function0.1604647.20.9750.00000258511

LoF frequencies by population

EthnicitySum of pLOFs p
African & African-American0.001290.00126
Ashkenazi Jewish0.000.00
East Asian0.0004990.000489
Finnish0.0001890.000185
European (Non-Finnish)0.0008160.000809
Middle Eastern0.0004990.000489
South Asian0.0007180.000686
Other0.0006640.000652

dbNSFP

Source: dbNSFP

Function
FUNCTION: The 2-oxoglutarate dehydrogenase complex catalyzes the overall conversion of 2-oxoglutarate to succinyl-CoA and CO(2). It contains multiple copies of three enzymatic components: 2- oxoglutarate dehydrogenase (E1), dihydrolipoamide succinyltransferase (E2) and lipoamide dehydrogenase (E3) (By similarity). {ECO:0000250}.;
Disease
DISEASE: Charcot-Marie-Tooth disease 2Q (CMT2Q) [MIM:615025]: An axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. {ECO:0000269|PubMed:23141294}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: 2-aminoadipic 2-oxoadipic aciduria (AMOXAD) [MIM:204750]: A metabolic disorder characterized by increased levels of 2- oxoadipate and 2-hydroxyadipate in the urine, and elevated 2- aminoadipate in the plasma. Patients can have mild to severe intellectual disability, muscular hypotonia, developmental delay, ataxia, and epilepsy. Most cases are asymptomatic. {ECO:0000269|PubMed:23141293}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Pathway
Lysine Degradation;Hyperlysinemia I, Familial;2-aminoadipic 2-oxoadipic aciduria;Pyridoxine dependency with seizures;Saccharopinuria/Hyperlysinemia II;Glutaric Aciduria Type I;Hyperlysinemia II or Saccharopinuria;Integrated Breast Cancer Pathway;Metabolism of amino acids and derivatives;2-amino-3-carboxymuconate semialdehyde degradation to glutaryl-CoA;Metabolism;L-kynurenine degradation;Glyoxylate metabolism and glycine degradation;lysine degradation II (pipecolate pathway);lysine degradation I (saccharopine pathway);superpathway of tryptophan utilization;tryptophan degradation (Consensus)

Intolerance Scores

loftool
0.341
rvis_EVS
0.99
rvis_percentile_EVS
90.48

Haploinsufficiency Scores

pHI
0.134
hipred
N
hipred_score
0.352
ghis
0.424

Essentials

essential_gene_CRISPR
N
essential_gene_CRISPR2
N
essential_gene_gene_trap
N
gene_indispensability_pred
N
gene_indispensability_score
0.194

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumHigh
CancerMediumMediumHigh

Mouse Genome Informatics

Gene name
Dhtkd1
Phenotype

Gene ontology

Biological process
hematopoietic progenitor cell differentiation;generation of precursor metabolites and energy;glycolytic process;tricarboxylic acid cycle
Cellular component
mitochondrion;mitochondrial matrix;cytosol;oxoglutarate dehydrogenase complex
Molecular function
oxoglutarate dehydrogenase (succinyl-transferring) activity;thiamine pyrophosphate binding