NM_002834.5(PTPN11):c.166A>G (p.Ile56Val) AND Noonan syndrome 1

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Nov 15, 2021
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:: RCV000995619.7

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]

Observations:

Condition(s)

Name:: Noonan syndrome 1 (NS1)
Synonyms:: Turner Syndrome, Male; Turner phenotype with normal karyotype; Female pseudo-Turner syndrome
Identifiers:: MONDO: MONDO:0008104; MedGen: C4551602; Orphanet: 648; OMIM: 163950

Recent activity

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Handroanthus impetiginosus isolate UFG-1 CDL12_scaffold3059, whole genome shotgu...
Handroanthus impetiginosus isolate UFG-1 CDL12_scaffold3059, whole genome shotgun sequence
gi|1276252584|gb|NKXS01003058.1||gn :NKXS01|CDL12_scaffold3059

Nucleotide
Handroanthus impetiginosus isolate UFG-1 CDL12_scaffold3060, whole genome shotgu...
Handroanthus impetiginosus isolate UFG-1 CDL12_scaffold3060, whole genome shotgun sequence
gi|1276252576|gb|NKXS01003059.1||gn :NKXS01|CDL12_scaffold3060

Nucleotide
DC049038 Osada Taira anterior endomesoderm (AEM) pCS105 cDNA library Xenopus lae...
DC049038 Osada Taira anterior endomesoderm (AEM) pCS105 cDNA library Xenopus laevis cDNA clone xlk141l03ex 5', mRNA sequence
gi|118987517|gnl|dbEST|43288040|dbj 9038.1|

Nucleotide
DC019780 Osada Taira anterior endomesoderm (AEM) pCS105 cDNA library Xenopus lae...
DC019780 Osada Taira anterior endomesoderm (AEM) pCS105 cDNA library Xenopus laevis cDNA clone rxlk1j11ex 3', mRNA sequence
gi|118997360|gnl|dbEST|43297883|dbj 9780.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001149898	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Likely pathogenic (Jun 6, 2018)	de novo	clinical testing	Citation Link,
SCV001573019	Genomic Medicine Lab, University of California San Francisco - CSER-P3EGS	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 26, 2020)	maternal	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002761907	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 15, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 32410215, 33619735, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001149898

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

criteria provided, single submitter

(Classification criteria August 2017)

Likely pathogenic
(Jun 6, 2018)

de novo

clinical testing

Citation Link,

SCV001573019

Genomic Medicine Lab, University of California San Francisco - CSER-P3EGS

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 26, 2020)

maternal

clinical testing

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

SCV002761907

Genetics and Molecular Pathology, SA Pathology

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Nov 15, 2021)

germline

clinical testing

PubMed (3)
[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	maternal	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	de novo	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Prenatal exome sequencing in fetuses with congenital heart defects.

Li R, Fu F, Yu Q, Wang D, Jing X, Zhang Y, Li F, Li F, Han J, Pan M, Zhen L, Li D, Liao C.

Clin Genet. 2020 Sep;98(3):215-230. doi: 10.1111/cge.13774. Epub 2020 Jun 9.

PubMed [citation]

PMID:: 32410215

De novo variants in neurodevelopmental disorders-experiences from a tertiary care center.

Brunet T, Jech R, Brugger M, Kovacs R, Alhaddad B, Leszinski G, Riedhammer KM, Westphal DS, Mahle I, Mayerhanser K, Skorvanek M, Weber S, Graf E, Berutti R, Necpál J, Havránková P, Pavelekova P, Hempel M, Kotzaeridou U, Hoffmann GF, Leiz S, Makowski C, et al.

Clin Genet. 2021 Jul;100(1):14-28. doi: 10.1111/cge.13946. Epub 2021 Mar 1.

PubMed [citation]

PMID:: 33619735

See all PubMed Citations (3)

Details of each submission

From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV001149898.1

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

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

From Genomic Medicine Lab, University of California San Francisco - CSER-P3EGS, SCV001573019.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	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	maternal	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetics and Molecular Pathology, SA Pathology, SCV002761907.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The PTPN11 c.166A>G variant is a single nucleotide change in exon 3/16 of the PTPN11 gene, which is predicted to change the amino acid isoleucine at position 56 in the protein to valine. This variant is absent from population databases (PM2), but has been reported at least 4 times in the literature in patients with a clinical presentation of Noonan syndrome or RASopathy (PS4_Moderate). A different pathogenic missense change, p.Ile56Thr, has been reported before at the same amino acid position (PM5). This variant has been identified as a de novo variant in at least two affected patients with no family history of this condition (Li et al, 2020 PMID: 32410215; Brunet et al, 2021 PMID 33619735) (PS2). The variant has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 40485). The variant has been reported in the HGMD database: CM161482. Computational predictions support a deleterious effect on the gene or gene product (PP3).

#	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		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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