ClinVar Genomic variation as it relates to human health
NM_002834.5(PTPN11):c.124A>G (p.Thr42Ala)
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.124A>G (p.Thr42Ala)
Variation ID: 40482 Accession: VCV000040482.32
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q24.13 12: 112446385 (GRCh38) [ NCBI UCSC ] 12: 112884189 (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 Jan 31, 2015 Feb 20, 2024 Oct 25, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002834.5:c.124A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002825.3:p.Thr42Ala missense NM_001330437.2:c.124A>G NP_001317366.1:p.Thr42Ala missense NM_001374625.1:c.124A>G NP_001361554.1:p.Thr42Ala missense NM_080601.3:c.124A>G NP_542168.1:p.Thr42Ala missense NC_000012.12:g.112446385A>G NC_000012.11:g.112884189A>G NG_007459.1:g.32654A>G LRG_614:g.32654A>G LRG_614t1:c.124A>G Q06124:p.Thr42Ala - Protein change
- T42A
- Other names
- p.T42A:ACA>GCA
- Canonical SPDI
- NC_000012.12:112446384:A: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
Help
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
Help
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
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
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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, single submitter
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Jun 21, 2022 | RCV000157675.6 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jun 19, 2015 | RCV000157002.13 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 25, 2023 | RCV000227194.7 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Sep 27, 2022 | RCV001330777.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 1, 2018 | RCV001813241.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 24, 2019 | RCV002399352.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 17, 2021 | RCV002482941.1 |
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
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. |
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Pathogenic
(Jun 19, 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: SCV000264157.2
First in ClinVar: Feb 27, 2016 Last updated: May 29, 2016 |
Number of individuals with the variant: 1
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Pathogenic
(Jun 03, 2020)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome 1
Affected status: yes
Allele origin:
de novo
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Baylor Genetics
Accession: SCV001522569.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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Pathogenic
(Dec 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome and Noonan-related syndrome
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002060946.1
First in ClinVar: Jan 20, 2022 Last updated: Jan 20, 2022 |
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Pathogenic
(Oct 24, 2019)
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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: SCV002669239.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.T42A pathogenic mutation (also known as c.124A>G), located in coding exon 2 of the PTPN11 gene, results from an A to G substitution at … (more)
The p.T42A pathogenic mutation (also known as c.124A>G), located in coding exon 2 of the PTPN11 gene, results from an A to G substitution at nucleotide position 124. The threonine at codon 42 is replaced by alanine, an amino acid with similar properties, and is located in the N-SH2 domain. This mutation has been reported in numerous individuals with Noonan syndrome, including at least two reportedly de novo cases (Tartaglia M et al. Am. J. Hum. Genet., 2002 Jun;70:1555-63; Sarkozy A et al. J. Med. Genet., 2003 Sep;40:704-8; Zenker M et al. J. Pediatr., 2004 Mar;144:368-74; Lee ST et al. Clin. Genet., 2007 Aug;72:150-5; van Nierop JWI et al. Int. J. Pediatr. Otorhinolaryngol., 2017 Jun;97:228-234). Functional studies showed increased phosphopeptide binding affinity and dephosphorylation (Martinelli S et al. Hum. Mol. Genet., 2008 Jul;17:2018-29). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jun 21, 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: SCV000057355.16
First in ClinVar: Apr 04, 2013 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a significant increase in phosphopeptide binding affinity without greatly altering binding specificity or secondary structure of the domain (Keilhack et al., … (more)
Published functional studies demonstrate a significant increase in phosphopeptide binding affinity without greatly altering binding specificity or secondary structure of the domain (Keilhack et al., 2005; Muller et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 16358218, 30417923, 30050098, 18372317, 23584145, 15987685, 25425531, 24803665, 21590266, 17661820, 28483241, 11992261, 22781091, 29988639, 29907801, 31219622, 31560489, 32164556, 31936901, 32668055, 29493581, 33258288, 32786180) (less)
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Pathogenic
(Jan 25, 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: SCV000061270.6
First in ClinVar: May 03, 2013 Last updated: May 29, 2016 |
Comment:
The Thr42Ala variant in PTPN11 has been reported in 10 individuals in the litera ture (Tartaglia 2002, Sarkozy 2003, Zenker 2004, Lee 2007, Shaw 2007, … (more)
The Thr42Ala variant in PTPN11 has been reported in 10 individuals in the litera ture (Tartaglia 2002, Sarkozy 2003, Zenker 2004, Lee 2007, Shaw 2007, Martinelli 2008, Digilio 2012) and one individual in our laboratory with clinical features of Noonan syndrome. This variant was reported to have occurred de novo in at le ast one of these individuals (Digilio 2012). In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM). (less)
Number of individuals with the variant: 4
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Pathogenic
(Mar 25, 2019)
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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: SCV001361724.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: PTPN11 c.124A>G (p.Thr42Ala) results in a non-conservative amino acid change located in the SH2 domain of the encoded protein sequence. Four of five … (more)
Variant summary: PTPN11 c.124A>G (p.Thr42Ala) results in a non-conservative amino acid change located in the SH2 domain 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 246614 control chromosomes (gnomAD). c.124A>G has been reported in the literature in multiple individuals affected with Noonan Syndrome, including de novo cases (Tartaglia_2002, Sarkozy_2003, Zenker_2004, Lee_2007, VanTrier_2015, Tamura_2018, Ezquieta_2012). These data indicate that the variant is very likely to be associated with disease. This variant exhibits increased affinity for mono-Tyr(P) peptide and phosphopeptide (Keilhack_2005 and Martinelli_2008), which is believed to be one of the mechanisms of SHP2's functional dysregulation. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Sep 17, 2021)
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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: SCV002785167.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(-)
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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:
germline
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Lifecell International Pvt. Ltd
Accession: SCV003841251.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
A Heterozygous Missense variant c.124A>G in Exon 2 of the PTPN11 gene that results in the amino acid substitution p.Thr42Ala was identified. The observed variant … (more)
A Heterozygous Missense variant c.124A>G in Exon 2 of the PTPN11 gene that results in the amino acid substitution p.Thr42Ala was identified. The observed variant has a minor allele frequency of 0% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. This variant has previously reported for patients with RASopathies by Digilio MC, et, al., 2012. Functional studies showed increased phosphopeptide binding affinity and dephosphorylation (Martinelli S et al.,2008.) ClinVar has also classified this variant as Pathogenic (Variant ID: 40482). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. (less)
Ethnicity/Population group: Asian
Geographic origin: India
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Pathogenic
(Oct 25, 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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Invitae
Accession: SCV000287692.7
First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 42 of the PTPN11 protein (p.Thr42Ala). … (more)
This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 42 of the PTPN11 protein (p.Thr42Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome (PMID: 15001945, 16358218, 17661820, 21590266, 22781091). ClinVar contains an entry for this variant (Variation ID: 40482). 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%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 15987685, 18372317, 23584145). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 27, 2022)
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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:
germline
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Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin
Additional submitter:
CUBI - Core Unit Bioinformatics, Berlin Institute of Health
Accession: SCV002578151.1
First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022 |
Clinical Features:
Cryptorchidism (present) , Osteoporosis (present) , Tetralogy of Fallot (present) , Thoracic scoliosis (present) , Short stature (present)
Sex: male
Tissue: Blood
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Pathogenic
(Jan 15, 2015)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV000207646.1
First in ClinVar: Feb 19, 2015 Last updated: Feb 19, 2015 |
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Pathogenic
(Jan 27, 2012)
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no assertion criteria provided
Method: clinical testing
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Noonan syndrome
Affected status: yes
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000206726.1
First in ClinVar: Jan 31, 2015 Last updated: Jan 31, 2015 |
Number of individuals with the variant: 1
Clinical Features:
Abnormality of the face (present) , Low-set nipples (present) , Phenotypic abnormality (present) , Pulmonic stenosis (present)
Family history: no
Sex: male
Ethnicity/Population group: Caucasian _ not further specified
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Noonan syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Molecular Genetics, Centre for Human Genetics
Accession: SCV004190080.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Number of individuals with the variant: 1
Secondary finding: no
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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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Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation. | Bessis D | The British journal of dermatology | 2019 | PMID: 30417923 |
Correction: 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: 30050098 |
Co-occurrence of hypertrophic cardiomyopathy and juvenile myelomonocytic leukemia in a neonate with Noonan syndrome, leading to premature death. | Tamura A | Clinical case reports | 2018 | PMID: 29988639 |
Cochlear implantation and clinical features in patients with Noonan syndrome and Noonan syndrome with multiple lentigines caused by a mutation in PTPN11. | van Nierop JWI | International journal of pediatric otorhinolaryngology | 2017 | PMID: 28483241 |
External ear anomalies and hearing impairment in Noonan Syndrome. | van Trier DC | International journal of pediatric otorhinolaryngology | 2015 | PMID: 25862627 |
Expanding the clinical spectrum of ocular anomalies in Noonan syndrome: Axenfeld-anomaly in a child with PTPN11 mutation. | Guerin A | American journal of medical genetics. Part A | 2015 | PMID: 25425531 |
Protein tyrosine phosphatase SHP2/PTPN11 mistargeting as a consequence of SH2-domain point mutations associated with Noonan Syndrome and leukemia. | Müller PJ | Journal of proteomics | 2013 | PMID: 23584145 |
Atrioventricular canal defect in patients with RASopathies. | Digilio MC | European journal of human genetics : EJHG | 2013 | PMID: 22781091 |
Phenotypic spectrum of 80 Greek patients referred as Noonan syndrome and PTPN11 mutation analysis: the value of initial clinical assessment. | Papadopoulou A | European journal of pediatrics | 2012 | PMID: 21590266 |
RASopathies: Clinical Diagnosis in the First Year of Life. | Digilio MC | Molecular syndromology | 2011 | PMID: 22190897 |
Diverse driving forces underlie the invariant occurrence of the T42A, E139D, I282V and T468M SHP2 amino acid substitutions causing Noonan and LEOPARD syndromes. | Martinelli S | Human molecular genetics | 2008 | PMID: 18372317 |
Mutation analysis of the genes involved in the Ras-mitogen-activated protein kinase (MAPK) pathway in Korean patients with Noonan syndrome. | Lee ST | Clinical genetics | 2007 | PMID: 17661820 |
The natural history of Noonan syndrome: a long-term follow-up study. | Shaw AC | Archives of disease in childhood | 2007 | PMID: 16990350 |
Additional evidence that PTPN11 mutations play only a minor role in the pathogenesis of non-syndromic atrioventricular canal defect. | Sarkozy A | American journal of medical genetics. Part A | 2006 | PMID: 16892325 |
Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. | Tartaglia M | American journal of human genetics | 2006 | PMID: 16358218 |
Diverse biochemical properties of Shp2 mutants. Implications for disease phenotypes. | Keilhack H | The Journal of biological chemistry | 2005 | PMID: 15987685 |
Genotype-phenotype correlations in Noonan syndrome. | Zenker M | The Journal of pediatrics | 2004 | PMID: 15001945 |
Correlation between PTPN11 gene mutations and congenital heart defects in Noonan and LEOPARD syndromes. | Sarkozy A | Journal of medical genetics | 2003 | PMID: 12960218 |
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 |
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Text-mined citations for rs397507501 ...
HelpRecord last updated Feb 28, 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.