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

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Apr 1, 2022
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:: RCV000037639.7

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]

Observations:

Condition(s)

Name:: Noonan syndrome (NS)
Synonyms:: Noonan's syndrome; Pseudo-Turner syndrome
Identifiers:: MONDO: MONDO:0018997; MeSH: D009634; MedGen: C0028326; OMIM: PS163950

Recent activity

Clear Turn Off Turn On

Flared nostrils
Flared nostrils

MedGen
Rattus norvegicus Rho GTPase activating protein 15 (Arhgap15), transcript varian...
Rattus norvegicus Rho GTPase activating protein 15 (Arhgap15), transcript variant 2, mRNA
gi|2722708041|ref|NM_001429793.1|

Nucleotide
sodium-coupled monocarboxylate transporter 2 isoform X5 [Homo sapiens]
sodium-coupled monocarboxylate transporter 2 isoform X5 [Homo sapiens]
gi|2462523246|ref|XP_054223800.1|

Protein
sodium-coupled monocarboxylate transporter 2 isoform X3 [Homo sapiens]
sodium-coupled monocarboxylate transporter 2 isoform X3 [Homo sapiens]
gi|2462523240|ref|XP_054223797.1|

Protein

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000061301	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 1, 2022)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 17177198, 20308328, 16358218, 16830086, 12634870, 15987685, 22190897, 11704759, 29493581, 30029678, 29907801, 25741868
SCV000840427	Center of Genomic medicine, Geneva, University Hospital of Geneva	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 13, 2018)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000061301

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 1, 2022)

germline

clinical testing

PubMed (12)
[See all records that cite these PMIDs]

SCV000840427

Center of Genomic medicine, Geneva, University Hospital of Geneva

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 13, 2018)

de novo

clinical testing

PubMed (1)
[See all records that cite this PMID]

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	de novo	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Structural and functional effects of disease-causing amino acid substitutions affecting residues Ala72 and Glu76 of the protein tyrosine phosphatase SHP-2.

Bocchinfuso G, Stella L, Martinelli S, Flex E, Carta C, Pantaleoni F, Pispisa B, Venanzi M, Tartaglia M, Palleschi A.

Proteins. 2007 Mar 1;66(4):963-74.

PubMed [citation]

PMID:: 17177198

Functional effects of PTPN11 (SHP2) mutations causing LEOPARD syndrome on epidermal growth factor-induced phosphoinositide 3-kinase/AKT/glycogen synthase kinase 3beta signaling.

Edouard T, Combier JP, Nédélec A, Bel-Vialar S, Métrich M, Conte-Auriol F, Lyonnet S, Parfait B, Tauber M, Salles JP, Lezoualc'h F, Yart A, Raynal P.

Mol Cell Biol. 2010 May;30(10):2498-507. doi: 10.1128/MCB.00646-09. Epub 2010 Mar 22.

PubMed [citation]

PMID:: 20308328
PMCID:: PMC2863708

See all PubMed Citations (12)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000061301.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

The p.Glu76Asp (c.228G>T) variant in PTPN11 has been reported in at least 10 individuals with clinical features of Noonan syndrome (Musante 2003 PMID: 12634870, Tartaglia 2006 PMID: 16358218, Power 2006 PMID: 16830086, Digilio 2011 PMID: 22190897, Zhu 2018 PMID: 30029678, Leach 2019 PMID: 29907801, LMM data) and has also been reported by other clinical laboratories in ClinVar (Variation ID 40502). It was absent from large population studies. Notably, a different nucleotide substitution at the same position (c.228G>C) resulting in the same amino acid change has been reported in >10 individuals with clinical features of Noonan syndrome (Tartaglia 2001 PMID: 11704759, Tartaglia 2006 PMID: 16358218, Edouard 2010 PMID: 20308328, LMM data). In addition, there are 4 other pathogenic amino acid substitutions at this position (p.Glu76Lys, p.Glu76Ala, p.Glu76Val, p.Glu76Gly); all these variants were also absent in large population studies. In vitro functional studies support an impact on protein function (Keilhack 2005 PMID: 15987685, Bocchinfuso 2007 PMID: 17177198, Edouard 2010 PMID: 20308328). Additionally, this variant lies in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (Gelb 2018 PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Noonan syndrome. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PM5_Strong, PS3_Supporting.

#	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 Center of Genomic medicine, Geneva, University Hospital of Geneva, SCV000840427.1

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

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

Last Updated: Oct 13, 2024

ClinVar

Relating variation to medicine