F8 and hyperinsulinemic hypoglycemia, familial, 4: Conversely, the c.602G > A (p.G201E), c.655G > A (p.A219T), and c.667G > A (p.E223G) missense variants are not associated with significant splicing alterations, indicating that FVIII deficiency is mainly caused by the underlying amino acid substitutions impairing protein biosynthesis/function.