The PTPN11 c.211T>C; p.Phe71Leu variant (rs397507512) has been reported as a germline variant in multiple individuals with Noonan syndrome (Musante 2003, Strullu 2014), and also as a somatic variant in cases of juvenile myeolmonocytic leukemia and related malignancies (Strullu 2014, Tartaglia 2003, Zhange 2011). This variant, like most PTPN11 pathogenic variants associated with Noonan syndrome and childhood malignancies, affects the N-terminal SH2 regulatory domain of the protein (Musante 2003), and multiple other variants affecting this amino acid and other nearby residues have also been reported as pathogenic, including p.Phe71Ile, p.Glu69Gln, p.Lys70Arg, and p.Ala72Gly (Niihori 2005, Musante 2003, Xu 2017, Tartaglia 2001). This variant is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism, and is classified as pathogenic/likely pathogenic in ClinVar (variant ID: 40499). Based on the available evidence, the p.Phe71Leu variant is classified as pathogenic.
ClinVar Genomic variation as it relates to human health
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- Interpretation:
-
Pathogenic/Likely pathogenic
- Review status:
- criteria provided, multiple submitters, no conflicts
- Submissions:
- 8
- First in ClinVar:
- Jan 30, 2015
- Most recent Submission:
- Mar 18, 2023
- Last evaluated:
- Sep 21, 2021
- Accession:
- VCV000040499.21
- Variation ID:
- 40499
- Description:
- single nucleotide variant
Help
NM_002834.5(PTPN11):c.211T>C (p.Phe71Leu)
- Allele ID
- 48969
- Variant type
- single nucleotide variant
- Variant length
- 1 bp
- Cytogenetic location
- 12q24.13
- Genomic location
- 12: 112450391 (GRCh38) GRCh38 UCSC
- 12: 112888195 (GRCh37) GRCh37 UCSC
- HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_002834.5:c.211T>C MANE Select NP_002825.3:p.Phe71Leu missense NM_001330437.2:c.211T>C NP_001317366.1:p.Phe71Leu missense NM_001374625.1:c.208T>C NP_001361554.1:p.Phe70Leu missense NM_080601.3:c.211T>C NP_542168.1:p.Phe71Leu missense NC_000012.12:g.112450391T>C NC_000012.11:g.112888195T>C NG_007459.1:g.36660T>C LRG_614:g.36660T>C LRG_614t1:c.211T>C Q06124:p.Phe71Leu - Protein change
- F71L, F70L
- Other names
- p.F71L:TTT>CTT
- Canonical SPDI
- NC_000012.12:112450390:T:C
- Functional consequence
- -
- Global minor allele frequency (GMAF)
- -
- Allele frequency
- -
- Links
- ClinGen: CA273215
- UniProtKB: Q06124#VAR_015995
- dbSNP: rs397507512
- VarSome
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Aggregate interpretations per condition
| Interpreted condition | Interpretation | Number of submissions | Review status | Last evaluated | Variation/condition record |
|---|---|---|---|---|---|
| Pathogenic | 4 | criteria provided, multiple submitters, no conflicts | Feb 29, 2020 | RCV000033470.16 | |
| Likely pathogenic | 1 | criteria provided, single submitter | Apr 5, 2013 | RCV000151689.4 | |
| Likely pathogenic | 1 | criteria provided, single submitter | Mar 27, 2017 | RCV000586528.1 | |
| Pathogenic | 1 | criteria provided, single submitter | Sep 21, 2021 | RCV000686123.3 | |
| Pathogenic | 1 | no assertion criteria provided | - | RCV003150933.1 |
Help
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation | Variation viewer | Related variants | ||
|---|---|---|---|---|---|---|
| HI score Help | TS score Help | Within gene | All | |||
| PTPN11 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
802 | 816 | |
Submitted interpretations and evidence
Help| Interpretation (Last evaluated) |
Review status (Assertion criteria) |
Condition (Inheritance) |
Submitter | More information | |
|---|---|---|---|---|---|
|
Pathogenic
(Apr 11, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000884431.1
First in ClinVar: May 27, 2015 Last updated: May 27, 2015 |
Comment:
The PTPN11 c.211T>C; p.Phe71Leu variant (rs397507512) has been reported as a germline variant in multiple individuals with Noonan syndrome (Musante 2003, Strullu 2014), and also … (more)
The PTPN11 c.211T>C; p.Phe71Leu variant (rs397507512) has been reported as a germline variant in multiple individuals with Noonan syndrome (Musante 2003, Strullu 2014), and also as a somatic variant in cases of juvenile myeolmonocytic leukemia and related malignancies (Strullu 2014, Tartaglia 2003, Zhange 2011). This variant, like most PTPN11 pathogenic variants associated with Noonan syndrome and childhood malignancies, affects the N-terminal SH2 regulatory domain of the protein (Musante 2003), and multiple other variants affecting this amino acid and other nearby residues have also been reported as pathogenic, including p.Phe71Ile, p.Glu69Gln, p.Lys70Arg, and p.Ala72Gly (Niihori 2005, Musante 2003, Xu 2017, Tartaglia 2001). This variant is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism, and is classified as pathogenic/likely pathogenic in ClinVar (variant ID: 40499). Based on the available evidence, the p.Phe71Leu variant is classified as pathogenic. (less)
|
|
|
Likely pathogenic
(Apr 05, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000199998.5
First in ClinVar: Jan 30, 2015 Last updated: Jan 30, 2015 |
Comment:
The Phe71Leu variant in PTPN11 has not been seen before in our laboratory; howev er it has been reported in the literature in clinical features … (more)
The Phe71Leu variant in PTPN11 has not been seen before in our laboratory; howev er it has been reported in the literature in clinical features of Noonan syndrom e and pediatric acute myeloid leukemia (AML; Musante 2003, Loh 2004, Chan 2006). The Phe71Leu variant has not been identified in large European American and Afr ican American populations by the NHLBI Exome Sequencing Project (http://evs.gs.w ashington.edu/EVS/). This variant has also been identified as an acquired somati c mutation in patients with hematological malignancies (Tartaglia 2006, Tartagli a 2005, Loh 2004, Chan 2006). The majority of identified pathogenic variants in the PTPN11 gene are located in exon 3 and involve the amino acids preceding and following the Phe71 residue, affect the N-SH2 domain, and are gain-of-function/a ctivating variants. Computational analyses (biochemical amino acid properties, c onservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for o r against an impact to the protein. In summary, this variant is likely pathogeni c, though additional studies are required to fully establish its clinical signif icance. (less)
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(Mar 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome 3
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000698068.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The PTPN11 c.211T>C (p.Phe71Leu) variant located in the N-SH2 domain involves the alteration of a conserved nucleotide and 3/4 in silico tools (SNPs&GO … (more)
Variant summary: The PTPN11 c.211T>C (p.Phe71Leu) variant located in the N-SH2 domain involves the alteration of a conserved nucleotide and 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome. The variant of interest has not been observed in 121630 control chromosomes (ExAC and publication controls). Multiple publications have cited the variant in affected individuals diagnosed with Noonan syndrome, pediatric acute myeloid leukemia (AML) or JMML (Juvenile Myelomonocytic Leukemia). The variant of interest has also been indicated as a somatic occurrence in multiple patients with the Leukemic presentation(s). It is important to note that somatic PTPN11 mutations have been reported to exist in up to 35% of patients with JMML while germline PTPN11 mutations cause Noonan syndrome. Furthermore, additonal variants causing the same missense change, c.213T>A and c.213T>G, or another missense change at this position, c.211T>A (p.Phe71Ile) have been reported in the pathogenic spectrum, therefore, indicating the location is important for protein function. In addition, multiple clinical diagnostic laboratories classify the variant as "likely pathogenic/pathogenic." No well-established functional studies supportive of a damaging effect on the protein product have been published. Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as "likely pathogenic." (less)
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Pathogenic
(Feb 29, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000057375.14
First in ClinVar: Apr 04, 2013 Last updated: May 27, 2015 |
Comment:
Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 32164556, 12634870, 24803665, 22681964, 19737548, 18759865, 18286234, 16358218, 14644997, 25097206, 26918529, 32794475) (less)
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Pathogenic
(Sep 21, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
RASopathy
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000813626.3
First in ClinVar: Oct 10, 2018 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces phenylalanine with leucine at codon 71 of the PTPN11 protein (p.Phe71Leu). The phenylalanine residue is moderately conserved and there is a … (more)
This sequence change replaces phenylalanine with leucine at codon 71 of the PTPN11 protein (p.Phe71Leu). The phenylalanine residue is moderately conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with clinical features of PTPN11-related conditions (PMID: 12634870, 14644997, 18759865, 19737548, 25097206; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40499). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This missense change is located in a region of the PTPN11 protein in which a significant number of missense variants have been reported (PMID: 18470943). These observations suggest that this may be a clinically significant region of the protein. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001953193.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001798140.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
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Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Noonan syndrome 1
Affected status: yes
Allele origin:
unknown
|
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand
Accession: SCV003840152.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Number of individuals with the variant: 1
|
Functional evidence
Help| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. | Nykamp K | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28492532 |
| Clonal and microclonal mutational heterogeneity in high hyperdiploid acute lymphoblastic leukemia. | de Smith AJ | Oncotarget | 2016 | PMID: 27683039 |
| Juvenile myelomonocytic leukaemia and Noonan syndrome. | Strullu M | Journal of medical genetics | 2014 | PMID: 25097206 |
| The spectrum of somatic mutations in high-risk acute myeloid leukaemia with -7/del(7q). | McNerney ME | British journal of haematology | 2014 | PMID: 24931631 |
| PTPN11-associated mutations in the heart: has LEOPARD changed Its RASpots? | Lauriol J | Trends in cardiovascular medicine | 2011 | PMID: 22681964 |
| Key pathways are frequently mutated in high-risk childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group. | Zhang J | Blood | 2011 | PMID: 21680795 |
| High resolution melting analysis for mutation detection for PTPN11 gene: applications of this method for diagnosis of Noonan syndrome. | Lo FS | Clinica chimica acta; international journal of clinical chemistry | 2009 | PMID: 19737548 |
| PTPN11 analysis for the prenatal diagnosis of Noonan syndrome in fetuses with abnormal ultrasound findings. | Lee KA | Clinical genetics | 2009 | PMID: 18759865 |
| The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders. | Aoki Y | Human mutation | 2008 | PMID: 18470943 |
| The tyrosine phosphatase Shp2 (PTPN11) in cancer. | Chan G | Cancer metastasis reviews | 2008 | PMID: 18286234 |
| Hyperactivation of the RAS signaling pathway in myelodysplastic syndrome with AML1/RUNX1 point mutations. | Niimi H | Leukemia | 2006 | PMID: 16467864 |
| Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. | Tartaglia M | American journal of human genetics | 2006 | PMID: 16358218 |
| The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease. | Kratz CP | Blood | 2005 | PMID: 15928039 |
| Somatic PTPN11 mutations in childhood acute myeloid leukaemia. | Tartaglia M | British journal of haematology | 2005 | PMID: 15842656 |
| PTPN11 mutations in pediatric patients with acute myeloid leukemia: results from the Children's Cancer Group. | Loh ML | Leukemia | 2004 | PMID: 15385933 |
| Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis. | Loh ML | Blood | 2004 | PMID: 14644997 |
| Spectrum of mutations in PTPN11 and genotype-phenotype correlation in 96 patients with Noonan syndrome and five patients with cardio-facio-cutaneous syndrome. | Musante L | European journal of human genetics : EJHG | 2003 | PMID: 12634870 |
Text-mined citations for rs397507512...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Mar 18, 2023