Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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Variant: NM_002834.5(PTPN11):c.417G>C (p.Glu139Asp)

CA177671

40513 (ClinVar)

Gene: PTPN11

Condition: Noonan syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: d42e8a4a-ba52-4c29-8f18-11134760c93e

Approved on: 2017-04-03

Published on: 2024-08-23

HGVS expressions

NM_002834.5:c.417G>C

NM_002834.5(PTPN11):c.417G>C (p.Glu139Asp)

NC_000012.12:g.112453279G>C

CM000674.2:g.112453279G>C

NC_000012.11:g.112891083G>C

CM000674.1:g.112891083G>C

NC_000012.10:g.111375466G>C

NG_007459.1:g.39548G>C

ENST00000639857.2:c.417G>C

ENST00000685487.1:c.417G>C

ENST00000687906.1:c.417G>C

ENST00000688597.1:c.417G>C

ENST00000690210.1:c.417G>C

ENST00000692624.1:c.417G>C

ENST00000351677.7:c.417G>C

ENST00000639857.1:c.417G>C

ENST00000351677.6:c.417G>C

ENST00000392597.5:c.417G>C

ENST00000635625.1:c.417G>C

NM_002834.3:c.417G>C

NM_080601.1:c.417G>C

NM_001330437.1:c.417G>C

NM_002834.4:c.417G>C

NM_080601.2:c.417G>C

NM_001330437.2:c.417G>C

NM_001374625.1:c.414G>C

NM_080601.3:c.417G>C

Pathogenic

PS3 PS4 PP3 PP2 PM2 PS2_Very Strong

Evidence Links 6

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.417G>C (p.Glu139Asp) variant in PTPN11 has been reported as a confirmed de novo occurrence in at least 2 patients and at least 5 other independent occurrences in patients with clinical features of a RASopathy (PS2_VeryStrong; PS4; GeneDx, Baylor, BC Children's internal data; SCV000057396.11, SCV000196664.1, SCV000803709.1; GTR Lab ID: 26957, 1006, 249401 PMID: 22315187, 17020470, 11992261). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). In vitro functional studies provide some evidence that the p.Glu139Asp variant may impact protein function (PS3; PMID: 23584145, 15987685, 18372317). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the c.417G>C (p.Glu139Asp) variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2_VeryStrong, PS3, PS4, PM2, PP2, PP3.

PS3

In vitro functional studies provide some evidence that the p.Glu139Asp variant may impact protein function (PS3; PMID: 23584145, 15987685, 18372317).

Further functional characterization indicating Mutations in SH2 of SHP2 can change their binding properties to known interaction partners PubMed:23584145

Assessed functional impact of the variant and investigated why it has been a highly recurrent variant PubMed:18372317

Finding: "Some SH2 domain mutants (T42A, D106A, and E139D) have only slightly increased basal activity, yet are more potently stimulated by Tyr(P) peptides than WT." PubMed:15987685

PS4

This paper reports the NM_002834.4(PTPN11):c.417G>C variant as well as c.417G>T variant that results in the same AA change. It is not clear how many patients were identified to carry these variants. PubMed:11992261

Case of uniparental disomy in a patient with NS with JMML PubMed:22315187

This paper reports a large cohort of patients, 2 of which carry the p.Glu139Asp variant. It appears that both patients carry the c.417G>C variant. PubMed:17020470

PP3

Computational prediction tools and conservation analysis suggest that the c.417G>C (p.Glu139Asp) variant may impact the protein (PP3).

PP2

The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581).

PM2

This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org).

PS2_Very Strong

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