ClinVar Genomic variation as it relates to human health
NM_002834.5(PTPN11):c.1502G>A (p.Arg501Lys)
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.1502G>A (p.Arg501Lys)
Variation ID: 40555 Accession: VCV000040555.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q24.13 12: 112489078 (GRCh38) [ NCBI UCSC ] 12: 112926882 (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 May 1, 2024 Jul 26, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002834.5:c.1502G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002825.3:p.Arg501Lys missense NM_001330437.2:c.1514G>A NP_001317366.1:p.Arg505Lys missense NM_001374625.1:c.1499G>A NP_001361554.1:p.Arg500Lys missense NC_000012.12:g.112489078G>A NC_000012.11:g.112926882G>A NG_007459.1:g.75347G>A LRG_614:g.75347G>A LRG_614t1:c.1502G>A LRG_614p1:p.Arg501Lys - Protein change
- R501K, R505K, R500K
- Other names
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p.R501K:AGG>AAG
- Canonical SPDI
- NC_000012.12:112489077: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.
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- Links
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 |
970 | 982 |
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 (5) |
criteria provided, multiple submitters, no conflicts
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Dec 7, 2022 | RCV000033541.22 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 26, 2016 | RCV000037618.14 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 26, 2023 | RCV000466382.20 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 13, 2021 | RCV001800333.9 | |
Pathogenic (1) |
no assertion criteria provided
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Jun 29, 2022 | RCV002260947.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 5, 2021 | RCV004018716.1 |
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
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
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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 26, 2016)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061280.6
First in ClinVar: May 03, 2013 Last updated: May 29, 2016 |
Comment:
The p.Arg501Lys variant in PTPN11 has been reported in >10 individuals with the clinical features of Noonan syndrome and segregated with disease in 1 affected … (more)
The p.Arg501Lys variant in PTPN11 has been reported in >10 individuals with the clinical features of Noonan syndrome and segregated with disease in 1 affected r elative (Tartaglia 2002, Limal 2006, Noordam 2008, Jefferies 2010, LMM unpublish ed data). It has not been identified in large population studies. In summary, th is variant meets our criteria to be classified as pathogenic for Noonan syndrome in an autosomal dominant manner based upon presence in multiple affected indivi duals, segregation studies, and absence in the general population. (less)
Number of individuals with the variant: 7
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Pathogenic
(Apr 19, 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: SCV000057446.15
First in ClinVar: Apr 04, 2013 Last updated: Mar 04, 2023 |
Comment:
Identified in several unrelated patients with Noonan syndrome in published literature (Tartaglia et al., 2002; Limal et al., 2006; Noordam et al., 2008; Jefferies et … (more)
Identified in several unrelated patients with Noonan syndrome in published literature (Tartaglia et al., 2002; Limal et al., 2006; Noordam et al., 2008; Jefferies et al., 2010); The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19795160, 24803665, 18562489, 11992261, 16263833, 18470943, 31134136, 33726816, 35325944) (less)
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Pathogenic
(Jul 26, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000549998.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates … (more)
For these reasons, this variant has been classified as 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. ClinVar contains an entry for this variant (Variation ID: 40555). This missense change has been observed in individuals with Noonan syndrome (PMID: 11992261, 16263833, 18470943, 18562489, 19795160). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 501 of the PTPN11 protein (p.Arg501Lys). (less)
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Pathogenic
(Oct 05, 2021)
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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: SCV003745277.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.1502G>A (p.R501K) alteration is located in exon 13 (coding exon 13) of the PTPN11 gene. This alteration results from a G to A substitution … (more)
The c.1502G>A (p.R501K) alteration is located in exon 13 (coding exon 13) of the PTPN11 gene. This alteration results from a G to A substitution at nucleotide position 1502, causing the arginine (R) at amino acid position 501 to be replaced by a lysine (K). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in multiple patients with Noonan syndrome (Tartaglia, 2002; Limal, 2006; Noordam, 2008; Jefferies, 2010; Moniez, 2018). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Mar 25, 2021)
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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: SCV001554571.1
First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
Variant summary: PTPN11 c.1502G>A (p.Arg501Lys) results in a conservative amino acid change located in the PTP type protein phosphatase domain (IPR000242) of the encoded protein … (more)
Variant summary: PTPN11 c.1502G>A (p.Arg501Lys) results in a conservative amino acid change located in the PTP type protein phosphatase domain (IPR000242) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251492 control chromosomes. c.1502G>A has been widely reported in the literature in individuals affected with Noonan Syndrome (example, Tartaglia_2002, Limal_2006, Aoki_2008, Noordam_2008, Jefferies_2010). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Dec 13, 2021)
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criteria provided, single submitter
Method: clinical testing
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Short stature
Microcephaly Abnormal cardiovascular system morphology Epicanthus Abnormal pinna morphology Wide nasal bridge Depressed nasal ridge
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, University Hospital Muenster
Accession: SCV002047380.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
Comment:
ACMG categories: PM1,PM2,PP3,PP4,PP5
Number of individuals with the variant: 1
Age: 0-9 years
Sex: female
Tissue: blood
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Pathogenic
(Dec 07, 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: SCV001714430.2
First in ClinVar: Jun 15, 2021 Last updated: Jan 26, 2024 |
Comment:
PP2, PP3, PM2_supporting, PS4
Number of individuals with the variant: 5
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001978659.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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Pathogenic
(Jun 29, 2022)
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no assertion criteria provided
Method: research
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Noonan syndrome 1
Affected status: yes
Allele origin:
germline
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Department of Genetics, Beijing BioBiggen Technology Co., Ltd.
Accession: SCV002540760.1
First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022 |
Clinical Features:
thickened pulmonary valve with increased pulmonary flow velocity (present) , mild pulmonary valve stenosis (present) , mild tricuspid regurgitation (present)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001977744.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001979338.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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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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Integration of whole genome sequencing into a healthcare setting: high diagnostic rates across multiple clinical entities in 3219 rare disease patients. | Stranneheim H | Genome medicine | 2021 | PMID: 33726816 |
Noonan syndrome males display Sertoli cell-specific primary testicular insufficiency. | Moniez S | European journal of endocrinology | 2018 | PMID: 30325180 |
PTPN11 mutation associated with aortic dilation and hypertrophic cardiomyopathy in a pediatric patient with Noonan syndrome. | Jefferies JL | Pediatric cardiology | 2010 | PMID: 19795160 |
Long-term GH treatment improves adult height in children with Noonan syndrome with and without mutations in protein tyrosine phosphatase, non-receptor-type 11. | Noordam C | European journal of endocrinology | 2008 | PMID: 18562489 |
The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders. | Aoki Y | Human mutation | 2008 | PMID: 18470943 |
PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects. | Kontaridis MI | The Journal of biological chemistry | 2006 | PMID: 16377799 |
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 |
Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. | Tartaglia M | Nature genetics | 2003 | PMID: 12717436 |
PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. | Tartaglia M | American journal of human genetics | 2002 | PMID: 11992261 |
Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. | Tartaglia M | Nature genetics | 2001 | PMID: 11704759 |
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Text-mined citations for rs397507543 ...
HelpRecord last updated Nov 03, 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.