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.188A>G (p.Tyr63Cys)

CA220146

13333 (ClinVar)

Gene: PTPN11

Condition: Noonan syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 579af108-04e2-4cf7-9a40-35cbaa82b116

HGVS expressions

NM_002834.4:c.188A>G

NM_002834.4(PTPN11):c.188A>G (p.Tyr63Cys)

NC_000012.12:g.112450368A>G

CM000674.2:g.112450368A>G

NC_000012.11:g.112888172A>G

CM000674.1:g.112888172A>G

NC_000012.10:g.111372555A>G

NG_007459.1:g.36637A>G

NM_002834.3:c.188A>G

NM_080601.1:c.188A>G

NM_001330437.1:c.188A>G

NM_080601.2:c.188A>G

ENST00000351677.6:c.188A>G

ENST00000392597.5:c.188A>G

ENST00000635625.1:n.188A>G

Pathogenic

PS3 PS4 PP2 PP3 PM1 PP1_Strong

PM2

Evidence Links 6

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.188A>G (p.Tyr63Cys) variant in PTPN11 has been reported in the literature in at least 6 unrelated individuals and has been found to segregate with clinical features of a RASopathy in at least 15 family members (PS4, PP1_Strong; 16498234, 12634870, 12325025, 11704759). In vitro functional studies provide some evidence that the p.Tyr63Cys variant may impact protein function (PS3; PMID: 22711529). 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 p.Tyr63Cys variant may impact the protein (PP3). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID 29493581). 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): PP1_Strong, PS4, PS3, PM1, PP2, PP3.

PS3

In vitro functional studies provide some evidence that the p.Tyr63Cys variant may impact protein function (PS3; PMID: 22711529).

Functional characterization identifies that the p.Tyr63Cys variant perturb the stability of the N-SH2/PTP interaction required to maintain SHP2 in its catalytically inactive conformation. PubMed:22711529

PS4

6 probands have been identified with NS/ NSML; this code was not applied in the Gelb 2018 paper

1 proband described (Family N-30) PubMed:11704759

1 proband with Noonan syndrome and a mature cataract PubMed:24219368

2 probands: ( 2 families w/ 9 affecteds and 4 index patients) unclear why there is a differential between number of index patients and famillies, but used the difference between probands and affecteds as the number of segregations PubMed:12634870

2 probands PubMed:12325025

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).

PP3

Computational prediction tools and conservation analysis suggest that the p.Tyr63Cys variant may impact the protein (PP3).

PM1

Variant is within the range of the directly interacting residues between N-SH2 and PTPN domains 58-63 AA

PP1_Strong

The c.188A>G (p.Tyr63Cys) variant in PTPN11 has been reported in the literature to segregate with clinical features of a RASopathy in at least 15 family members (PP1_Strong; 16498234, 12634870, 12325025).

5 segregations: ( 2 families w/ 9 affecteds and 4 index patients) unclear why there is a differential between number of index patients and famillies, but used the difference between probands and affecteds as the number of segregations PubMed:12634870

7 segregations in a family with NS PubMed:16498234

3 segregations: This paper describes two separate families; 1. a mother and her daughter 2. a mother and her two daughters PubMed:12325025

PM2

Initially described as met in previous ClinVar submission but has been identified in East Asian 1/17248 and Latino 1/33576. therefore not met

Approved on: 2017-04-03

Published on: 2019-07-15

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