VKORC1

Inheritance Pattern: AR

Disease ID:MONDO:0011837

Submitter: ClinGen

The relationship between *VKORC1* and combined deficiency of vitamin K-dependent clotting factors, type 2 (VKCFD2), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of July, 2025. *VKORC1* encodes the catalytic subunit of the vitamin K epoxide reductase complex, which is involved in the reduction of inactive vitamin K 2,3-epoxide to active vitamin K (RefSeq, Aug 2015). Patients with VKCFD2 present with severe bleeding manifestations and absent or reduced activity of vitamin K-dependent clotting factors. The condition, VKCFD, type 1 is caused by mutations in the GGCX gene. *VKORC1* was first reported in relation to autosomal recessive VKCFD2 in 2004 (Rost et al, PMID: 14765194). Only one missense variant has been reported in this gene in relation to VKCFD2. While several polymorphisms in *VKORC1* have been reported in association with variability in response to vitamin K antagonists (VKA), this does not constitute a clinical disease entity. These variants have not been included in this curation. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data (3 points): At least 3 patients from 3 families in 5 publications have been reported with the same homozygous missense variant, Arg98Trp, which is considered a mutational hotspot (PMID: 12704386). The variant segregated in 5 additional family members. The mechanism is expected to be biallelic loss of function. Summary of experimental data (3.5 points): This gene-disease association is supported by a knock-out mouse model that recapitulates the bleeding phenotype seen in human patients, however, it is more severe and lethal (PMID: 19492146). *VKORC1* function is not completely understood, but it localizes to the ER and its mislocalization due to the Arg98Trp variant is reported to be the mechanism of disease in VKCFD2 (PMID: 14765194, 24963046). Wild-type *VKORC1* restores VKOR activity in cell culture (PMID: 14765194). In summary, the level of evidence to support the gene-disease relationship of *VKORC1* and autosomal recessive combined deficiency of vitamin K-dependent clotting factors, type 2, is moderate. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally approved by the HT GCEP on 06/24/2020. It was reevaluated on 04/03/2023 and 07/29/2025. As a result of these reevaluations no new evidence was identified and the classification remained at Moderate (SOP Version 11).

Inheritance Pattern: AR

Disease ID:MONDO:0011837

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0007390

Submitter: PanelApp Australia

Inheritance Pattern: Unknown

Disease ID:MONDO:0011837

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0010187

Submitter: Orphanet