VCV000040502.22 - ClinVar

NM_002834.5(PTPN11):c.228G>T (p.Glu76Asp)

Germline

Classification

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.

(12)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002834.5(PTPN11):c.228G>T (p.Glu76Asp)

Variation ID: 40502 Accession: VCV000040502.22

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q24.13 12: 112450408 (GRCh38) [ NCBI UCSC ] 12: 112888212 (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	Jan 16, 2015	Oct 8, 2024	Oct 4, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_002834.5:c.228G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002825.3:p.Glu76Asp	missense
NM_001330437.1:c.228G>T
NM_001330437.2:c.228G>T	NP_001317366.1:p.Glu76Asp	missense
NM_001374625.1:c.225G>T	NP_001361554.1:p.Glu75Asp	missense
NM_080601.3:c.228G>T	NP_542168.1:p.Glu76Asp	missense
NC_000012.12:g.112450408G>T
NC_000012.11:g.112888212G>T
NG_007459.1:g.36677G>T
LRG_614:g.36677G>T
LRG_614t1:c.228G>T
	Q06124:p.Glu76Asp

... more HGVS ... less HGVS

Protein change

E76D, E75D

Other names

p.E76D:GAG>GAT

Canonical SPDI

NC_000012.12:112450407:G:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Links

ClinGen: CA261580 UniProtKB: Q06124#VAR_015610 dbSNP: rs397507514 VarSome

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
Gene	OMIM	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	970	982

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.
RASopathy	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Oct 4, 2023	RCV000033478.11
Noonan syndrome	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Apr 1, 2022	RCV000037639.7
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jul 13, 2022	RCV000254683.7
Juvenile myelomonocytic leukemia LEOPARD syndrome 1 Metachondromatosis Noonan syndrome 1	Pathogenic (1)	criteria provided, single submitter	Oct 31, 2018	RCV000762884.2
Noonan syndrome and Noonan-related syndrome	Pathogenic (1)	criteria provided, single submitter	Aug 5, 2020	RCV001813246.3
Noonan syndrome 1	Pathogenic (1)	no assertion criteria provided	-	RCV003150934.1
PTPN11-related disorder	Pathogenic (1)	no assertion criteria provided	Aug 17, 2024	RCV004734537.1

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.
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	LEOPARD syndrome 1 Metachondromatosis Noonan syndrome 1 Juvenile myelomonocytic leukemia Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893272.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Feb 11, 2019)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV000928217.1 First in ClinVar: Jul 31, 2019 Last updated: Jul 31, 2019 Comment: Patient analyzed with Noonan Syndrome Panel
Pathogenic (Aug 05, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome and Noonan-related syndrome Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002060932.1 First in ClinVar: Jan 20, 2022 Last updated: Jan 20, 2022
Pathogenic (Oct 04, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	RASopathy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001394745.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024	Publications: PubMed (8) PubMed: 11704759‚ 12634870‚ 16830086‚ 18678287‚ 22190897‚ 15834506‚ 16358218‚ 17177198 Comment: This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 76 of the PTPN11 … (more) This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 76 of the PTPN11 protein (p.Glu76Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome (PMID: 11704759, 12634870, 16830086, 18678287, 22190897). ClinVar contains an entry for this variant (Variation ID: 40502). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PTPN11 protein function. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 15834506, 16358218, 17177198). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 20, 2017)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	RASopathy Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000698072.1 First in ClinVar: May 27, 2015 Last updated: May 27, 2015	Publications: PubMed (16) PubMed: 22190897‚ 16377799‚ 12634870‚ 15987685‚ 12826400‚ 15928039‚ 26673822‚ 16987887‚ 12717436‚ 20308328‚ 15834506‚ 20186801‚ 16358218‚ 25862627‚ 19077116‚ 18470943 Comment: Variant summary: The PTPN11 c.228G>T (p.Glu76Asp) variant causes a missense change involving the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging … (more) Variant summary: The PTPN11 c.228G>T (p.Glu76Asp) variant causes a missense change involving the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 122184 control chromosomes (ACMG PM2). This variant is found in the N-SH2 domain (IPR000980), a regulatory module of intracellular signaling cascades through its interaction with high affinity to phosphotyrosine-containing target peptides (ACMG PM1). This is a hotspot, with multiple missense variants in the same residue being known likely pathogenic variants (p.Glu76Lys, p.Glu76Ala, p.Glu76Val, p.Glu76Gly). In addition, multiple functional studies (Tartaglia_AJHG_2006, Edouard_MCB_2010, Keilhack_JBC_2005) showed that this variant increased basal and stimulated phosphatase activity by as much as 3-fold, determining a gain-of-function phenotype (ACMG PS3). This variant, and another variant c.228G>C that leads to the same amino acid change (E76D) have been reported in several patients with a clinical diagnosis of Noonan syndrome (ACMG PS1). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic (ACMG PP5). Lastly, these evidences support the classification of this variant as "Pathogenic" based upon ACMG guidelines (PS1, PS3, PM1, PM2, PP5). Taken together, this variant is classified as Pathogenic. (less)
Pathogenic (Apr 13, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome Affected status: yes Allele origin: de novo	Center of Genomic medicine, Geneva, University Hospital of Geneva Accession: SCV000840427.1 First in ClinVar: May 29, 2016 Last updated: May 29, 2016	Number of individuals with the variant: 1 Age: 0-9 years Sex: female
Pathogenic (Feb 25, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000057383.15 First in ClinVar: Apr 04, 2013 Last updated: Mar 04, 2023	Comment: Reported previously in association with Noonan syndrome (Tartaglia et al., 2006; Musante et al., 2003); Published functional studies demonstrate a damaging effect; p.(E76D) results in … (more) Reported previously in association with Noonan syndrome (Tartaglia et al., 2006; Musante et al., 2003); Published functional studies demonstrate a damaging effect; p.(E76D) results in abnormally increased activity levels of the PTPN11 protein (Tartaglia et al., 2006; Bocchinfuso et al., 2007); Missense variants in this gene are often considered pathogenic (HGMD); 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; This variant is associated with the following publications: (PMID: 12634870, 20308328, 17177198, 29907801, 30029678, 16830086, 30050098, 32676024, 16358218, 24077912, 27535533, 11992261, 9491886, 16053901, 29493581) (less)
Pathogenic (Apr 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000061301.7 First in ClinVar: May 03, 2013 Last updated: Apr 20, 2024	Publications: PubMed (11) PubMed: 17177198‚ 20308328‚ 16358218‚ 16830086‚ 12634870‚ 15987685‚ 22190897‚ 11704759‚ 29493581‚ 30029678‚ 29907801 Comment: The p.Glu76Asp (c.228G>T) variant in PTPN11 has been reported in at least 10 individuals with clinical features of Noonan syndrome (Musante 2003 PMID: 12634870, Tartaglia … (more) The p.Glu76Asp (c.228G>T) variant in PTPN11 has been reported in at least 10 individuals with clinical features of Noonan syndrome (Musante 2003 PMID: 12634870, Tartaglia 2006 PMID: 16358218, Power 2006 PMID: 16830086, Digilio 2011 PMID: 22190897, Zhu 2018 PMID: 30029678, Leach 2019 PMID: 29907801, LMM data) and has also been reported by other clinical laboratories in ClinVar (Variation ID 40502). It was absent from large population studies. Notably, a different nucleotide substitution at the same position (c.228G>C) resulting in the same amino acid change has been reported in >10 individuals with clinical features of Noonan syndrome (Tartaglia 2001 PMID: 11704759, Tartaglia 2006 PMID: 16358218, Edouard 2010 PMID: 20308328, LMM data). In addition, there are 4 other pathogenic amino acid substitutions at this position (p.Glu76Lys, p.Glu76Ala, p.Glu76Val, p.Glu76Gly); all these variants were also absent in large population studies. In vitro functional studies support an impact on protein function (Keilhack 2005 PMID: 15987685, Bocchinfuso 2007 PMID: 17177198, Edouard 2010 PMID: 20308328). Additionally, this variant lies in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (Gelb 2018 PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Noonan syndrome. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PM5_Strong, PS3_Supporting. (less)
Pathogenic (Jul 13, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005197297.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Rasopathy Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV000196662.1 First in ClinVar: Jan 16, 2015 Last updated: Jan 16, 2015	Publications: PubMed (2) PubMed: 16358218‚ 20308328 Comment: Variant classified using ACMG guidelines
Pathogenic (-)	no assertion criteria provided Method: research	Noonan syndrome 1 Affected status: yes Allele origin: unknown	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand Accession: SCV003840156.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Number of individuals with the variant: 1
Pathogenic (Aug 17, 2024)	no assertion criteria provided Method: clinical testing	PTPN11-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005362203.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The PTPN11 c.228G>T variant is predicted to result in the amino acid substitution p.Glu76Asp. This variant has been reported in many individuals with Noonan syndrome … (more) The PTPN11 c.228G>T variant is predicted to result in the amino acid substitution p.Glu76Asp. This variant has been reported in many individuals with Noonan syndrome (Tartaglia et al. 2006. PubMed ID: 16358218; Table S3, Leach et al. 2019. PubMed ID: 29907801; Table S4, Zhu et al. 2018. PubMed ID: 30029678). Functional studies support this variants pathogenicity (Edouard et al. 2010. PubMed ID: 20308328). This variant has not been reported in a large population database, indicating this variant is rare. In ClinVar, this variant has been interpreted as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/40502/). An alternate nucleotide substitution resulting in the same missense variant (c.228G>C (p.Glu76Asp)) has been reported as pathogenic (ClinVar ID: 40503). Alternate amino acid substitutions affecting this amino acid (p.Glu76Gln, p.Glu76Ala, p.Glu76Gly, p.Glu76Val) have been interpreted as pathogenic in ClinVar (ClinVar IDs: 181496, 13339, 13338, 13337). This variant is interpreted as pathogenic. (less)
click to load more click to collapse

Comment:

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 76 of the PTPN11 protein (p.Glu76Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome (PMID: 11704759, 12634870, 16830086, 18678287, 22190897). ClinVar contains an entry for this variant (Variation ID: 40502). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PTPN11 protein function. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 15834506, 16358218, 17177198). For these reasons, this variant has been classified as Pathogenic.

Comment:

Variant summary: The PTPN11 c.228G>T (p.Glu76Asp) variant causes a missense change involving the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 122184 control chromosomes (ACMG PM2). This variant is found in the N-SH2 domain (IPR000980), a regulatory module of intracellular signaling cascades through its interaction with high affinity to phosphotyrosine-containing target peptides (ACMG PM1). This is a hotspot, with multiple missense variants in the same residue being known likely pathogenic variants (p.Glu76Lys, p.Glu76Ala, p.Glu76Val, p.Glu76Gly). In addition, multiple functional studies (Tartaglia_AJHG_2006, Edouard_MCB_2010, Keilhack_JBC_2005) showed that this variant increased basal and stimulated phosphatase activity by as much as 3-fold, determining a gain-of-function phenotype (ACMG PS3). This variant, and another variant c.228G>C that leads to the same amino acid change (E76D) have been reported in several patients with a clinical diagnosis of Noonan syndrome (ACMG PS1). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic (ACMG PP5). Lastly, these evidences support the classification of this variant as "Pathogenic" based upon ACMG guidelines (PS1, PS3, PM1, PM2, PP5). Taken together, this variant is classified as Pathogenic.

Comment:

Reported previously in association with Noonan syndrome (Tartaglia et al., 2006; Musante et al., 2003); Published functional studies demonstrate a damaging effect; p.(E76D) results in abnormally increased activity levels of the PTPN11 protein (Tartaglia et al., 2006; Bocchinfuso et al., 2007); Missense variants in this gene are often considered pathogenic (HGMD); 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; This variant is associated with the following publications: (PMID: 12634870, 20308328, 17177198, 29907801, 30029678, 16830086, 30050098, 32676024, 16358218, 24077912, 27535533, 11992261, 9491886, 16053901, 29493581)

Comment:

The p.Glu76Asp (c.228G>T) variant in PTPN11 has been reported in at least 10 individuals with clinical features of Noonan syndrome (Musante 2003 PMID: 12634870, Tartaglia 2006 PMID: 16358218, Power 2006 PMID: 16830086, Digilio 2011 PMID: 22190897, Zhu 2018 PMID: 30029678, Leach 2019 PMID: 29907801, LMM data) and has also been reported by other clinical laboratories in ClinVar (Variation ID 40502). It was absent from large population studies. Notably, a different nucleotide substitution at the same position (c.228G>C) resulting in the same amino acid change has been reported in >10 individuals with clinical features of Noonan syndrome (Tartaglia 2001 PMID: 11704759, Tartaglia 2006 PMID: 16358218, Edouard 2010 PMID: 20308328, LMM data). In addition, there are 4 other pathogenic amino acid substitutions at this position (p.Glu76Lys, p.Glu76Ala, p.Glu76Val, p.Glu76Gly); all these variants were also absent in large population studies. In vitro functional studies support an impact on protein function (Keilhack 2005 PMID: 15987685, Bocchinfuso 2007 PMID: 17177198, Edouard 2010 PMID: 20308328). Additionally, this variant lies in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (Gelb 2018 PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Noonan syndrome. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PM5_Strong, PS3_Supporting.

Comment:

The PTPN11 c.228G>T variant is predicted to result in the amino acid substitution p.Glu76Asp. This variant has been reported in many individuals with Noonan syndrome (Tartaglia et al. 2006. PubMed ID: 16358218; Table S3, Leach et al. 2019. PubMed ID: 29907801; Table S4, Zhu et al. 2018. PubMed ID: 30029678). Functional studies support this variants pathogenicity (Edouard et al. 2010. PubMed ID: 20308328). This variant has not been reported in a large population database, indicating this variant is rare. In ClinVar, this variant has been interpreted as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/40502/). An alternate nucleotide substitution resulting in the same missense variant (c.228G>C (p.Glu76Asp)) has been reported as pathogenic (ClinVar ID: 40503). Alternate amino acid substitutions affecting this amino acid (p.Glu76Gln, p.Glu76Ala, p.Glu76Gly, p.Glu76Val) have been interpreted as pathogenic in ClinVar (ClinVar IDs: 181496, 13339, 13338, 13337). This variant is interpreted as pathogenic.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
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: 29907801
Rare variants in SOX17 are associated with pulmonary arterial hypertension with congenital heart disease.	Zhu N	Genome medicine	2018	PMID: 30029678
ClinGen's RASopathy Expert Panel consensus methods for variant interpretation.	Gelb BD	Genetics in medicine : official journal of the American College of Medical Genetics	2018	PMID: 29493581
A tyrosine phosphatase SHP2 gain-of-function mutation enhances malignancy of breast carcinoma.	Hu Z	Oncotarget	2016	PMID: 26673822
External ear anomalies and hearing impairment in Noonan Syndrome.	van Trier DC	International journal of pediatric otorhinolaryngology	2015	PMID: 25862627
RASopathies: Clinical Diagnosis in the First Year of Life.	Digilio MC	Molecular syndromology	2011	PMID: 22190897
Functional effects of PTPN11 (SHP2) mutations causing LEOPARD syndrome on epidermal growth factor-induced phosphoinositide 3-kinase/AKT/glycogen synthase kinase 3beta signaling.	Edouard T	Molecular and cellular biology	2010	PMID: 20308328
Effects of germline mutations in the Ras/MAPK signaling pathway on adaptive behavior: cardiofaciocutaneous syndrome and Noonan syndrome.	Pierpont EI	American journal of medical genetics. Part A	2010	PMID: 20186801
Genotype differences in cognitive functioning in Noonan syndrome.	Pierpont EI	Genes, brain, and behavior	2009	PMID: 19077116
Clinical and molecular characterization of 40 patients with Noonan syndrome.	Ferrero GB	European journal of medical genetics	2008	PMID: 18678287
The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders.	Aoki Y	Human mutation	2008	PMID: 18470943
Structural and functional effects of disease-causing amino acid substitutions affecting residues Ala72 and Glu76 of the protein tyrosine phosphatase SHP-2.	Bocchinfuso G	Proteins	2007	PMID: 17177198
Noonan syndrome and related disorders: dysregulated RAS-mitogen activated protein kinase signal transduction.	Gelb BD	Human molecular genetics	2006	PMID: 16987887
Aortic root dilatation is a rare complication of Noonan syndrome.	Power PD	Pediatric cardiology	2006	PMID: 16830086
PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects.	Kontaridis MI	The Journal of biological chemistry	2006	PMID: 16377799
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
The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease.	Kratz CP	Blood	2005	PMID: 15928039
Functional analysis of PTPN11/SHP-2 mutants identified in Noonan syndrome and childhood leukemia.	Niihori T	Journal of human genetics	2005	PMID: 15834506
The 'Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling.	Neel BG	Trends in biochemical sciences	2003	PMID: 12826400
Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia.	Tartaglia M	Nature genetics	2003	PMID: 12717436
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
Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome.	Tartaglia M	Nature genetics	2001	PMID: 11704759
click to load more click to collapse

Text-mined citations for rs397507514 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_002834.5(PTPN11):c.228G>T (p.Glu76Asp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs397507514 ...