Clinical and Molecular Characterization of a Rare KRAS p.Val14Ile Variant in Noonan Syndrome: Integrative Phenotypic Analysis and Molecular Dynamics Simulation

Abstract Noonan syndrome (NS) is a genetically heterogeneous RASopathy caused by dysregulation of the RAS/mitogen-activated protein kinase (RAS/MAPK) signaling pathway. Although PTPN11 is the most frequently implicated gene, KRAS variants are relatively rare, and the genotype–phenotype relationships and molecular consequences of individual KRAS variants remain incompletely understood. Here, we report a patient with NS harboring a rare de novo KRAS variant, NM_004985.4:c.40G > A (p.Val14Ile), and systematically investigated its clinical and potential molecular characteristics. A total of 57 patients with NS carrying KRAS variants were identified from the literature, including 10 patients with p.Val14Ile and 47 patients with other KRAS variants. Comparative clinical analysis showed broadly similar phenotypic profiles between the two groups across most RASopathy-associated organ systems. However, lymphatic and hematological abnormalities were significantly less frequent in the p.Val14Ile group than in the other KRAS variant group (25.00% vs. 86.67%, P = 0.013; OR = 0.05, 95% CI: 0.00–0.77), while differences were also observed in central nervous system and urinary system abnormalities. HPO-based analysis showed an overall trend toward lower odds of the evaluated phenotypes in p.Val14Ile carriers, with a pooled OR of 0.63 (95% CI: 0.42–0.96) under the random-effects model and no significant heterogeneity (I² = 0%, P = 0.7938). ACMG-based assessment, together with multiple in silico prediction tools, supported the pathogenic potential of the variant. Conservation analysis demonstrated that Val14 is highly conserved and located within the P-loop region of the KRAS G domain. Molecular docking showed weaker predicted GTP binding to p.Val14Ile KRAS than to wild-type KRAS (− 7.829 vs. −8.387 kcal·mol⁻¹). Furthermore, 100-ns molecular dynamics simulations revealed increased local fluctuations, altered conformational sampling, reduced hydrogen-bonding interactions, and a less favorable MM/GBSA binding free energy for the mutant KRAS–GTP complex (− 34.27 vs. −48.64 kcal·mol⁻¹). These findings suggest that the p.Val14Ile substitution may alter the conformational dynamics and interaction network of the KRAS–GTP complex without substantially disrupting the overall protein structure. Collectively, this study expands the clinical and molecular spectrum of KRAS -associated NS and provides a potential mechanistic explanation for the phenotypic characteristics of the rare p.Val14Ile variant.