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]

Link to SEPIO compliant JSON-LD document

Variant: NM_002834.4(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

HGVS expressions

NM_002834.4:c.417G>C

NM_002834.4(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

NM_002834.3:c.417G>C

NM_080601.1:c.417G>C

NM_001330437.1:c.417G>C

NM_080601.2:c.417G>C

ENST00000351677.6:c.417G>C

ENST00000392597.5:c.417G>C

ENST00000635625.1:n.417G>C

Pathogenic

PS2_Very Strong PM2 PS3 PS4 PP3 PP2

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.

PS2_Very Strong

This variant has been seen in multiple confirmed de novo individuals referred for testing at GeneDx, Baylor, Genome clinic of geneva (PM6), Molecular genetics laboratory, BC childrens and BC women's hospital. This code is different from the PM6 that was used to classify the variant for the Gelb 2018 paper. May want to confirm with GeneDx that there have been at least 2 confirmed de novo cases.

PM2

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

PS3

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

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

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

PS4

Cannot be confidently assumed based on the ambiguous number of cases presented in both publications. However....may want to use PS4 because there are 36 individuals from 25 families that have been submitted to ClinVar, many of which have been diagnosed with a RASopathy. 22315187, 17020470, 11992261

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

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

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).

Approved on: 2017-04-03

Published on: 2019-06-28

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.