NM_001330437.1:c.417G>C (p.Glu139Asp) is a missense variant in PTPN11 that has been classified as Pathogenic by the ClinGen RASopathy Variant Curation Expert Panel (ClinVar variation ID 40513).

The variant has been observed as de novo with confirmed maternity and paternity in multiple unrelated probands with Noonan syndrome, meeting PS2 at Very_Strong level under the VCEP point-based scoring system (4 points).

Functional studies in two independent publications (Martinelli et al. 2008, PMID:18372317; Mueller et al. 2013, PMID:23584145) demonstrate altered SHP-2 biochemical behavior, ligand-binding properties, and SH2-domain interactions consistent with a gain-of-function mechanism, meeting PS3 at Moderate strength (two different approved assay approaches).

The variant is significantly enriched in affected individuals compared to population controls. It is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (1/1,613,776 alleles; AF=6.2e-7), meeting PS4_Supporting and PM2_Supporting.

In silico predictions support a deleterious effect: the REVEL score is 0.769, meeting the VCEP PP3 threshold of ≥0.7. PTPN11 also has a high missense constraint z-score (>3.09), meeting PP2.

Applying the ClinGen RASopathy VCEP v2.3.0 final classification rules: the variant has PS2_Very_Strong (1) and three Supporting-level criteria (PM2_Supporting, PP2, PP3), satisfying Rule4 which requires PS2_Very_Strong plus ≥2 Supporting criteria for a Pathogenic classification.

The overall classification is Pathogenic for Noonan syndrome and related RASopathies, consistent with the ClinGen RASopathy VCEP expert panel determination.