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

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Apr 3, 2017
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000521568.12

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]

Observations:

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000616373	ClinGen RASopathy Variant Curation Expert Panel	reviewed by expert panel (ClinGen RASopathy ACMG Specifications v1)	Pathogenic (Apr 3, 2017)	germline	curation	PubMed (6) [See all records that cite these PMIDs] 22315187, 11992261, 15987685, 17020470, 23584145, 18372317 Citation Link,
SCV002107106	DASA	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 5, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 23584145, 15987685, 22315187, 17020470, 11992261, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000616373

ClinGen RASopathy Variant Curation Expert Panel

reviewed by expert panel

(ClinGen RASopathy ACMG Specifications v1)

Pathogenic
(Apr 3, 2017)

germline

curation

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV002107106

DASA

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 5, 2022)

germline

clinical testing

PubMed (6)
[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	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation

Citations

PubMed

Diverse driving forces underlie the invariant occurrence of the T42A, E139D, I282V and T468M SHP2 amino acid substitutions causing Noonan and LEOPARD syndromes.

Martinelli S, Torreri P, Tinti M, Stella L, Bocchinfuso G, Flex E, Grottesi A, Ceccarini M, Palleschi A, Cesareni G, Castagnoli L, Petrucci TC, Gelb BD, Tartaglia M.

Hum Mol Genet. 2008 Jul 1;17(13):2018-29. doi: 10.1093/hmg/ddn099. Epub 2008 Mar 27.

PubMed [citation]

PMID:: 18372317
PMCID:: PMC2900904

Protein tyrosine phosphatase SHP2/PTPN11 mistargeting as a consequence of SH2-domain point mutations associated with Noonan Syndrome and leukemia.

Müller PJ, Rigbolt KT, Paterok D, Piehler J, Vanselow J, Lasonder E, Andersen JS, Schaper F, Sobota RM.

J Proteomics. 2013 Jun 12;84:132-47. doi: 10.1016/j.jprot.2013.04.005. Epub 2013 Apr 11.

PubMed [citation]

PMID:: 23584145

See all PubMed Citations (7)

Details of each submission

From ClinGen RASopathy Variant Curation Expert Panel, SCV000616373.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (6)

Description

The c.417G>C (p.Glu139Asp) variant in PTPN11 has been reported as a confirmed de novo occurrence in at least 2 patients and at least 5 other independent occurrences in patients with clinical features of a RASopathy (PS2_VeryStrong; PS4; GeneDx, Baylor, BC Children's internal data; SCV000057396.11, SCV000196664.1, SCV000803709.1; GTR Lab ID: 26957, 1006, 249401 PMID: 22315187, 17020470, 11992261). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). In vitro functional studies provide some evidence that the p.Glu139Asp variant may impact protein function (PS3; PMID: 23584145, 15987685, 18372317). 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 c.417G>C (p.Glu139Asp) variant may impact the protein (PP3). 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): PS2_VeryStrong, PS3, PS4, PM2, PP2, PP3.

#	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 DASA, SCV002107106.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (6)

Description

Same amino acid change as a previously established pathogenic variant regardless of nucleotide change (ClinVar ID: 40512 - c.417G>T;p.(Glu139Asp)) PS1.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 23584145; 15987685) - The c.417G>C;p.(Glu139Asp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 40513; PMID: 22315187; PMID: 17020470; PMID: 11992261) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (SH2) - PM1. This variant is not present in population databases (rs397507520- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Missense variant in PTPN11 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.

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

Last Updated: Nov 10, 2024

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