Familial Detection of a Novel Heterozygous F2 Variant Associated with Moderately Reduced Prothrombin Activity: A Case Report

Introduction Congenital prothrombin deficiency is among the rarest inherited bleeding disorders, with an estimated prevalence of around 1 in 2,000,000. It follows an autosomal-recessive inheritance pattern and is classified into two phenotypes: type I (hypoprothrombinemia) and type II (dysprothrombinemia). Heterozygous carriers typically exhibit prothrombin activity between 40–60% of normal and are often clinically asymptomatic. A family is reported in which a previously unreported heterozygous F2 variant was identified in a father and his two daughters, all exhibiting moderately reduced prothrombin activity and variable clinical findings. Method As part of the evaluation for mild bleeding symptoms, coagulation screening and targeted genetic analysis using Next Generation Sequencing (NGS) were performed in one daughter. NGS data were analyzed using Emedgene Software (Illumina). Following identification of a rare heterozygous F2 variant, familial testing was conducted. Prothrombin activity and aPTT were measured, and bleeding histories as well as CRP and BMI as environmental confounders were documented. Results All three individuals (father and both daughters) were heterozygous for the same F2 variant. Genetic analysis revealed a c.1606T>C substitution in exon 12 of the F2 gene, resulting in the amino acid change p.(Cys536Arg). This variant has not been previously reported in the literature and is not listed in ClinVar (as of 2025); Franklin classifies it as likely pathogenic. In silico analysis using PolyPhen-2 (HumVar and HumDiv both with a score of 1.000) predicts a damaging effect. The affected cysteine residue forms a conserved disulfide bond with Cys550, which is important for proper folding and structural integrity of the protein. Disruption of this bond may impair prothrombin conformation and function. Clinically, the father reported a history of frequent epistaxis during childhood, daily gingival bleeding, and increased bleeding following tooth extractions. One daughter exhibited a tendency to bruise easily and reported mild hypermenorrhea, while the other daughter remained asymptomatic. Conclusion A novel heterozygous F2 variant, c.1606T>C, p.(Cys536Arg), is reported to be associated with moderately reduced prothrombin activity within a family exhibiting variable bleeding symptoms. Structural modeling suggests disruption of a conserved disulfide bond critical for proper protein folding, supporting the likely pathogenic nature of the variant. This case highlights the importance of integrating molecular data, functional predictions, and clinical phenotyping to assess the relevance of rare coagulation factor variants. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany