ClinVar Genomic variation as it relates to human health
NM_002834.5(PTPN11):c.155C>T (p.Thr52Ile)
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.155C>T (p.Thr52Ile)
Variation ID: 40484 Accession: VCV000040484.17
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 12q24.13 12: 112450335 (GRCh38) [ NCBI UCSC ] 12: 112888139 (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 May 29, 2016 Feb 14, 2024 Apr 3, 2017 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_002834.5:c.155C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002825.3:p.Thr52Ile missense NM_001330437.2:c.155C>T NP_001317366.1:p.Thr52Ile missense NM_001374625.1:c.152C>T NP_001361554.1:p.Thr51Ile missense NM_080601.3:c.155C>T NP_542168.1:p.Thr52Ile missense NC_000012.12:g.112450335C>T NC_000012.11:g.112888139C>T NG_007459.1:g.36604C>T LRG_614:g.36604C>T LRG_614t1:c.155C>T - Protein change
- T52I, T51I
- Other names
- p.T52I:ACC>ATC
- NM_002834.4(PTPN11):c.155C>T
- Canonical SPDI
- NC_000012.12:112450334:C:T
-
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.
-
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. |
---|---|---|---|---|
Uncertain significance (1) |
criteria provided, single submitter
|
Apr 28, 2022 | RCV000033452.8 | |
Likely pathogenic (3) |
reviewed by expert panel
|
Apr 3, 2017 | RCV000037621.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Jan 15, 2023 | RCV000809051.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Sep 27, 2022 | RCV002287349.2 |
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
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. |
|
---|---|---|---|---|---|
Likely pathogenic
(Apr 03, 2017)
|
reviewed by expert panel
Method: curation
|
Noonan syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen RASopathy Variant Curation Expert Panel
Accession: SCV000616407.4
First in ClinVar: Dec 19, 2017 Last updated: Dec 11, 2022 |
Comment:
The c.155C>T (p.Thr52Ile) variant in PTPN11 has been identified in at least 5 independent occurrences in patients with a RASopathy (PS4_Moderate; PMID: 22465605, 25804457, GeneDx, … (more)
The c.155C>T (p.Thr52Ile) variant in PTPN11 has been identified in at least 5 independent occurrences in patients with a RASopathy (PS4_Moderate; PMID: 22465605, 25804457, GeneDx, Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg internal data; GTR ID's: 26957, 21766, 506381; SCV000057357.11; SCV000061283.5). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Thr52Ile 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 likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Moderate, PM2, PP3, PP2. (less)
|
|
Likely pathogenic
(Feb 11, 2016)
|
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: SCV000061283.6
First in ClinVar: May 03, 2013 Last updated: Aug 26, 2019 |
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
Number of individuals with the variant: 2
|
|
Likely pathogenic
(Sep 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin
Additional submitter:
CUBI - Core Unit Bioinformatics, Berlin Institute of Health
Accession: SCV002578163.1
First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022 |
Clinical Features:
Short stature (present) , Patent ductus arteriosus (present) , Abnormal pulmonary valve morphology (present) , Global developmental delay (present)
Sex: female
Tissue: Blood
|
|
Uncertain significance
(Apr 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000057357.14
First in ClinVar: Apr 04, 2013 Last updated: Mar 04, 2023 |
Comment:
Not observed in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant … (more)
Not observed in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in association with pulmonary stenosis and Noonan syndrome (Ezquieta et al., 2012; Gulec et al., 2015; Lazzaro et al., 2020); This variant is associated with the following publications: (PMID: 25804457, 22465605, 31366893, 32059087) (less)
|
|
Likely pathogenic
(Jan 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
RASopathy
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000949188.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 40484). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data … (more)
ClinVar contains an entry for this variant (Variation ID: 40484). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. This missense change has been observed in individuals with clinical features of Noonan syndrome (PMID: 22465605, 25804457; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 52 of the PTPN11 protein (p.Thr52Ile). (less)
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
Noonan syndrome
Affected status: yes
Allele origin:
unknown
|
Service de Génétique Moléculaire, Hôpital Robert Debré
Accession: SCV001438499.1
First in ClinVar: Oct 23, 2020 Last updated: Oct 23, 2020 |
|
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 |
---|---|---|---|---|
Novel mutations in PTPN11 gene in two girls with Noonan syndrome phenotype. | Gulec EY | International journal of cardiology | 2015 | PMID: 25804457 |
Alterations in RAS-MAPK genes in 200 Spanish patients with Noonan and other neuro-cardio-facio-cutaneous syndromes. Genotype and cardiopathy. | Ezquieta B | Revista espanola de cardiologia (English ed.) | 2012 | PMID: 22465605 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/c650daaa-d00c-411a-9439-fe0b0570e53e | - | - | - | - |
Text-mined citations for rs397507503 ...
HelpRecord last updated Feb 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.