NM_002834.5(PTPN11):c.228G>T (p.Glu76Asp) AND RASopathy

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Oct 4, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000033478.11

Allele description [Variation Report for NM_002834.5(PTPN11):c.228G>T (p.Glu76Asp)]

NM_002834.5(PTPN11):c.228G>T (p.Glu76Asp)

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.228G>T (p.Glu76Asp)

Other names:

p.E76D:GAG>GAT

HGVS:

NC_000012.12:g.112450408G>T
NG_007459.1:g.36677G>T
NM_001330437.2:c.228G>T
NM_001374625.1:c.225G>T
NM_002834.5:c.228G>TMANE SELECT
NM_080601.3:c.228G>T
NP_001317366.1:p.Glu76Asp
NP_001361554.1:p.Glu75Asp
NP_002825.3:p.Glu76Asp
NP_002825.3:p.Glu76Asp
NP_542168.1:p.Glu76Asp
LRG_614t1:c.228G>T
LRG_614:g.36677G>T
NC_000012.11:g.112888212G>T
NM_001330437.1:c.228G>T
NM_002834.3:c.228G>T
NM_002834.4:c.228G>T
Q06124:p.Glu76Asp
c.228G>T
p.(Glu76Asp)

Protein change:

E75D

Links:

UniProtKB: Q06124#VAR_015610; dbSNP: rs397507514

NCBI 1000 Genomes Browser:

rs397507514

Molecular consequence:

NM_001330437.2:c.228G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001374625.1:c.225G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_002834.5:c.228G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_080601.3:c.228G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: RASopathy
Synonyms:: rasopathies; Noonan spectrum disorder
Identifiers:: MONDO: MONDO:0021060; MedGen: C5555857

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000196662	Baylor Genetics	no assertion criteria provided	Pathogenic	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16358218, 20308328
SCV000698072	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Mar 20, 2017)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 22190897, 16377799, 12634870, 15987685, 12826400, 15928039, 26673822, 16987887, 12717436, 20308328, 15834506, 20186801, 16358218, 25862627, 19077116, 18470943 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV001394745	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 4, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 11704759, 12634870, 16830086, 18678287, 22190897, 15834506, 16358218, 17177198, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000196662

Baylor Genetics

no assertion criteria provided

Pathogenic

unknown

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV000698072

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Mar 20, 2017)

germline

clinical testing

PubMed (16)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV001394745

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 4, 2023)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

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
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects.

Kontaridis MI, Swanson KD, David FS, Barford D, Neel BG.

J Biol Chem. 2006 Mar 10;281(10):6785-92. Epub 2005 Dec 23.

PubMed [citation]

PMID:: 16377799

Diverse biochemical properties of Shp2 mutants. Implications for disease phenotypes.

Keilhack H, David FS, McGregor M, Cantley LC, Neel BG.

J Biol Chem. 2005 Sep 2;280(35):30984-93. Epub 2005 Jun 29.

PubMed [citation]

PMID:: 15987685

See all PubMed Citations (21)

Details of each submission

From Baylor Genetics, SCV000196662.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant classified using ACMG guidelines

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000698072.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

Variant summary: The PTPN11 c.228G>T (p.Glu76Asp) variant causes a missense change involving the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 122184 control chromosomes (ACMG PM2). This variant is found in the N-SH2 domain (IPR000980), a regulatory module of intracellular signaling cascades through its interaction with high affinity to phosphotyrosine-containing target peptides (ACMG PM1). This is a hotspot, with multiple missense variants in the same residue being known likely pathogenic variants (p.Glu76Lys, p.Glu76Ala, p.Glu76Val, p.Glu76Gly). In addition, multiple functional studies (Tartaglia_AJHG_2006, Edouard_MCB_2010, Keilhack_JBC_2005) showed that this variant increased basal and stimulated phosphatase activity by as much as 3-fold, determining a gain-of-function phenotype (ACMG PS3). This variant, and another variant c.228G>C that leads to the same amino acid change (E76D) have been reported in several patients with a clinical diagnosis of Noonan syndrome (ACMG PS1). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic (ACMG PP5). Lastly, these evidences support the classification of this variant as "Pathogenic" based upon ACMG guidelines (PS1, PS3, PM1, PM2, PP5). 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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001394745.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 76 of the PTPN11 protein (p.Glu76Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome (PMID: 11704759, 12634870, 16830086, 18678287, 22190897). ClinVar contains an entry for this variant (Variation ID: 40502). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PTPN11 protein function. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 15834506, 16358218, 17177198). For these reasons, this variant has been 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: Oct 13, 2024

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