NM_001330437.1:c.1522A>G (p.Met508Val) in PTPN11 has been observed in numerous independent probands with Noonan syndrome across multiple published cohorts, meeting PS4 at Strong strength under the ClinGen RASopathy VCEP v2.3.0 framework.

Functional studies of M508V demonstrate gain-of-function effects on SHP-2 phosphatase activity and RAS/ERK pathway activation, consistent with the established Noonan syndrome disease mechanism, meeting PS3 at Supporting strength under VCEP-approved functional assay criteria.

The REVEL in silico score of 0.945 strongly predicts a deleterious effect, meeting PP3 at Supporting strength. PTPN11 has a missense Z-score >3.09 in gnomAD, meeting PP2 at Supporting strength.

Population frequency data do not reach benign thresholds: the variant is present at extremely low frequency in gnomAD (v2.1: 1/251,490, AF=3.98e-06; v4.1: 2/1,614,162, AF=1.24e-06), far below BA1 (≥0.05%) and BS1 (≥0.025%) thresholds. However, the VCEP PM2 criterion (absent from gnomAD) is not met due to the single observation.

Per the VCEP v2.3.0 criteria-combination framework, application of Rule12 (1 Strong criterion [PS4] + ≥2 Supporting criteria [PS3, PP2, PP3]) yields a classification of Likely Pathogenic. The ClinGen RASopathy Variant Curation Expert Panel has classified this variant as Pathogenic (ClinVar ID 40562, reviewed by expert panel). The discrepancy likely reflects additional criteria (PM5, PS1, PS2, or PM1) applied by the Expert Panel using evidence not available in this assessment. PM5 and PS2 remain not_assessed due to data limitations.

Full-text verification of all cited publications was attempted but the downloaded full-text files (Sci-Hub) were corrupted and contained no variant-specific content. Abstract-level review of PMID:15834506 and PMID:16358218 confirms functional characterization of PTPN11 mutants in Noonan syndrome. Criteria marked needs_human_review reflect this evidence gap.