NM_002834.5(PTPN11):c.166A>G (p.Ile56Val) AND Noonan syndrome and Noonan-related syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 10, 2019
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:: RCV000788006.1

Allele description [Variation Report for NM_002834.5(PTPN11):c.166A>G (p.Ile56Val)]

NM_002834.5(PTPN11):c.166A>G (p.Ile56Val)

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.166A>G (p.Ile56Val)

Other names:

p.I56V:ATT>GTT; NM_002834.4(PTPN11):c.166A>G

HGVS:

NC_000012.12:g.112450346A>G
NG_007459.1:g.36615A>G
NM_001330437.2:c.166A>G
NM_001374625.1:c.163A>G
NM_002834.5:c.166A>GMANE SELECT
NM_080601.3:c.166A>G
NP_001317366.1:p.Ile56Val
NP_001361554.1:p.Ile55Val
NP_002825.3:p.Ile56Val
NP_002825.3:p.Ile56Val
NP_542168.1:p.Ile56Val
LRG_614t1:c.166A>G
LRG_614:g.36615A>G
NC_000012.11:g.112888150A>G
NM_002834.3:c.166A>G
NM_002834.4:c.166A>G

Protein change:

I55V

Links:

dbSNP: rs397507504

NCBI 1000 Genomes Browser:

rs397507504

Molecular consequence:

NM_001330437.2:c.166A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001374625.1:c.163A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_002834.5:c.166A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_080601.3:c.166A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Noonan syndrome and Noonan-related syndrome
Identifiers:: MONDO: MONDO:0020297; MedGen: C5681679; Orphanet: 98733

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000927038	ClinGen RASopathy Variant Curation Expert Panel	reviewed by expert panel (ClinGen RASopathy ACMG Specifications v1)	Pathogenic (May 10, 2019)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 26817465, 19506109 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000927038

ClinGen RASopathy Variant Curation Expert Panel

reviewed by expert panel

(ClinGen RASopathy ACMG Specifications v1)

Pathogenic
(May 10, 2019)

germline

curation

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

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	curation

Citations

PubMed

Mutation Spectrum and Phenotypic Features in Noonan Syndrome with PTPN11 Mutations: Definition of Two Novel Mutations.

Atik T, Aykut A, Hazan F, Onay H, Goksen D, Darcan S, Tukun A, Ozkinay F.

Indian J Pediatr. 2016 Jun;83(6):517-21. doi: 10.1007/s12098-015-1998-6. Epub 2016 Jan 28.

PubMed [citation]

PMID:: 26817465

Dominant-negative ALK2 allele associates with congenital heart defects.

Smith KA, Joziasse IC, Chocron S, van Dinther M, Guryev V, Verhoeven MC, Rehmann H, van der Smagt JJ, Doevendans PA, Cuppen E, Mulder BJ, Ten Dijke P, Bakkers J.

Circulation. 2009 Jun 23;119(24):3062-9. doi: 10.1161/CIRCULATIONAHA.108.843714. Epub 2009 Jun 8.

PubMed [citation]

PMID:: 19506109

Details of each submission

From ClinGen RASopathy Variant Curation Expert Panel, SCV000927038.1

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

Description

The c.166A>G (p.Ile56Val) variant in PTPN11 has been reported as a confirmed de novo occurrence in a patient with clinical features of a RASopathy (PS2; Invitae internal data; GTR Lab ID: 500031; ClinVar SCV000659037.2). The p.Ile56Val variant has been identified in at least 5 independent occurrences in patients with clinical features of a RASopathy (PS4; GeneDx, Partners LMM, Invitae, LabCorp internal data; GTR Lab IDs: 26957, 21766, 500031, 500026; ClinVar SCV SCV000057358.13, SCV000204234.4, SCV000659037.2, SCV000698061.1). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Ile56Val variant may impact the protein (PP3). 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). 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, PS4, PM2, PP3, PP2.

#	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: Apr 20, 2024

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