PDK3

pyruvate dehydrogenase kinase 3

Basic information

Region (hg38): X:24465244-24550466

Links

ENSG00000067992 ∙ NCBI:5165 ∙ OMIM:300906 ∙ HGNC:8811 ∙ Uniprot:Q15120 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Charcot-Marie-Tooth disease X-linked dominant 6 (Limited), mode of inheritance: XL
• Charcot-Marie-Tooth disease X-linked dominant 6 (Strong), mode of inheritance: XL
• Charcot-Marie-Tooth disease X-linked dominant 6 (Supportive), mode of inheritance: XL
• Charcot-Marie-Tooth disease X-linked dominant 6 (Definitive), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Charcot-Marie-Tooth disease, X-linked, dominant,6	XL	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	Neurologic	23297365

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PDK3 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PDK3 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			2	27	5	34
missense			60	1	3	64
nonsense			3			3
start loss						0
frameshift			6	1		7
inframe indel			1			1
splice donor/acceptor (+/-2bp)			1	1		2
splice region			7	8	4	19
non coding			1	24	27	52
Total	0	0	74	54	35

Variants in PDK3

This is a list of pathogenic ClinVar variants found in the PDK3 region.

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

Position	Type	Phenotype	Significance	ClinVar
X-24465288-T-G			Benign (Mar 06, 2021)
X-24465305-T-TGCTGCTGCG			Benign (May 20, 2021)
X-24465434-T-C		not specified	Benign (Apr 23, 2014)
X-24465468-C-T		Charcot-Marie-Tooth disease X-linked dominant 6	Uncertain significance (Jun 28, 2019)
X-24465473-G-C		Charcot-Marie-Tooth disease X-linked dominant 6	Uncertain significance (Feb 24, 2022)
X-24465478-T-C		Charcot-Marie-Tooth disease X-linked dominant 6	Uncertain significance (Dec 23, 2023)
X-24465491-G-A		Charcot-Marie-Tooth disease X-linked dominant 6	Benign (Nov 01, 2023)
X-24465497-G-C		Charcot-Marie-Tooth disease X-linked dominant 6 • not specified	Conflicting classifications of pathogenicity (Aug 01, 2023)
X-24465504-G-C		Charcot-Marie-Tooth disease X-linked dominant 6	Uncertain significance (Jun 01, 2021)
X-24465506-G-C		Charcot-Marie-Tooth disease X-linked dominant 6 • PDK3-related disorder	Benign (Nov 13, 2023)
X-24465541-T-A		Charcot-Marie-Tooth disease X-linked dominant 6	Uncertain significance (Mar 14, 2023)
X-24465572-G-A		Charcot-Marie-Tooth disease X-linked dominant 6	Likely benign (Sep 19, 2022)
X-24465574-C-CCA		Charcot-Marie-Tooth disease X-linked dominant 6	Uncertain significance (Oct 29, 2018)
X-24465579-G-A		Charcot-Marie-Tooth disease X-linked dominant 6	Likely benign (Nov 06, 2021)
X-24465579-G-C		Charcot-Marie-Tooth disease X-linked dominant 6	Likely benign (Oct 26, 2022)
X-24465826-G-C			Benign (Mar 26, 2021)
X-24486794-A-C		Charcot-Marie-Tooth disease X-linked dominant 6	Benign (Feb 01, 2024)
X-24494765-ACTT-A		Charcot-Marie-Tooth disease X-linked dominant 6	Uncertain significance (Oct 10, 2023)
X-24494767-T-C		Charcot-Marie-Tooth disease X-linked dominant 6	Likely benign (Sep 29, 2022)
X-24494772-A-G		Charcot-Marie-Tooth disease X-linked dominant 6	Uncertain significance (Feb 10, 2022)
X-24494773-T-C		Charcot-Marie-Tooth disease X-linked dominant 6	Likely benign (Jul 25, 2023)
X-24494784-G-A		Charcot-Marie-Tooth disease X-linked dominant 6	Uncertain significance (Jan 25, 2024)
X-24494783-C-CGAAAGGAACT		Charcot-Marie-Tooth disease X-linked dominant 6	Uncertain significance (Mar 30, 2022)
X-24494795-C-T		Charcot-Marie-Tooth disease X-linked dominant 6	Uncertain significance (Jan 23, 2018)
X-24494815-A-G		Charcot-Marie-Tooth disease X-linked dominant 6	Likely benign (Nov 12, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PDK3	protein_coding	protein_coding	ENST00000441463	12	74617

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.445	0.553	125658	4	1	125663	0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.32	67	146	0.460	0.0000109	2711
Missense in Polyphen		11	39.605	0.27774		697
Synonymous	0.770	47	54.2	0.867	0.00000410	786
Loss of Function	2.75	3	14.2	0.211	0.00000101	293

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000770	0.0000770
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000783	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.0000247	0.0000176
Middle Eastern	0.0000783	0.0000544
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Inhibits pyruvate dehydrogenase activity by phosphorylation of the E1 subunit PDHA1, and thereby regulates glucose metabolism and aerobic respiration. Can also phosphorylate PDHA2. Decreases glucose utilization and increases fat metabolism in response to prolonged fasting, and as adaptation to a high-fat diet. Plays a role in glucose homeostasis and in maintaining normal blood glucose levels in function of nutrient levels and under starvation. Plays a role in the generation of reactive oxygen species. {ECO:0000269|PubMed:10748134, ECO:0000269|PubMed:11486000, ECO:0000269|PubMed:15861126, ECO:0000269|PubMed:16436377, ECO:0000269|PubMed:17683942, ECO:0000269|PubMed:18718909, ECO:0000269|PubMed:22865452}.
• Disease: DISEASE: Charcot-Marie-Tooth disease, X-linked dominant, 6 (CMTX6) [MIM:300905]: A 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 characterized by severely reduced motor nerve conduction velocities (NCVs) (less than 38m/s) and segmental demyelination and remyelination, and primary peripheral axonal neuropathies characterized by normal or mildly reduced NCVs and chronic axonal degeneration and regeneration on nerve biopsy. {ECO:0000269|PubMed:23297365}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Signal Transduction;Regulation of pyruvate dehydrogenase (PDH) complex;Pyruvate metabolism;Pyruvate metabolism and Citric Acid (TCA) cycle;The citric acid (TCA) cycle and respiratory electron transport;Metabolism;Signaling by Retinoic Acid;Signaling by Nuclear Receptors (Consensus)

Recessive Scores

• pRec: 0.124

Intolerance Scores

• loftool: 0.384
• rvis_EVS: 0.13
• rvis_percentile_EVS: 62.74

Haploinsufficiency Scores

• pHI: 0.0724
• hipred: Y
• hipred_score: 0.749
• ghis: 0.481

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.973

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Pdk3

Gene ontology

• Biological process: glucose metabolic process;regulation of acetyl-CoA biosynthetic process from pyruvate;regulation of glucose metabolic process;peptidyl-serine phosphorylation;peroxisome proliferator activated receptor signaling pathway;cellular response to glucose stimulus;cellular response to fatty acid;hypoxia-inducible factor-1alpha signaling pathway;regulation of reactive oxygen species metabolic process
• Cellular component: nucleolus;mitochondrion;mitochondrial matrix
• Molecular function: protein kinase activity;protein serine/threonine kinase activity;pyruvate dehydrogenase (acetyl-transferring) kinase activity;protein binding;ATP binding