NM_002834.5(PTPN11):c.417G>C (p.Glu139Asp) AND Noonan syndrome 3

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 28, 2017
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000585988.9

Allele description [Variation Report for NM_002834.5(PTPN11):c.417G>C (p.Glu139Asp)]

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

Gene:

PTPN11:protein tyrosine phosphatase non-receptor type 11 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q24.13

Genomic location:

Preferred name:

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

Other names:

p.E139D:GAG>GAC; NM_002834.4(PTPN11):c.417G>C

HGVS:

NC_000012.12:g.112453279G>C
NG_007459.1:g.39548G>C
NM_001330437.2:c.417G>C
NM_001374625.1:c.414G>C
NM_002834.5:c.417G>CMANE SELECT
NM_080601.3:c.417G>C
NP_001317366.1:p.Glu139Asp
NP_001361554.1:p.Glu138Asp
NP_002825.3:p.Glu139Asp
NP_002825.3:p.Glu139Asp
NP_542168.1:p.Glu139Asp
LRG_614t1:c.417G>C
LRG_614:g.39548G>C
LRG_614p1:p.Glu139Asp
NC_000012.11:g.112891083G>C
NM_001330437.1:c.417G>C
NM_002834.3:c.417G>C
NM_002834.4:c.417G>C
Q06124:p.Glu139Asp

Protein change:

E138D

Links:

UniProtKB: Q06124#VAR_015613; dbSNP: rs397507520

NCBI 1000 Genomes Browser:

rs397507520

Molecular consequence:

NM_001330437.2:c.417G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001374625.1:c.414G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_002834.5:c.417G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_080601.3:c.417G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Noonan syndrome 3 (NS3)
Synonyms:: KRAS gene related Noonan syndrome
Identifiers:: MONDO: MONDO:0012371; MedGen: C1860991; Orphanet: 648; OMIM: 609942

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000698076	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 28, 2017)	germline	clinical testing	LabCorp Variant Classification Summary - May 2015.docx Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000698076

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Aug 28, 2017)

germline

clinical testing

LabCorp Variant Classification Summary - May 2015.docx

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000698076.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Variant summary: The PTPN11 c.417G>C (p.Glu139Asp) variant causes a missense change involving the alteration of a conserved nucleotide located in the SH2 domain (IPR000980) (InterPro). 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). Functional studies demonstrated the SHP2-D139E mutant to exhibit dramatically enhanced catalytic activation (3.5-fold), significant increase in phosphopeptide binding affinity of PTPN11, and approximately 4-fold increase in phosphatase activity after stimulation (Martinelli_2008, Tartaglia_2006). These findings from functional studies further corroborate the established molecular mechanism of disease (Gain of Function) attributed to pathogenic variants in the PTPN11 gene. The variant is absent in the control population datasets of ExAC in 121798 control chromosomes. This variant was reported in multiple patients with Noonan syndrome (Tartaglia_2006, Bertola_2006, Musante_2003). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 10, 2024

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