VKORC1

vitamin K epoxide reductase complex subunit 1

Basic information

Region (hg38): 16:31090841-31095980

Previous symbols: [ "VKCFD2" ]

Links

ENSG00000167397 ∙ NCBI:79001 ∙ OMIM:608547 ∙ HGNC:23663 ∙ Uniprot:Q9BQB6 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• vitamin K-dependent clotting factors, combined deficiency of, type 1 (Supportive), mode of inheritance: AR
• vitamin K-dependent clotting factors, combined deficiency of, type 2 (Limited), mode of inheritance: Unknown
• vitamin K-dependent clotting factors, combined deficiency of, type 2 (Moderate), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Vitamin K-dependent clotting factors, combined deficiency of, 2; Drug metabolism, VKORC1-related	AD/AR	Hematologic; Pharmacogenomic	Individuals may present with severe bleeding episodes (including, for example, fatal neonatal intracranial hemorrhage), and oral administration of vitamin K typically reverses bleeding tendency; Variants may have pharmacogenomic relevance (related to Drug metabolism, VKORC1-related) in regards to selection and dosing of medications (including warfarin)	Hematologic	11154138; 12384421; 14765194; 15930419; 15947090; 15888487; 16611310; 17653141; 18466099; 18535201; 18855533; 19207028; 19228618; 19300499; 20203262; 20833980; 19794411; 21148049; 22431865; 22528326; 23215886; 23276529; 23277416; 23279643; 23677510

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the VKORC1 gene.

• Vitamin K-dependent clotting factors, combined deficiency of, type 2 (22 variants)
• not provided (7 variants)
• warfarin response - Dosage (6 variants)
• not specified (4 variants)
• Warfarin response (3 variants)
• Vitamin K-Dependent Clotting Factors (3 variants)
• VKORC1-related condition (2 variants)
• Thrombus (1 variants)
• acenocoumarol response - Dosage (1 variants)
• Inborn genetic diseases (1 variants)
• phenprocoumon response - Dosage (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the VKORC1 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			5	1	1	7
missense			6	1	2	9
nonsense						0
start loss			1			1
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding			8	2	2	12
Total	0	0	20	4	5

Variants in VKORC1

This is a list of pathogenic ClinVar variants found in the VKORC1 region.

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

Position	Type	Phenotype	Significance	ClinVar
16-31090889-C-T		Vitamin K-dependent clotting factors, combined deficiency of, type 2	Uncertain significance (Jan 13, 2018)
16-31090891-C-T		Vitamin K-dependent clotting factors, combined deficiency of, type 2	Likely benign (Jan 12, 2018)
16-31090962-A-T		Vitamin K-dependent clotting factors, combined deficiency of, type 2	Uncertain significance (Jan 13, 2018)
16-31090989-A-G		Vitamin K-Dependent Clotting Factors	Uncertain significance (Jun 14, 2016)
16-31091000-C-T		warfarin response - Dosage • Vitamin K-dependent clotting factors, combined deficiency of, type 2	drug response (Mar 24, 2021)
16-31091124-G-C		Vitamin K-dependent clotting factors, combined deficiency of, type 2	Uncertain significance (Jan 13, 2018)
16-31091179-A-G		Vitamin K-dependent clotting factors, combined deficiency of, type 2	Uncertain significance (Apr 27, 2017)
16-31091243-A-C		Warfarin response	drug response (Aug 14, 2017)
16-31091247-C-T		Vitamin K-dependent clotting factors, combined deficiency of, type 2	Uncertain significance (Apr 27, 2017)
16-31091268-G-A		Vitamin K-dependent clotting factors, combined deficiency of, type 2	Benign (Jan 13, 2018)
16-31091274-C-G		Vitamin K-dependent clotting factors, combined deficiency of, type 2	Likely benign (Jan 12, 2018)
16-31091284-G-C		Vitamin K-dependent clotting factors, combined deficiency of, type 2	Uncertain significance (Jan 13, 2018)
16-31091334-G-A		Vitamin K-dependent clotting factors, combined deficiency of, type 2	Pathogenic (Feb 05, 2004)
16-31092475-A-G		warfarin response - Dosage	drug response (Mar 24, 2021)
16-31092475-A-A		not specified	Benign (Feb 27, 2018)
16-31092852-G-A		VKORC1-related disorder	Uncertain significance (Aug 29, 2023)
16-31092854-C-T		VKORC1-related disorder	Likely benign (Feb 28, 2019)
16-31092864-T-C		VKORC1-related disorder	Benign (Jun 27, 2019)
16-31093188-C-G		warfarin response - Dosage • not specified	drug response (Mar 24, 2021)
16-31093188-C-T			Likely benign (Sep 21, 2018)
16-31093328-T-A		Vitamin K-dependent clotting factors, combined deficiency of, type 2	Uncertain significance (Jan 13, 2018)
16-31093392-T-C		Vitamin K-dependent clotting factors, combined deficiency of, type 2	Benign (Apr 27, 2017)
16-31093393-G-A		Vitamin K-dependent clotting factors, combined deficiency of, type 2	Uncertain significance (Apr 28, 2017)
16-31093399-C-T		Warfarin response • Vitamin K-dependent clotting factors, combined deficiency of, type 2	Conflicting classifications of pathogenicity (Apr 12, 2018)
16-31093413-C-T		not specified	Uncertain significance (Dec 09, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
VKORC1	protein_coding	protein_coding	ENST00000394975	3	5139

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.162	0.780	125691	0	11	125702	0.0000438

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.305	85	93.3	0.911	0.00000503	1021
Missense in Polyphen		28	36.219	0.77307		434
Synonymous	0.537	38	42.5	0.895	0.00000227	347
Loss of Function	1.55	2	6.16	0.325	2.65e-7	63

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000303	0.000297
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000179	0.0000176
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Involved in vitamin K metabolism. Catalytic subunit of the vitamin K epoxide reductase (VKOR) complex which reduces inactive vitamin K 2,3-epoxide to active vitamin K. Vitamin K is required for the gamma-carboxylation of various proteins, including clotting factors, and is required for normal blood coagulation, but also for normal bone development. {ECO:0000269|PubMed:14765194, ECO:0000269|PubMed:14765195, ECO:0000269|PubMed:15879509, ECO:0000269|PubMed:16270630, ECO:0000269|PubMed:20978134, ECO:0000269|PubMed:22923610}.
• Disease: DISEASE: Combined deficiency of vitamin K-dependent clotting factors 2 (VKCFD2) [MIM:607473]: VKCFD leads to a bleeding tendency that is usually reversed by oral administration of vitamin K. {ECO:0000269|PubMed:14765194, ECO:0000269|PubMed:16270630}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Coumarin resistance (CMRES) [MIM:122700]: A condition characterized by partial or complete resistance to warfarin or other 4-hydroxycoumarin derivatives. These drugs are used as anti- coagulants for the prevention of thromboembolic diseases in subjects with deep vein thrombosis, atrial fibrillation, or mechanical heart valve replacement. {ECO:0000269|PubMed:14765194, ECO:0000269|PubMed:20946155}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Ubiquinone and other terpenoid-quinone biosynthesis - Homo sapiens (human);Warfarin Pathway, Pharmacodynamics;Aminocaproic Acid Action Pathway;Tranexamic Acid Action Pathway;Urokinase Action Pathway;Reteplase Action Pathway;Streptokinase Action Pathway;Tenecteplase Action Pathway;Alteplase Action Pathway;Anistreplase Action Pathway;Aprotinin Action Pathway;Phenindione Action Pathway;Dicoumarol Action Pathway;Warfarin Action Pathway;Acenocoumarol Action Pathway;Vitamin K Metabolism;Coagulation ;Bivalirudin Action Pathway;Argatroban Action Pathway;Ardeparin Action Pathway;Heparin Action Pathway;Fondaparinux Action Pathway;Enoxaparin Action Pathway;Phenprocoumon Action Pathway;Dicumarol Action Pathway;Ximelagatran Action Pathway;Lepirudin Action Pathway;Metabolism of fat-soluble vitamins;Metabolism;Metabolism of vitamins and cofactors;Metabolism of vitamin K (Consensus)

Intolerance Scores

• rvis_EVS: 0.19
• rvis_percentile_EVS: 66.57

Haploinsufficiency Scores

• pHI: 0.177
• hipred: N
• hipred_score: 0.139
• ghis: 0.458

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.979

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Vkorc1
• Phenotype: homeostasis/metabolism phenotype; skeleton phenotype; limbs/digits/tail phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); 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); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan)

Gene ontology

• Biological process: blood coagulation;response to organonitrogen compound;response to organic cyclic compound;drug metabolic process;peptidyl-glutamic acid carboxylation;regulation of blood coagulation;vitamin K metabolic process;response to antibiotic;oxidation-reduction process;bone development
• Cellular component: endoplasmic reticulum;endoplasmic reticulum membrane;integral component of membrane
• Molecular function: vitamin-K-epoxide reductase (warfarin-sensitive) activity;vitamin-K-epoxide reductase (warfarin-insensitive) activity;quinone binding