ClinVar Genomic variation as it relates to human health
NM_002834.5(PTPN11):c.1471C>A (p.Pro491Thr)
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.1471C>A (p.Pro491Thr)
Variation ID: 40549 Accession: VCV000040549.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q24.13 12: 112489047 (GRCh38) [ NCBI UCSC ] 12: 112926851 (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 Jan 26, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002834.5:c.1471C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002825.3:p.Pro491Thr missense NM_001330437.2:c.1483C>A NP_001317366.1:p.Pro495Thr missense NM_001374625.1:c.1468C>A NP_001361554.1:p.Pro490Thr missense NC_000012.12:g.112489047C>A NC_000012.11:g.112926851C>A NG_007459.1:g.75316C>A LRG_614:g.75316C>A LRG_614t1:c.1471C>A - Protein change
- P491T, P495T, P490T
- Other names
- p.P491T:CCC>ACC
- Canonical SPDI
- NC_000012.12:112489046:C: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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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
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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 (3) |
criteria provided, single submitter
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Jun 9, 2021 | RCV000033535.9 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 8, 2021 | RCV000694590.7 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Feb 28, 2020 | RCV000208219.9 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 6, 2019 | RCV000660240.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 9, 2022 | RCV002490445.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 26, 2024 | RCV004018714.1 |
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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Pathogenic
(Nov 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome 1
Affected status: yes
Allele origin:
germline
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Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000782253.1
First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018 |
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Pathogenic
(May 21, 2013)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061276.6
First in ClinVar: May 03, 2013 Last updated: May 29, 2016 |
Comment:
The Pro491Thr variant has been reported in at least 6 individuals with clinical features of Noonan syndrome (Chan 2006, Carcavilla Urqui 2006, Ezquieta 2012, LM … (more)
The Pro491Thr variant has been reported in at least 6 individuals with clinical features of Noonan syndrome (Chan 2006, Carcavilla Urqui 2006, Ezquieta 2012, LM M unpublished data). In one of these individuals, the variant was inherited fro m an affected mother (Chan 2006). At our laboratory, we have identified this var iant in 3 individuals with clinical features of Noonan syndrome and the variant was also identified in at least one affected family member in each case. We have also tested several additional individuals with clinical features of Noonan spe ctrum disorders who had other amino acid changes at this position (Pro491Leu, Pr o491Ser, Pro491His). In summary, this variant meets our criteria to be classifi ed as pathogenic (http://pcpgm.partners.org/LMM). (less)
Number of individuals with the variant: 9
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Likely pathogenic
(Sep 08, 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: SCV001983563.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
Comment:
Variant summary: PTPN11 c.1471C>A (p.Pro491Thr) results in a non-conservative amino acid change located in the PTP type protein phosphatase domain (IPR000242) of the encoded protein … (more)
Variant summary: PTPN11 c.1471C>A (p.Pro491Thr) results in a non-conservative amino acid change located in the PTP type protein phosphatase domain (IPR000242) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Other missense variants located at this codon have been reported in patients with Noonan syndrome within the HGMD database supporting the notion of critical functional relevance of this Proline residue. The variant was absent in 251480 control chromosomes. c.1471C>A has been reported in the literature in at-least one well genotyped Spanish individual affected with Noonan Syndrome (example, Ezquieta_2012) and in another individual with Noonan syndrome in whom the possibility of a cohort/patient overlap with the earlier ascertainment cannot be excluded within the context of this evaluation (Gomez-Carballa_2011). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=4)/likely pathogenic (n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, until additional clinical patients, confirmed de-novo origin and/or a functional study is identified, the variant was classified as likely pathogenic. (less)
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Pathogenic
(Feb 28, 2020)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome
Affected status: unknown
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV001423724.2
First in ClinVar: Jul 27, 2020 Last updated: Mar 04, 2023 |
Comment:
The PTPN11 c.1471C>A (p.Pro491Thr) variant is a missense variant that has been reported in at least one individual affected with Noonan syndrome who inherited the … (more)
The PTPN11 c.1471C>A (p.Pro491Thr) variant is a missense variant that has been reported in at least one individual affected with Noonan syndrome who inherited the variant from their affected father (Ezquieta et al. 2012). Other missense changes at the Pro491 residue, Pro491Ser, Pro491Leu and Pro491His have been reported to be pathogenic and have been found in individuals with Noonan syndrome (Binder et al. 2005; Ezquieta et al. 2012; Čizmárová et al. 2016). The p.Pro491Thr variant is not reported in the Genome Aggregation Database in a region of good sequence coverage, suggesting that it is a rare variant. Based on the collective evidence, de novo origin of the variant and application of the ACMG criteria, the p.Pro491Thr variant is classified as pathogenic for Noonan syndrome. (less)
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Pathogenic
(Jun 09, 2021)
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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: SCV000057440.14
First in ClinVar: Apr 04, 2013 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson … (more)
Not observed at significant frequency in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22781091, 21526175, 26582918, 22465605, 27535533) (less)
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Pathogenic
(Sep 11, 2015)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV000264161.2
First in ClinVar: Feb 27, 2016 Last updated: May 29, 2016 |
Number of individuals with the variant: 1
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Likely pathogenic
(Jun 06, 2019)
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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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Genomic Medicine Lab, University of California San Francisco
Study: CSER-P3EGS
Accession: SCV001573048.1 First in ClinVar: May 05, 2021 Last updated: May 05, 2021 |
Sex: male
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Likely pathogenic
(Feb 09, 2022)
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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: SCV002813883.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Mar 19, 2018)
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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: SCV000823041.4
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
Two different missense substitutions at this codon (p.Pro491Ser and p.Pro491Leu) have been determined to be pathogenic (PMID: 22465605, 22781091). This suggests that the proline residue … (more)
Two different missense substitutions at this codon (p.Pro491Ser and p.Pro491Leu) have been determined to be pathogenic (PMID: 22465605, 22781091). This suggests that the proline residue is critical for PTPN11 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic. This sequence change replaces proline with threonine at codon 491 of the PTPN11 protein (p.Pro491Thr). The proline residue is moderately conserved and there is a small physicochemical difference between proline and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Noonan syndrome (PMID: 21526175, 22465605; http://www.hkjpaed.org/details.asp?id=581&show=1234). ClinVar contains an entry for this variant (Variation ID: 40549). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). (less)
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Pathogenic
(Jan 26, 2024)
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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: SCV004934877.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
The c.1471C>A (p.P491T) alteration is located in exon 13 (coding exon 13) of the PTPN11 gene. This alteration results from a C to A substitution … (more)
The c.1471C>A (p.P491T) alteration is located in exon 13 (coding exon 13) of the PTPN11 gene. This alteration results from a C to A substitution at nucleotide position 1471, causing the proline (P) at amino acid position 491 to be replaced by a threonine (T)._x000D_ _x000D_ for PTPN11-related RASopathy; however, its clinical significance for metachondromatosis is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported in multiple individuals with features consistent with PTPN11-related RASopathy (Chan, 2006; Gómez-Carballa, 2011; Ezquieta, 2012; Valentino, 2021; Carcavilla, 2023). _x000D_ _x000D_ Three other alterations at the same codon, c.1472C>A (p.P491H), c.1471C>T (p.P491S), and c.1472C>T (p.P491L), have been described in individuals with clinical features consistent with PTPN11-related RASopathy (Bertola, 2006; DECIPHER v.9.32; Ambry internal data). 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
(-)
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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: SCV001956995.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 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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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001966781.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 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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Genotypic Findings in Noonan and Non-Noonan RASopathies and Patient Eligibility for Growth Hormone Treatment. | Carcavilla A | Journal of clinical medicine | 2023 | PMID: 37568403 |
Exome Sequencing in 200 Intellectual Disability/Autistic Patients: New Candidates and Atypical Presentations. | Valentino F | Brain sciences | 2021 | PMID: 34356170 |
New Mutations Associated with Rasopathies in a Central European Population and Genotype-Phenotype Correlations. | Čizmárová M | Annals of human genetics | 2016 | PMID: 26607044 |
Atrioventricular canal defect in patients with RASopathies. | Digilio MC | European journal of human genetics : EJHG | 2013 | PMID: 22781091 |
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 |
Evolutionary analyses of entire genomes do not support the association of mtDNA mutations with Ras/MAPK pathway syndromes. | Gómez-Carballa A | PloS one | 2011 | PMID: 21526175 |
PTPN11 gene analysis in 74 Brazilian patients with Noonan syndrome or Noonan-like phenotype. | Bertola DR | Genetic testing | 2006 | PMID: 17020470 |
PTPN11 mutations are associated with mild growth hormone resistance in individuals with Noonan syndrome. | Binder G | The Journal of clinical endocrinology and metabolism | 2005 | PMID: 15985475 |
Text-mined citations for rs397507539 ...
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.