The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!


Variant: NM_002834.5(PTPN11):c.188A>G (p.Tyr63Cys)

CA220146

13333 (ClinVar)

Gene: PTPN11
Condition: Noonan syndrome
Inheritance Mode: Autosomal dominant inheritance
UUID: 579af108-04e2-4cf7-9a40-35cbaa82b116
Approved on: 2024-09-17
Published on: 2024-10-01

HGVS expressions

NM_002834.5:c.188A>G
NM_002834.5(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
ENST00000639857.2:c.188A>G
ENST00000685487.1:c.188A>G
ENST00000687906.1:c.188A>G
ENST00000688597.1:c.188A>G
ENST00000690210.1:c.188A>G
ENST00000692624.1:c.188A>G
ENST00000351677.7:c.188A>G
ENST00000639857.1:c.188A>G
ENST00000351677.6:c.188A>G
ENST00000392597.5:c.188A>G
ENST00000635625.1:c.188A>G
NM_002834.3:c.188A>G
NM_080601.1:c.188A>G
NM_001330437.1:c.188A>G
NM_002834.4:c.188A>G
NM_080601.2:c.188A>G
NM_001330437.2:c.188A>G
NM_001374625.1:c.185A>G
NM_080601.3:c.188A>G
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Pathogenic

Met criteria codes 6
PS4 PS3 PP3 PP2 PM1 PP1_Strong
Not Met criteria codes 1
PM2

Evidence Links 6

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTPN11 Version 2.1.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The c.188A>G (p.Tyr63Cys) variant in PTPN11 (NM_002834.5(PTPN11):c.188A>G (p.Tyr63Cys)) 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; PMID: 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: PP1_Strong, PS4, PS3, PM1, PP2, PP3 (Version 2.1; 09/17/2024).
Met criteria codes
PS4
6 probands have been identified with NS/ NSML; this code was not applied in the Gelb 2018 paper

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

PP3
Computational prediction tools and conservation analysis suggest that the p.Tyr63Cys 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).
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).

Not Met criteria codes
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
Curation History
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