ClinVar Genomic variation as it relates to human health
NM_002834.5(PTPN11):c.173A>G (p.Asn58Ser)
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.
Likely pathogenic(2); Uncertain significance(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002834.5(PTPN11):c.173A>G (p.Asn58Ser)
Variation ID: 372483 Accession: VCV000372483.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q24.13 12: 112450353 (GRCh38) [ NCBI UCSC ] 12: 112888157 (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 Jun 12, 2018 Apr 15, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002834.5:c.173A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002825.3:p.Asn58Ser missense NM_001330437.2:c.173A>G NP_001317366.1:p.Asn58Ser missense NM_001374625.1:c.170A>G NP_001361554.1:p.Asn57Ser missense NM_080601.3:c.173A>G NP_542168.1:p.Asn58Ser missense NC_000012.12:g.112450353A>G NC_000012.11:g.112888157A>G NG_007459.1:g.36622A>G LRG_614:g.36622A>G LRG_614t1:c.173A>G - Protein change
- N58S, N57S
- Other names
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- Canonical SPDI
- NC_000012.12:112450352:A:G
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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.
Exome Aggregation Consortium (ExAC) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00004
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
Help
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
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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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Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Feb 1, 2024 | RCV000413828.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 11, 2024 | RCV000691488.5 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Feb 22, 2019 | RCV000780655.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 24, 2019 | RCV002411277.1 |
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
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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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Uncertain significance
(Apr 02, 2018)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000918108.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: PTPN11 c.173A>G (p.Asn58Ser) results in a conservative amino acid change located in the first SH2 domain (IPR000980) of the encoded protein sequence. Four … (more)
Variant summary: PTPN11 c.173A>G (p.Asn58Ser) results in a conservative amino acid change located in the first 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 observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.26 fold of the estimated maximal expected allele frequency for a pathogenic variant in PTPN11 causing Noonan Syndrome and Related Conditions phenotype (6.3e-05), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.173A>G in individuals affected with Noonan Syndrome and Related Conditions has been reported. However, c.173A>G (p.Asn58Ser) has been observed previously as a somatic mutation in a lung cancer cell line (Bentires-Alj 2004) and was reported in association with childhood acute lymphoblastic leukemia in an individual as a somatic and germline variant (Case 2008). Other missense variants affecting the same amino acid position have been reported in Noonan syndrome (N58K, N58D, N58K; Kratz 2005, Tartaglia 2006) and childhood acute leukemia (N58Y, somatic, Tartaglia 2004); these reports might indicate the importance of this residue for protein function. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. The c.173A>G has been identified in an internal sample undergoing genetic testing due to abnormal US findings and was confirmed to be is maternally inherited. However, mother was not evaluated by clinical geneticist and, therefore association of N58S with NS remains to be established (internal data). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Feb 22, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002068571.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Uncertain significance
(May 24, 2019)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002715170.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.N58S variant (also known as c.173A>G), located in coding exon 3 of the PTPN11 gene, results from an A to G substitution at nucleotide … (more)
The p.N58S variant (also known as c.173A>G), located in coding exon 3 of the PTPN11 gene, results from an A to G substitution at nucleotide position 173. The asparagine at codon 58 is replaced by serine, an amino acid with highly similar properties. Alternate amino acid substitutions at this position, p.N58H, p.N58D, and p.N58K, have been reported in individuals with Noonan syndrome (Tartaglia M et al. Am. J. Hum. Genet., 2006 Feb;78:279-90). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Number of individuals with the variant: 1
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Uncertain significance
(May 19, 2023)
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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: SCV000490755.8
First in ClinVar: Jan 09, 2017 Last updated: May 27, 2023 |
Comment:
Observed as a somatic variant in a lung cancer cell line (Bentires-Alj et al., 2004) and as a germline variant in an individual with childhood … (more)
Observed as a somatic variant in a lung cancer cell line (Bentires-Alj et al., 2004) and as a germline variant in an individual with childhood acute lymphoblastic leukemia (Case et al., 2008); 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 (HGMD); This variant is associated with the following publications: (PMID: 25695693, 26214590, 15604238, 18701506, 23825065, 23957426, 24480804, 20579941, 27168466, 30050098, 11992261, 9491886, 16053901, 29493581, 35385746, 29625052, 29907801) (less)
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Likely pathogenic
(Jan 11, 2024)
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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: SCV000819269.4
First in ClinVar: Oct 10, 2018 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 58 of the PTPN11 protein (p.Asn58Ser). … (more)
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 58 of the PTPN11 protein (p.Asn58Ser). This variant is present in population databases (rs751437780, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of PTPN11-related conditions (PMID: 29907801). ClinVar contains an entry for this variant (Variation ID: 372483). 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 with a positive predictive value of 95%. 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: 15956085, 16263833, 16804314, 19125092, 25914815). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Likely pathogenic
(Feb 01, 2024)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004700976.2
First in ClinVar: Mar 10, 2024 Last updated: Apr 15, 2024 |
Comment:
PTPN11: PM1, PM5, PP3, PP4
Number of individuals with the variant: 1
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001551408.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The PTPN11 p.Asn58Ser variant was identified in dbSNP (ID: rs751437780), ClinVar (classified as a VUS by Invitae, GeneDx and Integrated Genetics/Laboratory Corporation of America) and … (more)
The PTPN11 p.Asn58Ser variant was identified in dbSNP (ID: rs751437780), ClinVar (classified as a VUS by Invitae, GeneDx and Integrated Genetics/Laboratory Corporation of America) and Cosmic (FATHMM prediction of pathogenic; score=0.99). The variant was also identified in control databases in 10 of 282404 chromosomes at a frequency of 0.000035 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European (non-Finnish) population in 10 of 128726 chromosomes (freq: 0.000078), but not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other or South Asian populations. The N58S variant has been identified somatically in a metastatic breast tumor (Goswami_2015_PMID:25695693). Germline mutations at the same residue (N58H, N58D and N58K) have been identified in patients with Noonan syndrome and LEOPARD syndrome, and the N58Y somatic mutation was identified in patients with hematologic malignancies (Coromilas_2015_PMID:25914815; Tartaglia_2006_PMID:16358218). The p.Asn58 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002034178.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002035009.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
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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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Comparative assessment of gene-specific variant distribution in prenatal and postnatal cohorts tested for Noonan syndrome and related conditions. | Leach NT | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 29907801 |
Nonspecific phenotype of Noonan syndrome diagnosed by whole exome sequencing. | Coromilas A | Clinical case reports | 2015 | PMID: 25914815 |
Hotspot mutation panel testing reveals clonal evolution in a study of 265 paired primary and metastatic tumors. | Goswami RS | Clinical cancer research : an official journal of the American Association for Cancer Research | 2015 | PMID: 25695693 |
Identification of cryptotanshinone as an inhibitor of oncogenic protein tyrosine phosphatase SHP2 (PTPN11). | Liu W | Journal of medicinal chemistry | 2013 | PMID: 23957426 |
Targeting protein tyrosine phosphatase SHP2 for the treatment of PTPN11-associated malignancies. | Yu B | Molecular cancer therapeutics | 2013 | PMID: 23825065 |
Genomic analysis reveals few genetic alterations in pediatric acute myeloid leukemia. | Radtke I | Proceedings of the National Academy of Sciences of the United States of America | 2009 | PMID: 19651601 |
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 |
Mutation of genes affecting the RAS pathway is common in childhood acute lymphoblastic leukemia. | Case M | Cancer research | 2008 | PMID: 18701506 |
The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders. | Aoki Y | Human mutation | 2008 | PMID: 18470943 |
Does the rare A172G mutation of PTPN11 gene convey a mild Noonan syndrome phenotype? | Kitsiou-Tzeli S | Hormone research | 2006 | PMID: 16804314 |
Protein-tyrosine phosphatases and cancer. | Ostman A | Nature reviews. Cancer | 2006 | PMID: 16557282 |
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 |
The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease. | Kratz CP | Blood | 2005 | PMID: 15928039 |
Activating mutations of the noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia. | Bentires-Alj M | Cancer research | 2004 | PMID: 15604238 |
Genetic evidence for lineage-related and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia. | Tartaglia M | Blood | 2004 | PMID: 14982869 |
Crystal structure of the tyrosine phosphatase SHP-2. | Hof P | Cell | 1998 | PMID: 9491886 |
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Text-mined citations for rs751437780 ...
HelpRecord last updated Apr 15, 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.