DHTKD1

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

Basic information

Region (hg38): 10:12068953-12123221

Links

ENSG00000181192 ∙ NCBI:55526 ∙ OMIM:614984 ∙ HGNC:23537 ∙ Uniprot:Q96HY7 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

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

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Charcot-Marie-Tooth disease, axonal, type 2Q; Alpha-aminoadipic and alpha-ketoadipic aciduria	AD/AR	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Biochemical; Musculoskeletal; Neurologic	23141293; 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 (556 variants)
• not provided (123 variants)
• Inborn genetic diseases (57 variants)
• not specified (26 variants)
• Charcot-Marie-Tooth disease axonal type 2Q (21 variants)
• Tip-toe gait (4 variants)
• Charcot-Marie-Tooth disease type 2A2 (3 variants)
• DHTKD1-related condition (3 variants)
• 2-aminoadipic 2-oxoadipic aciduria;Charcot-Marie-Tooth disease axonal type 2Q (2 variants)
• Charcot-Marie-Tooth disease axonal type 2Q;2-aminoadipic 2-oxoadipic aciduria (1 variants)
• Nephrotic syndrome (1 variants)
• - (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.

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			1	122	12	135
missense		1	292	12	4	309
nonsense	10	4				14
start loss			1			1
frameshift	11	5	1			17
inframe indel			3			3
splice donor/acceptor (+/-2bp)		8	4			12
splice region			20	7	2	29
non coding			3	64	49	116
Total	21	18	305	198	65

Highest pathogenic variant AF is 0.0000592

Variants in DHTKD1

This is a list of pathogenic ClinVar variants found in the DHTKD1 region.

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

Position	Type	Phenotype	Significance	ClinVar
10-12069034-A-G		2-aminoadipic 2-oxoadipic aciduria • Charcot-Marie-Tooth disease type 2A2	Conflicting classifications of pathogenicity (May 22, 2019)
10-12069035-T-G		2-aminoadipic 2-oxoadipic aciduria	Uncertain significance (Oct 09, 2023)
10-12069041-C-G		2-aminoadipic 2-oxoadipic aciduria	Uncertain significance (Jan 17, 2024)
10-12069042-T-A		2-aminoadipic 2-oxoadipic aciduria	Likely benign (Jun 17, 2023)
10-12069055-G-A		2-aminoadipic 2-oxoadipic aciduria	Uncertain significance (Sep 07, 2022)
10-12069066-G-A		2-aminoadipic 2-oxoadipic aciduria	Likely benign (Jan 17, 2024)
10-12069069-C-A		2-aminoadipic 2-oxoadipic aciduria	Likely benign (Jun 01, 2021)
10-12069073-G-C		2-aminoadipic 2-oxoadipic aciduria • Inborn genetic diseases	Uncertain significance (Sep 01, 2023)
10-12069073-G-T		2-aminoadipic 2-oxoadipic aciduria	Uncertain significance (Jul 19, 2022)
10-12069074-G-C		2-aminoadipic 2-oxoadipic aciduria	Uncertain significance (Jul 21, 2023)
10-12069079-G-A		2-aminoadipic 2-oxoadipic aciduria	Uncertain significance (Oct 23, 2022)
10-12069082-C-T		2-aminoadipic 2-oxoadipic aciduria	Uncertain significance (Mar 03, 2023)
10-12069085-C-T		2-aminoadipic 2-oxoadipic aciduria	Uncertain significance (Mar 13, 2023)
10-12069090-C-T		DHTKD1-related disorder	Likely benign (Dec 08, 2020)
10-12069091-T-C		2-aminoadipic 2-oxoadipic aciduria • not specified • Charcot-Marie-Tooth disease axonal type 2Q	Benign (Feb 01, 2024)
10-12069091-T-T		2-aminoadipic 2-oxoadipic aciduria	Benign (Jan 31, 2024)
10-12069096-G-T		Charcot-Marie-Tooth disease axonal type 2Q	Uncertain significance (Mar 29, 2024)
10-12069097-C-A		2-aminoadipic 2-oxoadipic aciduria	Uncertain significance (Oct 07, 2023)
10-12069104-A-G		2-aminoadipic 2-oxoadipic aciduria	Uncertain significance (Jul 12, 2022)
10-12069109-ACCGAGCGGGGCGTTTACGGCTACCGGCCGAGGAAGCCCGAGAGCCGCGAG-A		2-aminoadipic 2-oxoadipic aciduria	Conflicting classifications of pathogenicity (Nov 21, 2023)
10-12069127-G-A		2-aminoadipic 2-oxoadipic aciduria	Uncertain significance (Apr 23, 2022)
10-12069133-C-A		2-aminoadipic 2-oxoadipic aciduria	Uncertain significance (Oct 16, 2021)
10-12069135-G-A		2-aminoadipic 2-oxoadipic aciduria	Likely benign (Oct 01, 2022)
10-12069137-C-T		2-aminoadipic 2-oxoadipic aciduria • Inborn genetic diseases	Uncertain significance (Feb 01, 2024)
10-12069146-C-G		2-aminoadipic 2-oxoadipic aciduria	Uncertain significance (Sep 01, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
DHTKD1	protein_coding	protein_coding	ENST00000263035	17	54254

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.79e-30	0.0000951	125588	0	160	125748	0.000636

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.116	539	531	1.01	0.0000294	6007
Missense in Polyphen		175	188.67	0.92756		2120
Synonymous	-1.16	238	216	1.10	0.0000133	1811
Loss of Function	0.160	46	47.2	0.975	0.00000258	511

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00129	0.00126
Ashkenazi Jewish	0.00	0.00
East Asian	0.000499	0.000489
Finnish	0.000189	0.000185
European (Non-Finnish)	0.000816	0.000809
Middle Eastern	0.000499	0.000489
South Asian	0.000718	0.000686
Other	0.000664	0.000652

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

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

Mouse Genome Informatics

• Gene name: Dhtkd1

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