ClinVar Genomic variation as it relates to human health
NM_002834.5(PTPN11):c.172A>C (p.Asn58His)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002834.5(PTPN11):c.172A>C (p.Asn58His)
Variation ID: 40486 Accession: VCV000040486.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q24.13 12: 112450352 (GRCh38) [ NCBI UCSC ] 12: 112888156 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Feb 19, 2015 Feb 28, 2024 Oct 4, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002834.5:c.172A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002825.3:p.Asn58His missense NM_001330437.2:c.172A>C NP_001317366.1:p.Asn58His missense NM_001374625.1:c.169A>C NP_001361554.1:p.Asn57His missense NM_080601.3:c.172A>C NP_542168.1:p.Asn58His missense NC_000012.12:g.112450352A>C NC_000012.11:g.112888156A>C NG_007459.1:g.36621A>C LRG_614:g.36621A>C LRG_614t1:c.172A>C - Protein change
- N58H, N57H
- Other names
- p.N58H:AAC>CAC
- Canonical SPDI
- NC_000012.12:112450351:A:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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PTPN11 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
944 | 956 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Mar 25, 2022 | RCV000037626.8 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Oct 4, 2023 | RCV000157676.10 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 9, 2022 | RCV000456871.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 11, 2020 | RCV002470725.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Nov 22, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000057359.12
First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018 |
Comment:
The N58H missense variants in the PTPN11 gene has been reported previously in association with autosomal dominant Noonan syndrome (Limal et al., 2006). The N58H … (more)
The N58H missense variants in the PTPN11 gene has been reported previously in association with autosomal dominant Noonan syndrome (Limal et al., 2006). The N58H variant lies in the N-SH2 domain of the gene, which is a hot spot for Noonan syndrome variants and is the first of two sites involved in switching the protein between its inactive and active conformations. The N58H variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. (less)
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Pathogenic
(Mar 21, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000340585.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Oct 23, 2015)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061288.6
First in ClinVar: May 03, 2013 Last updated: May 29, 2016 |
Comment:
The p.Asn58His variant in PTPN11 has been previously identified in at least 8 in dividuals with clinical features of Noonan syndrome or Cardio-facio-cutaneous sy ndrome, … (more)
The p.Asn58His variant in PTPN11 has been previously identified in at least 8 in dividuals with clinical features of Noonan syndrome or Cardio-facio-cutaneous sy ndrome, including two reportedly de novo occurrences (Tartaglia 2006, Limal 2006 , Ezquieta 2012, Bertelloni 2013, LMM unpublished data). It was absent from larg e population studies. In addition, two different amino acid changes at this posi tion (Asn58Asp, Asn58Lys) has also been reported in individuals with clinical fe atures of Noonan syndrome (Mustante 2003, Zenker 2004, Tartaglia 2006, Sherman 2 009, Digilio 2011, Coromilas 2015). Computational prediction tools and conservat ion analysis suggest that this variant may impact the protein, though this infor mation is not predictive enough to determine pathogenicity. In summary, this var iant meets our criteria to be classified as pathogenic for Noonan syndrome in an autosomal dominant manner (http://pcpgmwww.partners.org/personalizedmedicince/L MM) based upon segregation studies and absence from controls. (less)
Number of individuals with the variant: 5
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Pathogenic
(Jul 19, 2021)
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criteria provided, single submitter
Method: clinical testing
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RASopathy
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001774647.1
First in ClinVar: Aug 07, 2021 Last updated: Aug 07, 2021 |
Comment:
Variant summary: PTPN11 c.172A>C (p.Asn58His) results in a conservative amino acid change located in the SH2 domain (IPR000980) of the encoded protein sequence. Four of … (more)
Variant summary: PTPN11 c.172A>C (p.Asn58His) results in a conservative amino acid change located in the SH2 domain (IPR000980) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251000 control chromosomes (gnomAD). c.172A>C has been reported in the literature in multiple individuals affected with Noonan Syndrome (e.g. Tartaglia_2005, Limal_2006, Bertelloni_2013, Hakami_2016, Bessis_2019, Li_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Other missense variants at the same codon (N58D, N58K, N58I) have been classified as pathogenic by our laboratory indicating the asparagine residue is critical for the protein function. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jun 11, 2020)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome 1
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002769147.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms … (more)
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. Metachondromatosis and LEOPARD syndrome have been associated with a loss of function, whereas Noonan syndrome is caused by gain of function variants (OMIM). (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to histidine (exon 3). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (10 heterozygotes, 0 homozygotes). (N) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (SH2 domain; PDB, Decipher). (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Multiple alternative changes at the same residue, to tyrosine, aspartic acid and lysine, have previously been reported as pathogenic in multiple patients with Noonan syndrome (ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as pathogenic in multiple patients with Noonan syndrome (PMID: 16263833, ClinVar). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (less)
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Pathogenic
(Oct 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004562567.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The PTPN11 c.172A>C; p.Asn58His variant (rs397507505) is reported in the literature in several individuals with Noonan syndrome (Hakami 2016, Kiel 2014, Li 2019, Limal 2006). … (more)
The PTPN11 c.172A>C; p.Asn58His variant (rs397507505) is reported in the literature in several individuals with Noonan syndrome (Hakami 2016, Kiel 2014, Li 2019, Limal 2006). This variant is also reported in ClinVar (Variation ID: 40486). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.76). Additionally, the variant is located in the N-SH2 domain of PTPN11 (Hof 1998), and other variants at this residue have been implicated in Noonan syndrome (Tartaglia 2006). Based on available information, the p.Asn58His variant is considered to be pathogenic. References: Hakami F et al. Retrospective study of prenatal ultrasound findings in newborns with a Noonan spectrum disorder. Prenat Diagn. 2016 May;36(5):418-23. PMID: 26918529. Hof P et al. Crystal structure of the tyrosine phosphatase SHP-2. Cell. 1998 Feb 20;92(4):441-50. PMID: 9491886. Kiel C et al. Structure-energy-based predictions and network modelling of RASopathy and cancer missense mutations. Mol Syst Biol. 2014 May 6;10(5):727. PMID: 24803665. Limal JM et al. Noonan syndrome: relationships between genotype, growth, and growth factors. J Clin Endocrinol Metab. 2006 Jan;91(1):300-6. PMID: 16263833. Li X et al. Molecular and phenotypic spectrum of Noonan syndrome in Chinese patients. Clin Genet. 2019 Oct;96(4):290-299. PMID: 31219622. Tartaglia M et al. Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet. 2006 Feb;78(2):279-90. PMID: 16358218. (less)
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Pathogenic
(Jul 09, 2022)
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criteria provided, single submitter
Method: clinical testing
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RASopathy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000549997.6
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asn58 amino acid residue in PTPN11. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asn58 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15001945, 15956085, 19125092). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PTPN11 protein function. ClinVar contains an entry for this variant (Variation ID: 40486). This missense change has been observed in individuals with Noonan syndrome (PMID: 16263833, 16358218, 21204800, 23624134, 23756559). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 58 of the PTPN11 protein (p.Asn58His). (less)
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Pathogenic
(Sep 06, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
de novo
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000511378.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Pathogenic
(Mar 25, 2022)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome
Affected status: yes
Allele origin:
germline
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DASA
Accession: SCV002318975.1
First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022 |
Comment:
The c.172A>C;p.(Asn58His) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 40486; PMID:22465605; PMID:33128510; PMID:16263833; PMID:16358218; … (more)
The c.172A>C;p.(Asn58His) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 40486; PMID:22465605; PMID:33128510; PMID:16263833; PMID:16358218; PMID:23624134; PMID:26918529)- PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (SH2 domain; PMID: 20301303) - PM1. Pathogenic missense variant in this residue have been reported (Clinvar ID: 40487; PMID: 26918529; 15001945; 22465605) - PM5. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 22465605) - PM6. 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 (less)
Number of individuals with the variant: 1
Sex: female
Geographic origin: Brazil
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Pathogenic
(Jan 15, 2015)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV000207647.1
First in ClinVar: Feb 19, 2015 Last updated: Feb 19, 2015 |
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Pathogenic
(Jun 07, 2016)
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no assertion criteria provided
Method: clinical testing
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Noonan syndrome
Affected status: yes
Allele origin:
germline
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Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000805099.1
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
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Germline Functional Evidence
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 germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Phenotype-genotype analysis of 242 individuals with RASopathies: 18-year experience of a tertiary center in Brazil. | Bertola DR | American journal of medical genetics. Part C, Seminars in medical genetics | 2020 | PMID: 33128510 |
Molecular and phenotypic spectrum of Noonan syndrome in Chinese patients. | Li X | Clinical genetics | 2019 | PMID: 31219622 |
Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation. | Bessis D | The British journal of dermatology | 2019 | PMID: 30417923 |
Genomic Classification and Prognosis in Acute Myeloid Leukemia. | Papaemmanuil E | The New England journal of medicine | 2016 | PMID: 27276561 |
The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. | Arber DA | Blood | 2016 | PMID: 27069254 |
Retrospective study of prenatal ultrasound findings in newborns with a Noonan spectrum disorder. | Hakami F | Prenatal diagnosis | 2016 | PMID: 26918529 |
Nonspecific phenotype of Noonan syndrome diagnosed by whole exome sequencing. | Coromilas A | Clinical case reports | 2015 | PMID: 25914815 |
Subclonal mutations in SETBP1 confer a poor prognosis in juvenile myelomonocytic leukemia. | Stieglitz E | Blood | 2015 | PMID: 25395418 |
Juvenile myelomonocytic leukaemia and Noonan syndrome. | Strullu M | Journal of medical genetics | 2014 | PMID: 25097206 |
Structure-energy-based predictions and network modelling of RASopathy and cancer missense mutations. | Kiel C | Molecular systems biology | 2014 | PMID: 24803665 |
Molecular characterization of Chilean patients with a clinical diagnosis of Noonan syndrome. | Rodríguez FA | Journal of pediatric endocrinology & metabolism : JPEM | 2014 | PMID: 24150203 |
Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia. | Sakaguchi H | Nature genetics | 2013 | PMID: 23832011 |
Functional evaluation of circulating hematopoietic progenitors in Noonan syndrome. | Timeus F | Oncology reports | 2013 | PMID: 23756559 |
IGF-I generation test in prepubertal children with Noonan syndrome due to mutations in the PTPN11 gene. | Bertelloni S | Hormones (Athens, Greece) | 2013 | PMID: 23624134 |
Alterations in RAS-MAPK genes in 200 Spanish patients with Noonan and other neuro-cardio-facio-cutaneous syndromes. Genotype and cardiopathy. | Ezquieta B | Revista espanola de cardiologia (English ed.) | 2012 | PMID: 22465605 |
RASopathies: Clinical Diagnosis in the First Year of Life. | Digilio MC | Molecular syndromology | 2011 | PMID: 22190897 |
Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation. | Jongmans MC | European journal of human genetics : EJHG | 2011 | PMID: 21407260 |
Bone resorption in syndromes of the Ras/MAPK pathway. | Stevenson DA | Clinical genetics | 2011 | PMID: 21204800 |
Leukemogenic Ptpn11 causes fatal myeloproliferative disorder via cell-autonomous effects on multiple stages of hematopoiesis. | Chan G | Blood | 2009 | PMID: 19179468 |
Primary mixed glioneuronal tumor of the central nervous system in a patient with noonan syndrome: a case report and review of the literature. | Sherman CB | Journal of pediatric hematology/oncology | 2009 | PMID: 19125092 |
Correlation of clinical features with the mutational status of GM-CSF signaling pathway-related genes in juvenile myelomonocytic leukemia. | Yoshida N | Pediatric research | 2009 | PMID: 19047918 |
Characterization of acute myeloid leukemia with PTPN11 mutation: the mutation is closely associated with NPM1 mutation but inversely related to FLT3/ITD. | Hou HA | Leukemia | 2008 | PMID: 17972951 |
Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. | Tartaglia M | American journal of human genetics | 2006 | PMID: 16358218 |
Noonan syndrome: relationships between genotype, growth, and growth factors. | Limal JM | The Journal of clinical endocrinology and metabolism | 2006 | PMID: 16263833 |
PTPN11 (protein tyrosine phosphatase, nonreceptor type 11) mutations and response to growth hormone therapy in children with Noonan syndrome. | Ferreira LV | The Journal of clinical endocrinology and metabolism | 2005 | PMID: 15956085 |
Prognostic, therapeutic, and mechanistic implications of a mouse model of leukemia evoked by Shp2 (PTPN11) mutations. | Mohi MG | Cancer cell | 2005 | PMID: 15710330 |
PTPN11 mutations in pediatric patients with acute myeloid leukemia: results from the Children's Cancer Group. | Loh ML | Leukemia | 2004 | PMID: 15385933 |
Genotype-phenotype correlations in Noonan syndrome. | Zenker M | The Journal of pediatrics | 2004 | PMID: 15001945 |
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 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PTPN11 | - | - | - | - |
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Text-mined citations for rs397507505 ...
HelpRecord last updated Feb 28, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.