ClinVar Genomic variation as it relates to human health
NM_002834.5(PTPN11):c.174C>G (p.Asn58Lys)
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.174C>G (p.Asn58Lys)
Variation ID: 40489 Accession: VCV000040489.40
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q24.13 12: 112450354 (GRCh38) [ NCBI UCSC ] 12: 112888158 (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 May 27, 2015 Apr 20, 2024 Jan 4, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002834.5:c.174C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002825.3:p.Asn58Lys missense NM_001330437.2:c.174C>G NP_001317366.1:p.Asn58Lys missense NM_001374625.1:c.171C>G NP_001361554.1:p.Asn57Lys missense NM_080601.3:c.174C>G NP_542168.1:p.Asn58Lys missense NC_000012.12:g.112450354C>G NC_000012.11:g.112888158C>G NG_007459.1:g.36623C>G LRG_614:g.36623C>G LRG_614t1:c.174C>G Q06124:p.Asn58Lys - Protein change
- N58K, N57K
- Other names
- p.N58K:AAC>AAG
- Canonical SPDI
- NC_000012.12:112450353:C:G
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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
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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 |
944 | 956 |
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
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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 (2) |
criteria provided, multiple submitters, no conflicts
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Nov 1, 2022 | RCV000033457.23 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 4, 2012 | RCV000037630.5 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 22, 2022 | RCV000211846.11 | |
Pathogenic (1) |
criteria provided, single submitter
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May 18, 2017 | RCV000515267.3 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 4, 2024 | RCV000588173.9 |
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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Pathogenic
(May 18, 2017)
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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: SCV000611302.1
First in ClinVar: Nov 11, 2017 Last updated: Nov 11, 2017 |
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Pathogenic
(Apr 03, 2017)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000698063.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The PTPN11 c.174C>G (p.Asn58Lys) variant located in the mutational hotspot, SH2 domain, involves the alteration of a non-conserved nucleotide and by 4/4 in-silico … (more)
Variant summary: The PTPN11 c.174C>G (p.Asn58Lys) variant located in the mutational hotspot, SH2 domain, involves the alteration of a non-conserved nucleotide and by 4/4 in-silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome, although these predictions have yet to be functionally assessed. This variant is absent in 122184 control chromosomes including broad and large populations from ExAC. Publications have cited this variant as a pathogenic variant and has been detected in several patients with Noonans syndrome, including multiple instances of a de novo origin (Musante_2003, Tartaglia_2006, Derbent_2010, Digilio_2011, Ezquieta_2012, Croonen_2012, Coromilas_2015, and Cizmarova_2015). Other missense variants at this residue (N58Y, N58D, N58H, and N58S) are reported in association with Noonan syndrome and are classified as pathogenic/likely pathogenic by submitters in ClinVar, strongly suggesting that the codon itself is a mutational hotspot. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as Pathogenic. (less)
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Pathogenic
(Dec 18, 2017)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome
Affected status: yes
Allele origin:
inherited
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000746841.2
First in ClinVar: Jun 05, 2016 Last updated: Dec 11, 2022 |
Age: 0-9 years
Sex: female
Geographic origin: Iran
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Likely pathogenic
(Dec 04, 2012)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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UCLA Clinical Genomics Center, UCLA
Study: CES
Accession: SCV000255445.2 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Age: 20-29 years
Sex: male
Ethnicity/Population group: European Caucasian
Testing laboratory: UCLA Clinical Genomics Center
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Pathogenic
(Nov 01, 2022)
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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: SCV000057362.16
First in ClinVar: Apr 04, 2013 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); Multiple pathogenic missense variants at this residue (p.N58D, p.N58Y, p.N58H) have been reported in association with Noonan spectrum disorders; This variant is associated with the following publications: (PMID: 22190897, 26607044, 32164556, 12634870, 23321623, 25914815, 24803665, 28425981, 16358218, 15928039, 20954246, 15723289, 18286234, 30417923, 30050098, 29907801, 11992261, 9491886, 16053901, 29493581) (less)
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Pathogenic
(Jan 04, 2024)
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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: SCV001392879.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 58 of the PTPN11 protein (p.Asn58Lys). … (more)
This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 58 of the PTPN11 protein (p.Asn58Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome (PMID: 12634870, 20954246, 22190897, 23321623). ClinVar contains an entry for this variant (Variation ID: 40489). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PTPN11 protein function with a positive predictive value of 95%. This variant disrupts the p.Asn58 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15001945, 16263833, 19125092). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001246726.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Nov 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061292.8
First in ClinVar: May 03, 2013 Last updated: Apr 20, 2024 |
Comment:
The c.174C>G, p.Asn58Lys variant in PTPN11 has been reported in at least 6 individuals with clinical features of Noonan syndrome and segregated with disease in … (more)
The c.174C>G, p.Asn58Lys variant in PTPN11 has been reported in at least 6 individuals with clinical features of Noonan syndrome and segregated with disease in at least 4 affected relatives from one family (Musant 2003 PMID:12634870, Tartaglia 2006 PMID:16358218, Derbent 2010 PMID:20954246, Digilio 2011 PMID:22190897, Croonen 2013 PMID:23321623, LMM data). It has also been reported by other clinical laboratories in ClinVar (Variation ID 40489) and absent from large population studies. Computational tools and conservation analyses are consistent with pathogenicity. Another variant resulting in the same missense change (c.172A>C, p.Asn58His) and two additional variants involving this codon (p.Asn58Asp and p.Asn58His) have also been reported in ClinVar as a Pathogenic variant by several clinical laboratories, including this laboratory. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Noonan syndrome. ACMG/AMP criteria applied: PS4, PP1, PM2_Supporting, PM5_strong, PP3. (less)
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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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New Mutations Associated with Rasopathies in a Central European Population and Genotype-Phenotype Correlations. | Čizmárová M | Annals of human genetics | 2016 | PMID: 26607044 |
Nonspecific phenotype of Noonan syndrome diagnosed by whole exome sequencing. | Coromilas A | Clinical case reports | 2015 | PMID: 25914815 |
Prenatal diagnostic testing of the Noonan syndrome genes in fetuses with abnormal ultrasound findings. | Croonen EA | European journal of human genetics : EJHG | 2013 | PMID: 23321623 |
RASopathies: Clinical Diagnosis in the First Year of Life. | Digilio MC | Molecular syndromology | 2011 | PMID: 22190897 |
Clinical and hematologic findings in Noonan syndrome patients with PTPN11 gene mutations. | Derbent M | American journal of medical genetics. Part A | 2010 | PMID: 20954246 |
Primary mixed glioneuronal tumor of the central nervous system in a patient with noonan syndrome: a case report and review of the literature. | Sherman CB | Journal of pediatric hematology/oncology | 2009 | PMID: 19125092 |
The tyrosine phosphatase Shp2 (PTPN11) in cancer. | Chan G | Cancer metastasis reviews | 2008 | PMID: 18286234 |
Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. | Tartaglia M | American journal of human genetics | 2006 | PMID: 16358218 |
Noonan syndrome: relationships between genotype, growth, and growth factors. | Limal JM | The Journal of clinical endocrinology and metabolism | 2006 | PMID: 16263833 |
The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease. | Kratz CP | Blood | 2005 | PMID: 15928039 |
Genotypic and phenotypic characterization of Noonan syndrome: new data and review of the literature. | Jongmans M | American journal of medical genetics. Part A | 2005 | PMID: 15723289 |
Genotype-phenotype correlations in Noonan syndrome. | Zenker M | The Journal of pediatrics | 2004 | PMID: 15001945 |
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 |
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Text-mined citations for rs397507506 ...
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.