Identification of novel heterozygous protein C variants associated with type I protein C deficiency

Introduction Protein C (PC) is a vitamin K-dependent serine protease and natural anticoagulant. Genetic mutations in the PROC gene, which encodes PC, can cause hereditary PC deficiency by impairing its function, synthesis, or structure. This deficiency is classified into type I (quantitative, with reduced antigen and activity levels) and type II (qualitative, with normal antigen but reduced activity). PC deficiency is a risk factor of venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE). In this study, six novel heterozygous PROC gene variants were identified in seven unrelated patients, all exhibiting reduced levels of PC antigen (PC:Ag) and functional activity (PC:Act), indicating a type I PC deficiency. Method Thrombophilia screening was conducted as part of the diagnostic evaluation in patients with thrombosis or a family history of thrombophilia. Standard laboratory parameters associated with thrombophilia, including PC:Ag and PC:Act (Clotting (CL) assay and chromogen (CHR) assay) were performed. Next-generation sequencing (NGS) was implemented using a thrombophilia panel. To identify and assess PROC gene variants, NGS data were processed utilizing the Emedgene software platform (Illumina). Results Six novel PROC gene variants, none of which had been reported previously, were identified in seven individuals. Genetic analysis revealed the deletion of three amino acids (p.(Gly114_Gly116del)) in the EGF1-like domain of PROC , potentially affecting protein folding and stability.Two variants in the EGF2-like domain include p.(Cys151Gly), disrupting a conserved disulfide bond crucial for structural integrity, and p.(Arg185GlyfsTer2), an insertion causing a frameshift that leads to a premature stop codon, probably targeting the mRNA for nonsense-mediated decay (NMD). Three additional variants (p.(Ala240Thr); p.(Met406Val); and p.(Thr436Ile)) identified within the protease domain, may alter enzymatic activity or affect folding, stability, transport, or secretion of PC. Individuals harboring these variants exhibited decreased PC:Ag levels [38-57%] alongside diminished PC:Act, as determined by both CHR [38-64%] and CL [36-53%] assay. Four patients experienced either DVT, PE, or both. Meanwhile, three patients had no thromboembolic events at the time of assessment; however, family members exhibited histories of DVT or PE. Conclusion Six novel heterozygous PROC gene variants associated with decreased plasmatic PC:Ag and PC:Act levels were identified. A medical history of VTE was present in the patients carrying these genetic variants or in their family members. The clinical, familial, pathogenetic, and laboratory findings associated with the newly identified variants support the hypothesis that these variants lead to type I PC deficiency and increase the risk of VTE. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany