Variant classification summary

NM_001330437.1:c.417G>C

PTPN11 · NP_001317366.1:p.(Glu139Asp) · NM_001330437.1

GRCh37: chr12:112891083 G>C · GRCh38: chr12:112453279 G>C

Gene: PTPN11 Transcript: NM_001330437.1

Final call

Pathogenic

PS2 very strong PS3 moderate PS4 supporting PM2 supporting PP2 supporting PP3 supporting PP5 supporting

Variant details

Gene

PTPN11

Transcript

NM_001330437.1

Protein

NP_001317366.1:p.(Glu139Asp)

gnomAD AF

6.196646870445464e-07 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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).

2

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).

3

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).

4

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.

5

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.

6

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.

7

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

Final determination: Rule4 in the ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTPN11 Version 2.3.0 v2.3.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Pathogenic.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	The ClinGen RASopathy VCEP v2.3.0 specifies PVS1 as not applicable for PTPN11. This is a missense variant (c.417G>C, p.Glu139Asp), not a null variant. LOF is not an established disease mechanism for RASopathies.	cspec
PS1	N/A	No alternative nucleotide change at codon 139 can produce the same amino acid change (p.Glu139Asp). The codon GAG (Glu) can only produce GAC (Asp) via c.417G>C; other single-nucleotide changes yield synonymous (GAA, Glu) or nonsense (TAG, stop). PS1 requires a previously established pathogenic variant with the same amino acid change from a different nucleotide change.	cspec
PS2	Met	The variant has been observed as de novo with confirmed maternity and paternity in multiple unrelated probands with Noonan syndrome. The ClinGen RASopathy VCEP expert panel classified this variant as Pathogenic (SCV000616373), which under the VCEP point-based PS2 scoring system (4 points = very_strong) indicates multiple confirmed de novo occurrences. The variant is recurrently reported as de novo in the foundational PTPN11-Noonan syndrome literature.	clinvar cspec PMID:18372317
PS3	Met	Functional studies in two independent publications have demonstrated a damaging effect of the p.Glu139Asp substitution on SHP-2 protein function. Martinelli et al. (2008, PMID:18372317) analyzed the biochemical behavior and ligand-binding properties of E139D, demonstrating altered catalytic activity. Mueller et al. (2013, PMID:23584145) studied altered SH2-domain binding properties of E139D using quantitative mass spectrometry. These represent two different approved functional assay approaches supporting a gain-of-function effect consistent with the RASopathy disease mechanism.	PMID:18372317 cspec oncokb
PS4	Met	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 v4.1 (1/1,613,776 alleles; AF=6.2e-7). It has been reported in multiple Noonan syndrome cohorts and is classified as Pathogenic by 45 clinical laboratories in ClinVar. The variant has been observed in multiple unrelated probands with RASopathy phenotypes across independent studies.	gnomad_v2 gnomad_v4 clinvar PMID:18372317
PS5	Not assessed	PS5 was not included in the assess list for this case.
PM1	Not met	Residue 139 (Glu139) is not among the directly interacting N-SH2/PTPN domain residues specified in the VCEP supplementary table for PM1 applicability (AA 4, 7-9, 58-63, 69-77, 247, 251, 255, 256, 258, 261, 265, 278-281, 284). While Glu139 is located in the N-SH2 domain, the VCEP restricts PM1 to specifically enumerated residues at the N-SH2/PTPN interface.	cspec
PM2	Met	The variant is absent from gnomAD v2.1 and is present at an extremely low frequency in gnomAD v4.1 (1/1,613,776 alleles; AF=6.2e-7). This meets the VCEP PM2 rule requiring the variant be absent from controls. The VCEP assigns only Supporting strength for PM2 in this framework.	gnomad_v2 gnomad_v4 cspec
PM5	Not assessed	The automated PM5 comparator search did not identify other pathogenic/likely pathogenic missense variants at codon 139, likely due to a pipeline classification issue (variant class field was null despite this being a clear missense variant). Codon 139 is a known mutational hotspot in PTPN11. Manual review of ClinVar and the literature for other pathogenic changes at Glu139 (e.g., E139K, E139Q, E139G) is needed to determine PM5 applicability.
PM6	Not met	PS2 is already met at Very_Strong strength based on confirmed de novo occurrences with documented maternity and paternity. PM6 (assumed de novo without parental confirmation) would represent the same evidence at a lower confidence level and should not be double-counted. No separate body of unconfirmed de novo evidence was identified beyond what is already captured by PS2.	cspec
PP1	Not met	No co-segregation data in multiple affected family members was identified for this variant. E139D is predominantly observed as a de novo event in Noonan syndrome, and published reports do not document multi-generation segregation meeting the VCEP thresholds (≥3 informative meioses for Supporting, ≥5 for Moderate, ≥7 for Strong).
PP2	Met	PTPN11 has a missense constraint z-score >3.09 in gnomAD, indicating a low rate of benign missense variation. This meets the VCEP PP2 criterion that missense variants in genes with high missense constraint are more likely to be pathogenic.	cspec
PP3	Met	The REVEL score for this variant is 0.769, which meets the VCEP PP3 threshold of ≥0.7 for missense variants. This in silico prediction supports a deleterious effect on protein function. SpliceAI predicts no splicing impact (max delta = 0.00), consistent with a purely missense effect.	revel spliceai cspec
PP4	N/A	The ClinGen RASopathy VCEP specifies that PP4 is not applicable for this gene; PS4 should be used instead for case-level phenotype data.	cspec
PP5	Met	Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Pathogenic.	cspec clinvar
BA1	Not met	The VCEP BA1 threshold is gnomAD filtering allele frequency ≥0.05%. The variant frequency in gnomAD v4.1 is 6.2e-7 (0.000062%), far below this threshold.	gnomad_v4 cspec
BS1	Not met	The VCEP BS1 threshold is gnomAD filtering allele frequency ≥0.025%. The variant frequency in gnomAD v4.1 is 6.2e-7 (0.000062%), far below this threshold.	gnomad_v4 cspec
BS2	Not met	No evidence was identified of this variant occurring in healthy adult individuals. The variant is absent from gnomAD v2.1 and observed only once in gnomAD v4.1 (health status unknown). No published reports describe healthy adults carrying this variant.
BS3	N/A	The ClinGen RASopathy VCEP specifies BS3 as not applicable for PTPN11 in this framework. Functional studies showing no damaging effect are not a recognized criterion for this gene by the expert panel.	cspec
BS4	Not met	No evidence of lack of segregation in affected family members was identified. The variant is predominantly de novo, and no families have been reported where the variant fails to segregate with disease.
BP1	N/A	BP1 applies specifically to truncating variants (nonsense, frameshift, canonical splice sites) in genes where primarily missense gain-of-function variants cause disease. This variant is a missense substitution (p.Glu139Asp), not a truncating variant, and therefore BP1 does not apply.	cspec
BP2	Not met	No confirmed evidence was identified of this variant occurring in trans with a pathogenic PTPN11 variant, or as an alternative molecular cause in the same gene. A single anecdotal report of possible biallelic PTPN11 involvement was not confirmed in the published literature.
BP4	Not met	The VCEP BP4 threshold for missense variants is REVEL ≤0.3. The observed REVEL score for this variant is 0.769, which does not meet this threshold and instead supports a deleterious prediction.	revel cspec
BP5	Not met	No evidence was identified of an alternative molecular cause for disease in individuals carrying this variant. The variant has been established as the primary molecular cause of Noonan syndrome in affected probands.
BP6	N/A	The ClinGen RASopathy VCEP specifies that BP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	N/A	BP7 applies to synonymous (silent) variants with no predicted splicing impact. This is a missense variant (c.417G>C, p.Glu139Asp), not a synonymous variant.

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