ClinVar Genomic variation as it relates to human health
NM_002834.5(PTPN11):c.1504T>A (p.Ser502Thr)
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.1504T>A (p.Ser502Thr)
Variation ID: 13332 Accession: VCV000013332.6
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q24.13 12: 112489080 (GRCh38) [ NCBI UCSC ] 12: 112926884 (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 31, 2015 Mar 22, 2021 Nov 18, 2019 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002834.5:c.1504T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002825.3:p.Ser502Thr missense NM_001330437.2:c.1516T>A NP_001317366.1:p.Ser506Thr missense NM_001374625.1:c.1501T>A NP_001361554.1:p.Ser501Thr missense NC_000012.12:g.112489080T>A NC_000012.11:g.112926884T>A NG_007459.1:g.75349T>A LRG_614:g.75349T>A LRG_614t1:c.1504T>A - Protein change
- S502T, S506T, S501T
- Other names
- p.S502T:TCA>ACA
- Canonical SPDI
- NC_000012.12:112489079:T: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
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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
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 |
953 | 965 |
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
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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Nov 18, 2019 | RCV000014260.30 | |
Pathogenic (1) |
no assertion criteria provided
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Sep 29, 2015 | RCV000033543.5 | |
Pathogenic (1) |
no assertion criteria provided
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Jan 30, 2012 | RCV000156995.1 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 22, 2018 | RCV000212897.2 |
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
(Jan 22, 2018)
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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: SCV000884432.1
First in ClinVar: Jun 11, 2016 Last updated: Jun 11, 2016 |
Comment:
The p.Ser502Thr variant (rs121918458) has been reported in multiple patients diagnosed with Noonan syndrome (Niihori 2005, Tartaglia 2006, van Trier 2016, Yoshida 2004), and reported … (more)
The p.Ser502Thr variant (rs121918458) has been reported in multiple patients diagnosed with Noonan syndrome (Niihori 2005, Tartaglia 2006, van Trier 2016, Yoshida 2004), and reported as a presumed de-novo variant (Joyce 2016, Kondoh 2003, Maheshwari 2002). The serine residue is located in the phospho-tyrosine phosphatase domain of PTPN11, and interacts with the N-SH2 domain to mediate regulatory inhibition (Hof 1998). Functional characterization of the p.Ser502Thr protein indicates increased catalytic activity of the phosphatase (Niihori 2005), consistent with the established disease mechanisms of Noonan syndrome. (less)
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Pathogenic
(Dec 05, 2016)
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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: SCV000057448.13
First in ClinVar: Apr 04, 2013 Last updated: Jun 11, 2016 |
Comment:
The S502T variant has been published as an assumed de novo pathogenic variant in a patient diagnosed with Noonan syndrome (Niihori et al., 2005). Another … (more)
The S502T variant has been published as an assumed de novo pathogenic variant in a patient diagnosed with Noonan syndrome (Niihori et al., 2005). Another patient who harbored this variant developed leukocytosis and neuroblastoma at 3 months and 6 months of age respectively (Kondoh et al., 2003). In vitro functional studies demonstrated that the presence of the S502T variant resulted in a significant increase in phosphatase activity over wild-type (Niihori et al., 2005). The S502T 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. The S502T variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in this residue (S502A, S502L) have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014). Therefore, this variant is pathogenic. (less)
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Pathogenic
(Feb 14, 2017)
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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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Blueprint Genetics
Accession: SCV000927150.1
First in ClinVar: Jul 31, 2019 Last updated: Jul 31, 2019 |
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Pathogenic
(Nov 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome 1
Affected status: yes
Allele origin:
germline
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Center for Human Genetics, Inc,Center for Human Genetics, Inc
Accession: SCV000782254.1
First in ClinVar: Aug 22, 2016 Last updated: Aug 22, 2016 |
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Pathogenic
(Nov 18, 2019)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome 1
Affected status: yes
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001522570.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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Pathogenic
(Sep 29, 2015)
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no assertion criteria provided
Method: clinical testing
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Noonan syndrome
Juvenile myelomonocytic leukemia (Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine
Accession: SCV000204062.5
First in ClinVar: Jan 31, 2015 Last updated: Aug 26, 2019 |
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
Number of individuals with the variant: 2
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Pathogenic
(Jul 01, 2003)
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no assertion criteria provided
Method: literature only
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NOONAN SYNDROME 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034508.3
First in ClinVar: Apr 04, 2013 Last updated: Sep 09, 2019 |
Comment on evidence:
Maheshwari et al. (2002) found a de novo ser502-to-thr (S502T) substitution in exon 13 in 2 unrelated subjects with Noonan syndrome (NS1; 163950). Kondoh et … (more)
Maheshwari et al. (2002) found a de novo ser502-to-thr (S502T) substitution in exon 13 in 2 unrelated subjects with Noonan syndrome (NS1; 163950). Kondoh et al. (2003) described a transient leukemoid reaction and an apparently spontaneously regressing neuroblastoma in a Japanese infant with Noonan syndrome and the S502T mutation. (less)
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Pathogenic
(Jan 30, 2012)
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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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ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories
Accession: SCV000206719.1
First in ClinVar: Jan 31, 2015 Last updated: Jan 31, 2015 |
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Cryptorchidism (present) , Global developmental delay (present) , Pulmonic stenosis (present) , Short stature (present)
Family history: yes
Sex: male
Ethnicity/Population group: Caucasian
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Abnormality of the face (present) , Global developmental delay (present) , Short stature (present)
Family history: yes
Sex: male
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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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Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. | Tartaglia M | American journal of human genetics | 2006 | PMID: 16358218 |
Functional analysis of PTPN11/SHP-2 mutants identified in Noonan syndrome and childhood leukemia. | Niihori T | Journal of human genetics | 2005 | PMID: 15834506 |
Protein-tyrosine phosphatase, nonreceptor type 11 mutation analysis and clinical assessment in 45 patients with Noonan syndrome. | Yoshida R | The Journal of clinical endocrinology and metabolism | 2004 | PMID: 15240615 |
Noonan syndrome with leukaemoid reaction and overproduction of catecholamines: a case report. | Kondoh T | European journal of pediatrics | 2003 | PMID: 12739139 |
PTPN11 mutations in Noonan syndrome type I: detection of recurrent mutations in exons 3 and 13. | Maheshwari M | Human mutation | 2002 | PMID: 12325025 |
Text-mined citations for rs121918458 ...
HelpRecord last updated Mar 18, 2022
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.