ClinVar Genomic variation as it relates to human health
NM_002834.5(PTPN11):c.642G>A (p.Gln214=)
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.642G>A (p.Gln214=)
Variation ID: 235046 Accession: VCV000235046.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q24.13 12: 112454680 (GRCh38) [ NCBI UCSC ] 12: 112892484 (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 2, 2016 May 1, 2024 Feb 28, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002834.5:c.642G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002825.3:p.Gln214= synonymous NM_001330437.2:c.642G>A NP_001317366.1:p.Gln214= synonymous NM_001374625.1:c.639G>A NP_001361554.1:p.Gln213= synonymous NM_080601.3:c.642G>A NP_542168.1:p.Gln214= synonymous NC_000012.12:g.112454680G>A NC_000012.11:g.112892484G>A NG_007459.1:g.40949G>A LRG_614:g.40949G>A LRG_614t1:c.642G>A - Protein change
- Other names
- p.Gln214=
- Canonical SPDI
- NC_000012.12:112454679: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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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 |
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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Uncertain significance (1) |
no assertion criteria provided
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Nov 1, 2013 | RCV000223920.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 12, 2017 | RCV000248716.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 28, 2023 | RCV000538418.7 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Dec 5, 2022 | RCV000680327.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 5, 2021 | RCV002494609.1 |
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
(Jul 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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LEOPARD syndrome 1
Metachondromatosis Noonan syndrome 1 Juvenile myelomonocytic leukemia
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002779887.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Feb 02, 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: SCV000491023.3
First in ClinVar: Sep 22, 2018 Last updated: Sep 22, 2018 |
Comment:
The c.642 G>A variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The … (more)
The c.642 G>A variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The c.642 G>A 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. Several in-silico splice prediction models predict that c.642 G>A may damage the natural splice donor site of intron 5 and result in abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Of note, Noonan syndrome and related rasopathies are caused by gain-of-function mutations and no loss-of-function mutations PTPN11 have been reported to date in association with a Noonan spectrum disorder. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. (less)
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Uncertain significance
(Jul 12, 2017)
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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: SCV000318856.7
First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024 |
Comment:
The c.642G>A variant (also known as p.Q214Q), located in coding exon 5 of the PTPN11 gene, results from a G to A substitution at nucleotide … (more)
The c.642G>A variant (also known as p.Q214Q), located in coding exon 5 of the PTPN11 gene, results from a G to A substitution at nucleotide position 642. This nucleotide substitution does not change the at codon 214. However, this change occurs in the last base pair of coding exon 5, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Dec 05, 2022)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226383.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PM2
Number of individuals with the variant: 1
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Uncertain significance
(Feb 28, 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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Invitae
Accession: SCV000659047.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change affects codon 214 of the PTPN11 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid … (more)
This sequence change affects codon 214 of the PTPN11 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PTPN11 protein. This variant also falls at the last nucleotide of exon 5, which is part of the consensus splice site for this exon. This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with PTPN11-related conditions. ClinVar contains an entry for this variant (Variation ID: 235046). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. (less)
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Uncertain significance
(Dec 27, 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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Eurofins Ntd Llc (ga)
Accession: SCV000858850.1
First in ClinVar: Sep 22, 2018 Last updated: Sep 22, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Uncertain significance
(Nov 01, 2013)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280429.1
First in ClinVar: Jun 02, 2016 Last updated: Jun 02, 2016 |
Comment:
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case … (more)
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. PTPN11 p.Q214Q (c.642G>A) This variant is novel. This variant is located in the last nucleotide position of coding exon 5 (of 15 exons). This nucleotide substitution does not change the amino acid glutamine at codon 214, however per the Ambry report, because this change occurs in the last base pair of coding exon 5, it is likely to have some effect on normal mRNA splicing. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to decrease the efficiency of the native splice donor site. The glutamine at codon 214 is conserved across species, as are neighboring amino acids. In total the variant has not been seen in ~6,500 individuals from publicly available population datasets. There is no variation at codon 642 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 8/26/13). Note that this dataset does not match the patient's ancestry (Guatemala). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 8/26/13). The variant was not observed in the following laboratory and published control samples: Ambry did not report any internal control data. Given the patient's lack of other features supporting a diagnosis of a RASopathy, it is unlikely that this variant is the cause of the patient's isolated HCM. (less)
Number of individuals with the variant: 1
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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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Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PTPN11 | - | - | - | - |
Text-mined citations for rs876661383 ...
HelpRecord last updated May 01, 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.