ClinVar Genomic variation as it relates to human health
NM_002834.5(PTPN11):c.166A>G (p.Ile56Val)
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
-
NM_002834.5(PTPN11):c.166A>G (p.Ile56Val)
Variation ID: 40485 Accession: VCV000040485.22
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 12q24.13 12: 112450346 (GRCh38) [ NCBI UCSC ] 12: 112888150 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Dec 19, 2017 Mar 16, 2024 May 10, 2019 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_002834.5:c.166A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002825.3:p.Ile56Val missense NM_001330437.2:c.166A>G NP_001317366.1:p.Ile56Val missense NM_001374625.1:c.163A>G NP_001361554.1:p.Ile55Val missense NM_080601.3:c.166A>G NP_542168.1:p.Ile56Val missense NC_000012.12:g.112450346A>G NC_000012.11:g.112888150A>G NG_007459.1:g.36615A>G LRG_614:g.36615A>G LRG_614t1:c.166A>G - Protein change
- I56V, I55V
- Other names
- p.I56V:ATT>GTT
- NM_002834.4(PTPN11):c.166A>G
- Canonical SPDI
- NC_000012.12:112450345:A:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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. |
|||
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. |
---|---|---|---|---|
Likely pathogenic (1) |
criteria provided, single submitter
|
Feb 27, 2018 | RCV000154561.7 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 20, 2023 | RCV000557839.10 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 23, 2023 | RCV000518841.5 | |
Pathogenic (1) |
reviewed by expert panel
|
May 10, 2019 | RCV000788006.1 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Nov 15, 2021 | RCV000995619.6 | |
Pathogenic (1) |
criteria provided, single submitter
|
Dec 7, 2023 | RCV003415759.5 |
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. |
|
---|---|---|---|---|---|
Pathogenic
(May 10, 2019)
|
reviewed by expert panel
Method: curation
|
Noonan syndrome and Noonan-related syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen RASopathy Variant Curation Expert Panel
Accession: SCV000927038.1
First in ClinVar: Jul 22, 2019 Last updated: Jul 22, 2019 |
Comment:
The c.166A>G (p.Ile56Val) variant in PTPN11 has been reported as a confirmed de novo occurrence in a patient with clinical features of a RASopathy (PS2; … (more)
The c.166A>G (p.Ile56Val) variant in PTPN11 has been reported as a confirmed de novo occurrence in a patient with clinical features of a RASopathy (PS2; Invitae internal data; GTR Lab ID: 500031; ClinVar SCV000659037.2). The p.Ile56Val variant has been identified in at least 5 independent occurrences in patients with clinical features of a RASopathy (PS4; GeneDx, Partners LMM, Invitae, LabCorp internal data; GTR Lab IDs: 26957, 21766, 500031, 500026; ClinVar SCV SCV000057358.13, SCV000204234.4, SCV000659037.2, SCV000698061.1). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Ile56Val variant may impact the protein (PP3). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2, PS4, PM2, PP3, PP2. (less)
|
|
Likely pathogenic
(Feb 27, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000204234.5
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
|
|
Pathogenic
(Nov 19, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Rasopathy
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000698061.2
First in ClinVar: Dec 19, 2017 Last updated: Feb 03, 2020 |
Comment:
Variant Summary: PTPN11 c.166A>G (p.Ile56Val) results in a conservative amino acid change located in the SH2 domain (IPR000980) of the encoded protein sequence. Three of … (more)
Variant Summary: PTPN11 c.166A>G (p.Ile56Val) results in a conservative amino acid change located in the SH2 domain (IPR000980) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251170 control chromosomes (gnomAD). The variant, c.166A>G, has been reported in the literature and by clinical laboratories in multiple individuals affected with features of Noonan Syndrome and Related Conditions (Smith_2009, Atik_2016, Leach_2018, ClinVar database). Additionally, one reportedly de novo occurrence was observed by a clinical laboratory (ClinVar database). In addition, this variant was identified at our laboratory in one patient with pulmonary stenosis and ASD. These data indicate that the variant is very likely to be associated with disease. Several mutations in neighboring codons (N58K, N58H, and N58D) have been published in association with Noonan Syndrome, emphasizing the functional importance of this residue and/or SH2 region.To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters including ClinGen RASopathy Variant Curation Expert Panel (evaluation after 2014) cite the variant as likely pathogenic (3x) and pathogenic (2x). Based on the evidence outlined above, the variant was re-classified as pathogenic. (less)
|
|
Pathogenic
(Nov 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
RASopathy
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000659037.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 56 of the PTPN11 protein (p.Ile56Val). … (more)
This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 56 of the PTPN11 protein (p.Ile56Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (NS) (PMID: 26817465; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40485). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTPN11 function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Dec 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
PTPN11-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004109387.2
First in ClinVar: Nov 20, 2023 Last updated: Mar 16, 2024 |
Comment:
The PTPN11 c.166A>G variant is predicted to result in the amino acid substitution p.Ile56Val. This variant has been reported in multiple individuals with Noonan syndrome … (more)
The PTPN11 c.166A>G variant is predicted to result in the amino acid substitution p.Ile56Val. This variant has been reported in multiple individuals with Noonan syndrome and in some of these cases was determined to have arisen de novo (Atik et al. 2016. PubMed ID: 26817465; Li et al. 2020. PubMed ID: 32410215; Brunet et al. 2021. PubMed ID: 33619735; Table S3 in Leach et al. 2019. PubMed ID: 29907801). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been classified as pathogenic by an expert panel on the ClinVar database (www.ncbi.nlm.nih.gov/clinvar/variation/40485). This variant is interpreted as pathogenic. (less)
|
|
Likely pathogenic
(Aug 17, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV000927861.1
First in ClinVar: Jul 31, 2019 Last updated: Jul 31, 2019 |
|
|
Likely pathogenic
(Jun 06, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001149898.1
First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020 |
Sex: male
Tissue: blood
|
|
Likely pathogenic
(Mar 26, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
maternal
|
Genomic Medicine Lab, University of California San Francisco
Study: CSER-P3EGS
Accession: SCV001573019.1 First in ClinVar: May 10, 2021 Last updated: May 10, 2021 |
Sex: female
|
|
Pathogenic
(Nov 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002761907.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
Comment:
The PTPN11 c.166A>G variant is a single nucleotide change in exon 3/16 of the PTPN11 gene, which is predicted to change the amino acid isoleucine … (more)
The PTPN11 c.166A>G variant is a single nucleotide change in exon 3/16 of the PTPN11 gene, which is predicted to change the amino acid isoleucine at position 56 in the protein to valine. This variant is absent from population databases (PM2), but has been reported at least 4 times in the literature in patients with a clinical presentation of Noonan syndrome or RASopathy (PS4_Moderate). A different pathogenic missense change, p.Ile56Thr, has been reported before at the same amino acid position (PM5). This variant has been identified as a de novo variant in at least two affected patients with no family history of this condition (Li et al, 2020 PMID: 32410215; Brunet et al, 2021 PMID 33619735) (PS2). The variant has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 40485). The variant has been reported in the HGMD database: CM161482. Computational predictions support a deleterious effect on the gene or gene product (PP3). (less)
|
|
Pathogenic
(Oct 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000057358.16
First in ClinVar: Apr 04, 2013 Last updated: Nov 25, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26817465, 29907801, 32410215, 30050098, 29493581, 36555586, 33619735) (less)
|
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 |
---|---|---|---|---|
De novo variants in neurodevelopmental disorders-experiences from a tertiary care center. | Brunet T | Clinical genetics | 2021 | PMID: 33619735 |
Prenatal exome sequencing in fetuses with congenital heart defects. | Li R | Clinical genetics | 2020 | PMID: 32410215 |
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 |
Mutation Spectrum and Phenotypic Features in Noonan Syndrome with PTPN11 Mutations: Definition of Two Novel Mutations. | Atik T | Indian journal of pediatrics | 2016 | PMID: 26817465 |
ALK2 mutation in a patient with Down's syndrome and a congenital heart defect. | Joziasse IC | European journal of human genetics : EJHG | 2011 | PMID: 21248739 |
Dominant-negative ALK2 allele associates with congenital heart defects. | Smith KA | Circulation | 2009 | PMID: 19506109 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/43db1167-715a-4f5d-8517-8487caffe8af | - | - | - | - |
Text-mined citations for rs397507504 ...
HelpRecord last updated Apr 20, 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.