In silico report on five high-risk protein C pathogenic variants: G403R, P405S, S421N, C238S, and I243T

Area of Science:

• Genetics
• Biochemistry
• Molecular Biology

Background:

• Protein C deficiency is a rare inherited thrombophilia.
• Variants of Uncertain Significance (VUS) in the PROC gene pose diagnostic challenges.
• Accurate classification of PROC VUS is crucial for patient management and genetic counseling.

Purpose of the Study:

• To reclassify five specific PROC variants (C238S, I243T, G403R, P405S, S421N) from VUS to pathogenic.
• To investigate the molecular mechanisms underlying the pathogenicity of these PROC variants.
• To evaluate the potential of these variants as diagnostic markers and therapeutic targets for protein C deficiency.

Main Methods:

• In silico analysis was employed to assess the impact of the five PROC variants.
• Computational tools were used to predict effects on protein structure, function, and properties.
• Analysis included assessment of active site proximity, B-factor gain, phosphorylation site disruption, metal binding, and transmembrane properties.

Main Results:

• Five PROC variants (C238S, I243T, G403R, P405S, S421N) were reclassified as pathogenic.
• G403R is predicted to impair catalytic activity by reducing local coil domain flexibility near the active site.
• S421N disrupts a CK2 phosphorylation site, C238S alters metal binding, and I243T may affect transmembrane properties.

Conclusions:

• The reclassification of these five PROC variants provides critical insights into thrombophilia.
• These pathogenic variants represent promising diagnostic markers for protein C deficiency.
• The identified variants may serve as potential targets for future therapeutic interventions.