ClinVar Genomic variation as it relates to human health
NM_002834.5(PTPN11):c.226G>A (p.Glu76Lys)
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.
Pathogenic(5); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002834.5(PTPN11):c.226G>A (p.Glu76Lys)
Variation ID: 13336 Accession: VCV000013336.32
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q24.13 12: 112450406 (GRCh38) [ NCBI UCSC ] 12: 112888210 (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 Jan 16, 2015 Apr 15, 2024 Jan 1, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002834.5:c.226G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002825.3:p.Glu76Lys missense NM_001330437.2:c.226G>A NP_001317366.1:p.Glu76Lys missense NM_001374625.1:c.223G>A NP_001361554.1:p.Glu75Lys missense NM_002834.4:c.226G>A NM_080601.3:c.226G>A NP_542168.1:p.Glu76Lys missense NC_000012.12:g.112450406G>A NC_000012.11:g.112888210G>A NG_007459.1:g.36675G>A LRG_614:g.36675G>A LRG_614t1:c.226G>A Q06124:p.Glu76Lys - Protein change
- E76K, E75K
- Other names
- p.E76K:GAG>AAG
- Canonical SPDI
- NC_000012.12:112450405:G:A
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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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
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
Help
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
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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, single submitter
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Jun 21, 2019 | RCV000014264.10 | |
Uncertain significance (2) |
criteria provided, single submitter
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Mar 4, 2020 | RCV000033476.13 | |
Pathogenic (1) |
no assertion criteria provided
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May 10, 2013 | RCV000156974.9 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 1, 2023 | RCV000212892.10 | |
Likely pathogenic (1) |
no assertion criteria provided
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May 31, 2016 | RCV000422541.2 | |
Likely pathogenic (1) |
no assertion criteria provided
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May 31, 2016 | RCV000433549.2 | |
Likely pathogenic (1) |
no assertion criteria provided
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May 31, 2016 | RCV000432364.2 | |
Likely pathogenic (1) |
no assertion criteria provided
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May 31, 2016 | RCV000422851.2 | |
Likely pathogenic (1) |
no assertion criteria provided
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May 31, 2016 | RCV000439757.2 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV001254876.2 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV003335036.1 | |
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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
Help
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
Help
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
(Apr 09, 2018)
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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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Blueprint Genetics
Accession: SCV000927623.1
First in ClinVar: Jul 31, 2019 Last updated: Jul 31, 2019 |
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Pathogenic
(Jun 21, 2019)
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criteria provided, single submitter
Method: clinical testing
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Juvenile myelomonocytic leukemia
Affected status: unknown
Allele origin:
somatic
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV001365520.1
First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020 |
Comment:
The p.Glu76Lys variant in PTPN11 is an established pathogenic variant that has been identified as a somatic change in >40 individuals with JMML (Tartaglia 2003, … (more)
The p.Glu76Lys variant in PTPN11 is an established pathogenic variant that has been identified as a somatic change in >40 individuals with JMML (Tartaglia 2003, Loh 2004, Kratz 2005, Tartaglia 2005, Aoki 2008, Yoshida 2009) and is absent from large population studies. In vitro and in vivo functional studies show that this variant has a strong gain of function impact (Tartaglia 2003, Loh 2004, Xu 2011, Yu 2013, Chang 2016, Dong 2016). Several other variants involving this codon have been identified in individuals with Noonan syndrome and/or hematological malignancies. In summary, this variant meets criteria to be classified as pathogenic for JMML. (less)
Number of individuals with the variant: 1
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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PTPN11-Related Disorders
Affected status: yes
Allele origin:
germline
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Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046253.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
This variant has not been previously reported as a germline variant to our knowledge; however, it has been observed as a somatic variant in individuals … (more)
This variant has not been previously reported as a germline variant to our knowledge; however, it has been observed as a somatic variant in individuals with acute myeloid leukemia, myelodysplastic syndrome, and juvenile myelomonocytic leukemia (PMID:14644997, 14982869, 12717436). This variant is in the N-SH2 domain, which is a hotspot domain for pathogenic variants associated with PTPN11 - related disorders. Different amino acid changes at the same residue (p.Glu76Asp, p.Glu76Gln, p.Glu76Gly, p.Glu76Val) have been previously reported in individuals with Noonan syndrome and/or hematological malignancies (PMID: 16830086, 11704759, 18678287, 12634870). Functional studies showed that the c.226G>A (p.Glu76Lys) variant has a gain-of-function effect on the PTPN11 protein (PMID: 14974085, 19509418, 27783593). It is absent from the gnomAD population database and thus is presumed to be rare. The c.226G>A (p.Glu76Lys) variant is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.226G>A (p.Glu76Lys) variant is classified as Pathogenic. (less)
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Pathogenic
(Jan 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV003917245.7
First in ClinVar: Apr 23, 2023 Last updated: Apr 15, 2024 |
Comment:
PTPN11: PM1, PM2, PM5, PP2, PP3, PS3:Supporting, PS4:Supporting
Number of individuals with the variant: 1
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Pathogenic
(Jun 03, 2021)
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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: SCV000057381.12
First in ClinVar: Apr 04, 2013 Last updated: Jun 03, 2016 |
Comment:
Reported in published literature in patients with juvenile myelomonocytic leukemia (Kratz et al., 2005); Reported in published literature in association with somatic hematologic malignancies (Tartaglia … (more)
Reported in published literature in patients with juvenile myelomonocytic leukemia (Kratz et al., 2005); Reported in published literature in association with somatic hematologic malignancies (Tartaglia et al., 2006); Published functional studies demonstrate a damaging effect on protein function and structure (Tartaglia et al., 2006; Gagne-Sansfaon et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 22391158, 17177198, 29206716, 27582544, 15928039, 16358218, 9491886, 16053901, 11992261, 29493581, 27535533, 27783593, 23825065, 31222725, 15842656, 15385933, 14982869, 32697817, 12717436, 21930766, 19047918, 18470943, 14644997) (less)
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Uncertain significance
(Mar 04, 2020)
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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: SCV001535902.4
First in ClinVar: Mar 22, 2021 Last updated: Feb 20, 2024 |
Comment:
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant … (more)
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Glu76 amino acid residue in PTPN11. Other variants that disrupt this residue have been determined to be pathogenic (PMID: 16830086, 11704759, 18678287, 12634870). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has been reported to affect PTPN11 protein function (PMID: 14974085, 19509418). This variant has been observed as a somatic variant in many individuals with acute myeloid leukemia, myelodysplastic syndrome, and juvenile myelomonocytic leukemia or JMML; however, it has not been reported as a germline variant in affected individuals (PMID:14644997, 14982869, 12717436). ClinVar contains an entry for this variant (Variation ID: 13336). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 76 of the PTPN11 protein (p.Glu76Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Rasopathy
Affected status: yes
Allele origin:
unknown
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Baylor Genetics
Accession: SCV000196661.1
First in ClinVar: Jan 16, 2015 Last updated: Jan 16, 2015 |
Comment:
Variant classified using ACMG guidelines
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Pathogenic
(May 10, 2013)
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no assertion criteria provided
Method: clinical testing
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Noonan syndrome
Affected status: yes
Allele origin:
somatic
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000206696.1
First in ClinVar: Jan 31, 2015 Last updated: Jan 31, 2015 |
Number of individuals with the variant: 1
Family history: unknown
Sex: female
Ethnicity/Population group: Caucasian _ not further specified
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Pathogenic
(Jun 01, 2003)
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no assertion criteria provided
Method: literature only
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LEUKEMIA, JUVENILE MYELOMONOCYTIC, SOMATIC
Affected status: not provided
Allele origin:
somatic
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OMIM
Accession: SCV000034513.2
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
Tartaglia et al. (2003) identified somatic missense mutations in PTPN11 in 21 of 62 individuals with JMML (607785) but without Noonan syndrome. A 226G-A transition … (more)
Tartaglia et al. (2003) identified somatic missense mutations in PTPN11 in 21 of 62 individuals with JMML (607785) but without Noonan syndrome. A 226G-A transition predicting a glu76-to-lys (E76K) substitution within the N-SH2 domain accounted for 25% of the total number of mutations. Codon 76 was a mutation hotspot for JMML, with 4 different amino acid substitutions predicted among 8 individuals: in addition to E76K, which was present in 5 cases, E76V (176876.0015), E76G (176876.0016), and E76A (176876.0017) were each present in 1 case. (less)
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Likely pathogenic
(May 31, 2016)
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no assertion criteria provided
Method: literature only
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Squamous cell lung carcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000507245.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Likely pathogenic
(May 31, 2016)
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no assertion criteria provided
Method: literature only
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Multiple myeloma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000507244.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Likely pathogenic
(May 31, 2016)
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no assertion criteria provided
Method: literature only
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Neuroblastoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000507247.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Likely pathogenic
(May 31, 2016)
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no assertion criteria provided
Method: literature only
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Neoplasm of the large intestine
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000507246.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Likely pathogenic
(May 31, 2016)
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no assertion criteria provided
Method: literature only
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Astrocytoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000507248.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: research
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cancer
Affected status: unknown
Allele origin:
unknown
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Investigational Cancer Therapeutics, MD Anderson Cancer Center
Accession: SCV001424769.1
First in ClinVar: Aug 29, 2020 Last updated: Aug 29, 2020 |
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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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Leukaemogenic effects of Ptpn11 activating mutations in the stem cell microenvironment. | Dong L | Nature | 2016 | PMID: 27783593 |
Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity. | Chang MT | Nature biotechnology | 2016 | PMID: 26619011 |
Targeting protein tyrosine phosphatase SHP2 for the treatment of PTPN11-associated malignancies. | Yu B | Molecular cancer therapeutics | 2013 | PMID: 23825065 |
Non-lineage/stage-restricted effects of a gain-of-function mutation in tyrosine phosphatase Ptpn11 (Shp2) on malignant transformation of hematopoietic cells. | Xu D | The Journal of experimental medicine | 2011 | PMID: 21930766 |
Negative regulation of Stat3 by activating PTPN11 mutants contributes to the pathogenesis of Noonan syndrome and juvenile myelomonocytic leukemia. | Zhang W | The Journal of biological chemistry | 2009 | PMID: 19509418 |
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 |
Clinical and molecular characterization of 40 patients with Noonan syndrome. | Ferrero GB | European journal of medical genetics | 2008 | PMID: 18678287 |
The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders. | Aoki Y | Human mutation | 2008 | PMID: 18470943 |
Aortic root dilatation is a rare complication of Noonan syndrome. | Power PD | Pediatric cardiology | 2006 | PMID: 16830086 |
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 |
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 |
Noonan syndrome-associated SHP2/PTPN11 mutants cause EGF-dependent prolonged GAB1 binding and sustained ERK2/MAPK1 activation. | Fragale A | Human mutation | 2004 | PMID: 14974085 |
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 |
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 |
Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. | Tartaglia M | Nature genetics | 2001 | PMID: 11704759 |
http://docm.genome.wustl.edu/variants/ENST00000351677:c.226G>A | - | - | - | - |
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Text-mined citations for rs121918464 ...
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.