PTPN11
protein-codingprotein tyrosine phosphatase non-receptor type 11, the group of Protein tyrosine phosphatases non-receptor type|SH2 domain containing
Gene summary
The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains two tandem Src homology-2 domains, which function as phospho-tyrosine binding domains and mediate the interaction of this PTP with its substrates. This PTP is widely expressed in most tissues and plays a regulatory role in various cell signaling events that are important for a diversity of cell functions, such as mitogenic activation, metabolic control, transcription regulation, and cell migration. Mutations in this gene are a cause of Noonan syndrome as well as acute myeloid leukemia. [provided by RefSeq, Aug 2016]
- NS1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~91.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0100082
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0008104
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0008104
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0007893
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007979
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008104
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0009026
Submitter: ClinGen
There has been one reported case suggesting that Costello syndrome (CS) was caused by a de novo PTPN11 variant; however this diagnosis was made prenatally and the pregnancy was terminated (Levaillant et al., 2006). There is no further evidence supporting the pathogenicity of this variant. Furthermore, a cohort of 27 CS patients contained no PTPN11 variants. Therefore, the association is Disputed. The HRAS gene is believed to be the only gene associated with CS (Aoki et al., 2005; Estep, Tidyman, Teitell, Cotter, & Rauen, 2006; Gripp et al., 2006; Kerr et al., 2006; Zampino et al., 2007). Of note, PTPN11 has also been classified as Definitive in association with Noonan syndrome (NS) and NS with multiple lentigines and as Disputed in association with cardiofaciocutaneous syndrome. The ClinGen RASopathy Expert Panel found no evidence associating PTPN11 with NS-like disorder with loose anagen hair. This curation was approved by the ClinGen RASopathy Gene Curation Expert Panel on 5/31/18 (SOP Version 5).
Inheritance Pattern: AD
Disease ID:MONDO:0018997
Submitter: ClinGen
There is a definitive association between alteration of the PTPN11 gene and the Noonan syndrome (NS) phenotype. The maximum amount of scorable genetic evidence has been published showing de novo as well as segregating variants occur in PTPN11 in patients with NS (Atik et al., 2016; Christensen, Yaish, Leon, Sola-Visner, & Agrawal, 2013; Demir, Yntema, Altincik, & Bober, 2010; Gulec, Ocak, Candan, Ataman, & Yarar, 2015; Jefferies, Belmont, Pignatelli, Towbin, & Craigen, 2010; Schollen, Matthijs, Gewillig, Fryns, & Legius, 2003; Tartaglia et al., 2001). Additionally, the mechanism of disease has been characterized as GOF due to increased activity, while PTPN11 variants associated with NS with multiple lentigines (NSML) are predicted to be neomorphic alleles with reduced phosphatase activity (Araki et al., 2004; Maridet, Sole, Morice-Picard, & Taieb, 2016; Oishi et al., 2006; Oishi et al., 2009; Pannone et al., 2017; Yu et al., 2014). The PTPN11 gene is also located in the Ras/MAPK pathway, which is associated with the NS phenotype and variants found in NS patients in this gene disrupt the RAS pathway function as demonstrated by mouse and fly models (Araki et al., 2004; Oishi et al., 2006). Of note, PTPN11 has also been classified as Definitive in association with NSML and as Disputed in association with Costello syndrome and cardiofaciocutaneous syndrome. The ClinGen RASopathy Expert Panel found no evidence associating PTPN11 with NS-like disorder with loose anagen hair. This curation was approved by the ClinGen RASopathy Gene Curation Expert Panel on 7/24/2018 (SOP Version 5).
Inheritance Pattern: AD
Disease ID:MONDO:0015280
Submitter: ClinGen
There has only been one case that was suspected to have cardiofaciocutaneous (CFC) syndrome with a (de novo) PTPN11 variant; however, multiple lentigines appeared later in the disease course, leading to a reevaluation of the initial diagnosis (Kleefstra et al., 2011). Since PTPN11 is Definitively associated with Noonan syndrome with multiple lentigines, this case should not be counted and therefore the PTPN11 association with CFC is Disputed. Of note, PTPN11 has also been classified as Definitive in association with Noonan syndrome (NS) and as Disputed in association with Costello syndrome. The ClinGen RASopathy Expert Panel found no evidence associating PTPN11 with NS-like disorder with loose anagen hair. This curation was approved by the ClinGen RASopathy Gene Curation Expert Panel on 5/30/18 (SOP Version 5).
Inheritance Pattern: AD
Disease ID:MONDO:0100082
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008104
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0007979
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0007979
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0018997
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007893
Submitter: ClinGen
There is a definitive association between alteration of the PTPN11 gene and the Noonan syndrome with multiple lentigines (NSML) phenotype. The maximum amount of scorable genetic evidence has been published showing de novo as well as segregating variants occur in PTPN11 in patients with NSML (Digilio et al., 2002; Kim, Kim, Kim, Lee, & Lee, 2011; Lin, Wang, Chao, Wu, & Lin, 2009; Maridet et al., 2016; Motegi et al., 2015; Sarkozy, 2004). Additionally, the mechanism of disease has been characterized as LOF compared to that of PTPN11-NS, which is GOF (Edouard et al., 2010; Hanna et al., 2006; Marin et al., 2011; Stewart et al., 2010). The PTPN11 gene is also located in the Ras/MAPK pathway, which is associated with the NSML phenotype and variants found in NSML patients in this gene disrupt the RAS pathway function as demonstrated by mouse and zebrafish models (Aoki et al., 2016; Marin et al., 2011; Rauen, 2013; Stewart et al., 2010). Variants observed in NSML patients are predicted to be neomorphic alleles with reduced phosphatase activity (e.g. p.Thr468Met) (Edouard et al., 2010; Hanna et al., 2006; Keilhack, David, McGregor, Cantley, & Neel, 2005; Kontaridis, Swanson, David, Barford, & Neel, 2006; Oishi et al., 2006; Oishi et al., 2009; Tartaglia et al., 2006; Yu et al., 2014). Of note, PTPN11 has also been classified as Definitive in association with NS and as Disputed in association with Costello syndrome and cardiofaciocutaneous syndrome. The ClinGen RASopathy Expert Panel found no evidence associating PTPN11 with NS-like disorder with loose anagen hair. This curation was approved by the ClinGen RASopathy Gene Curation Expert Panel on 7/25/2018 (SOP Version 5).
Inheritance Pattern: AD
Disease ID:MONDO:0100082
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0008104
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0100082
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0007979
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Dermatologic; Genitourinary; Hematologic; Musculoskeletal; Neurologic; Oncologic; Ophthalmologic; Renal
Intervention: Cardiovascular; Hematologic; Oncologic; Renal
Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; Surveillance and treatment related to manifestations such as cardiac anomalies (which include pulmonic stenosis, hypertrophic cardiomyopathy, and arrhythmias) can be beneficial; The conditions can include bleeding diathesis, and recognition and preventive measures (eg, in surgical situations) can be beneficial; Individuals appear to be at increased risk for malignancy, and although specific surveillance may not be warranted, awareness may allow prompt detection and treatment; Awareness of increased risk of renal anomalies and hydronephrosis can allow prophylaxis and early and aggressive management of related manifestations (eg, infections)
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PTPN11 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002834.5. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 2 | 8 | 297 | 7 | 314 | |
| missense | 70 | 93 | 455 | 17 | 5 | 640 |
| nonsense | 12 | 5 | 17 | |||
| start loss | 1 | 1 | ||||
| frameshift | 19 | 3 | 2 | 24 | ||
| splice donor/acceptor (+/-2bp) | 2 | 7 | 6 | 15 | ||
| Total | 103 | 111 | 471 | 314 | 12 | 1011 |
Highest pathogenic variant AF is 0.000018600591
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002825.3 | 15 | MANE Select | |
| Ensembl | ENSP00000340944.3 | 15 | MANE Select | |
| RefSeq | NP_001317366.1 | 15 | Standard | |
| RefSeq | NP_001361554.1 | 15 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| ptpn11a | Danio rerio | Structure: melanocyte Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Chronic myeloid leukemia - Homo sapiens (human)
- Adipocytokine signaling pathway - Homo sapiens (human)
- Renal cell carcinoma - Homo sapiens (human)
- Neurotrophin signaling pathway - Homo sapiens (human)
- Insulin resistance - Homo sapiens (human)
Biological Process
- DNA damage checkpoint
- activation of MAPK activity
- triglyceride metabolic process
- epidermal growth factor receptor signaling pathway
- integrin-mediated signaling pathway
Molecular Function
- phosphotyrosine residue binding
- phosphoprotein phosphatase activity
- protein tyrosine phosphatase activity
- non-membrane spanning protein tyrosine phosphatase activity
- SH3/SH2 adaptor activity
Cellular Component
- nucleus
- nucleoplasm
- cytoplasm
- mitochondrion
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000351677
- Coding exons
- 15
- Length
- 91563
- Individuals with no LoFs
- 123755
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 1
- Defined
- 123756
- p
- 0.00000404
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.13 | 171 | 331 | 0.516 | 0.0000198 | 3938 |
| Missense (PolyPhen) | 50 | 129.77 | 0.38529 | 1662 | ||
| Synonymous | 0.824 | 112 | 124 | 0.906 | 0.00000824 | 1070 |
| Loss of Function | 5.34 | 1 | 35.2 | 0.0284 | 0.00000184 | 417 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.0000091 | 0.0000091 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Acts downstream of various receptor and cytoplasmic protein tyrosine kinases to participate in the signal transduction from the cell surface to the nucleus. Positively regulates MAPK signal transduction pathway (PubMed:28074573). Dephosphorylates GAB1, ARHGAP35 and EGFR (PubMed:28074573). Dephosphorylates ROCK2 at 'Tyr-722' resulting in stimulatation of its RhoA binding activity. Dephosphorylates CDC73 (PubMed:26742426). {ECO:0000269|PubMed:10655584, ECO:0000269|PubMed:18559669, ECO:0000269|PubMed:18829466, ECO:0000269|PubMed:26742426, ECO:0000269|PubMed:28074573}.;
- Disease
- DISEASE: LEOPARD syndrome 1 (LPRD1) [MIM:151100]: A disorder characterized by lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness. {ECO:0000269|PubMed:12058348, ECO:0000269|PubMed:14961557, ECO:0000269|PubMed:15121796, ECO:0000269|PubMed:15389709, ECO:0000269|PubMed:15520399, ECO:0000269|PubMed:15690106, ECO:0000269|PubMed:16679933, ECO:0000269|PubMed:16733669, ECO:0000269|PubMed:24891296, ECO:0000269|PubMed:26742426}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Noonan syndrome 1 (NS1) [MIM:163950]: A form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. Individuals with Noonan syndrome are at risk of juvenile myelomonocytic leukemia, a myeloproliferative disorder characterized by excessive production of myelomonocytic cells. Some patients with NS1 develop multiple giant cell lesions of the jaw or other bony or soft tissues, which are classified as pigmented villonodular synovitis (PVNS) when occurring in the jaw or joints. {ECO:0000269|PubMed:11704759, ECO:0000269|PubMed:11992261, ECO:0000269|PubMed:12161469, ECO:0000269|PubMed:12325025, ECO:0000269|PubMed:12529711, ECO:0000269|PubMed:12634870, ECO:0000269|PubMed:12717436, ECO:0000269|PubMed:12739139, ECO:0000269|PubMed:12960218, ECO:0000269|PubMed:15384080, ECO:0000269|PubMed:15889278, ECO:0000269|PubMed:15948193, ECO:0000269|PubMed:19020799, ECO:0000269|PubMed:24891296, ECO:0000269|PubMed:28074573}. Note=The disease is caused by mutations affecting the gene represented in this entry. Mutations in PTPN11 account for more than 50% of the cases.; DISEASE: Leukemia, juvenile myelomonocytic (JMML) [MIM:607785]: An aggressive pediatric myelodysplastic syndrome/myeloproliferative disorder characterized by malignant transformation in the hematopoietic stem cell compartment with proliferation of differentiated progeny. Patients have splenomegaly, enlarged lymph nodes, rashes, and hemorrhages. {ECO:0000269|PubMed:12717436, ECO:0000269|PubMed:26742426}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Metachondromatosis (MC) [MIM:156250]: A skeletal disorder with radiologic features of both multiple exostoses and Ollier disease, characterized by the presence of exostoses, commonly of the bones of the hands and feet, and enchondromas of the metaphyses of long bones and iliac crest. {ECO:0000269|PubMed:20577567}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.729
Intolerance Scores
- LoFtool
- 0.0482
- RVIS EVS
- -0.43
- RVIS percentile EVS
- 25.15
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- E
- Essential (gene trap)
- K
- Indispensability pred.
- E
- Indispensability score
- 0.991
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |