ClinVar Genomic variation as it relates to human health
NM_002834.5(PTPN11):c.182A>T (p.Asp61Val)
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.182A>T (p.Asp61Val)
Variation ID: 40496 Accession: VCV000040496.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q24.13 12: 112450362 (GRCh38) [ NCBI UCSC ] 12: 112888166 (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 Oct 10, 2018 Feb 14, 2024 Nov 7, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002834.5:c.182A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002825.3:p.Asp61Val missense NM_001330437.2:c.182A>T NP_001317366.1:p.Asp61Val missense NM_001374625.1:c.179A>T NP_001361554.1:p.Asp60Val missense NM_080601.3:c.182A>T NP_542168.1:p.Asp61Val missense NC_000012.12:g.112450362A>T NC_000012.11:g.112888166A>T NG_007459.1:g.36631A>T LRG_614:g.36631A>T LRG_614t1:c.182A>T Q06124:p.Asp61Val - Protein change
- D61V, D60V
- Other names
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- Canonical SPDI
- NC_000012.12:112450361:A:T
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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 |
954 | 966 |
Conditions - Germline
Condition
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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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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 7, 2023 | RCV000687319.11 |
Submissions - Germline
Classification
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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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Pathogenic
(Nov 07, 2023)
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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: SCV004223451.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
Variant summary: PTPN11 c.182A>T (p.Asp61Val) results in a non-conservative amino acid change located in the SH2 domain of the encoded protein sequence. Five of five … (more)
Variant summary: PTPN11 c.182A>T (p.Asp61Val) results in a non-conservative amino acid change located in the SH2 domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251014 control chromosomes. c.182A>T has been reported in the literature in individuals affected with Noonan Syndrome, as well as patients with JMML, AML, and other Noonan syndrome-related phenotypes (ie. Mohan_2022, Tartaglia_2004, Kratz_2005, etc). D61V confers a gain of function to the Ptpn11 protein as demonstrated by increased macrophage progenitor proliferation and colony formation (Chan_2005), hypersensitivity to ligand stimulation and increased Erk phosphorylation (Chan_2005), and elevated basal phosphatase activity in cultured cells (PMID: 30375388). Several other variants affecting the same codon have been reported as pathogenic/likely pathogenic (p.Asp61Asn, p.Asp61Tyr, p.Asp61His, p.Asp61Gly, p.Asp61Ala). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Nov 26, 2019)
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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: SCV000814882.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. The p.Asp61 amino acid residue in PTPN11 has been determined to be clinically significant (PMID:¬†25039348,¬†15521065,¬†11992261, … (more)
For these reasons, this variant has been classified as Pathogenic. The p.Asp61 amino acid residue in PTPN11 has been determined to be clinically significant (PMID: 25039348, 15521065, 11992261, 26242988, 24803665, 27521173, 20112233, 24803665, 11704759, 15273746, 24718990, 26242988, 15987685, 24803665, 16377799, 19835954, 25383899, 28366775, 24628801, 22371576, 27521173, 19008228, 20651068, 19927903). This suggests that variants that disrupt this residue are likely to be causative of disease. Experimental studies have shown that this missense change demonstrates hypersensitivity to granulocyte-macrophage colony-stimulating factor leading to sustained phospho-Erk activation (PMID: 17053061, 15644411). This variant has been observed in several patients affected with acute myeloid leukemia, myelodysplastic syndrome, and juvenile myelomonocytic leukemia (JMML) (PMID: 14982869, 12717436, 25097206, 18470943, 15928039, 23832011). It has also been observed to be de novo in an individual with clinical features consistent with a PTPN11-related disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 40496). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with valine at codon 61 of the PTPN11 protein (p.Asp61Val). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and valine. (less)
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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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Clinical experience with non-invasive prenatal screening for single-gene disorders. | Mohan P | Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology | 2022 | PMID: 34358384 |
The Clinical impact of PTPN11 mutations in adults with acute myeloid leukemia. | Alfayez M | Leukemia | 2021 | PMID: 32561839 |
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 |
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 |
Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia. | Sakaguchi H | Nature genetics | 2013 | PMID: 23832011 |
Leukemogenic Ptpn11 causes fatal myeloproliferative disorder via cell-autonomous effects on multiple stages of hematopoiesis. | Chan G | Blood | 2009 | PMID: 19179468 |
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 |
The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders. | Aoki Y | Human mutation | 2008 | PMID: 18470943 |
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 |
PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase. | Chan RJ | Blood | 2007 | PMID: 17053061 |
The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease. | Kratz CP | Blood | 2005 | PMID: 15928039 |
Prognostic, therapeutic, and mechanistic implications of a mouse model of leukemia evoked by Shp2 (PTPN11) mutations. | Mohi MG | Cancer cell | 2005 | PMID: 15710330 |
Human somatic PTPN11 mutations induce hematopoietic-cell hypersensitivity to granulocyte-macrophage colony-stimulating factor. | Chan RJ | Blood | 2005 | PMID: 15644411 |
PTPN11 mutations in pediatric patients with acute myeloid leukemia: results from the Children's Cancer Group. | Loh ML | Leukemia | 2004 | PMID: 15385933 |
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 |
Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis. | Loh ML | Blood | 2004 | PMID: 14644997 |
Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. | Tartaglia M | Nature genetics | 2003 | PMID: 12717436 |
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Text-mined citations for rs121918461 ...
HelpRecord last updated Jun 23, 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.