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rs121918459

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PS1PM1PP2PP3_StrongPP5_Very_Strong

The NM_002834.5(PTPN11):c.188A>G(p.Tyr63Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,613,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

PTPN11
NM_002834.5 missense

Scores

15
3
1

Clinical Significance

Pathogenic reviewed by expert panel P:46U:1

Conservation

PhyloP100: 9.31
Variant links:
Genes affected
PTPN11 (HGNC:9644): (protein tyrosine phosphatase non-receptor type 11) The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains two tandem Src homology-2 domains, which function as phospho-tyrosine binding domains and mediate the interaction of this PTP with its substrates. This PTP is widely expressed in most tissues and plays a regulatory role in various cell signaling events that are important for a diversity of cell functions, such as mitogenic activation, metabolic control, transcription regulation, and cell migration. Mutations in this gene are a cause of Noonan syndrome as well as acute myeloid leukemia. [provided by RefSeq, Aug 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PS1
Transcript NM_002834.5 (PTPN11) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 372674
PM1
In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_002834.5
PP2
Missense variant where missense usually causes diseases, PTPN11
PP3
MetaRNN computational evidence supports a deleterious effect, 0.985
PP5
Variant 12-112450368-A-G is Pathogenic according to our data. Variant chr12-112450368-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 13333.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-112450368-A-G is described in Lovd as [Likely_pathogenic]. Variant chr12-112450368-A-G is described in Lovd as [Pathogenic]. Variant chr12-112450368-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PTPN11NM_002834.5 linkuse as main transcriptc.188A>G p.Tyr63Cys missense_variant 3/16 ENST00000351677.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PTPN11ENST00000351677.7 linkuse as main transcriptc.188A>G p.Tyr63Cys missense_variant 3/161 NM_002834.5 A1Q06124-2

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152184
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
251010
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135640
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000882
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000821
AC:
12
AN:
1460960
Hom.:
0
Cov.:
31
AF XY:
0.00000688
AC XY:
5
AN XY:
726828
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000810
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152184
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74342
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000192
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:46Uncertain:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Noonan syndrome 1 Pathogenic:15Uncertain:1
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteSep 02, 2022Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss of function and gain of function are known mechanisms of disease for this gene. Metachondromatosis (MIM#156250) and Noonan syndrome with multiple lentigines have been associated with loss of function variants, whereas Noonan syndrome 1 (MIM#163950) is caused by gain of function variants (PMIDs: 11992261, 24935154, 21533187). (I) 0107 - This gene is known to be associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 20301303). (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine. (I) 0251 - Variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and is highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (N-SH2 domain; DECIPHER). (SP) 0801 - The variant has strong previous evidence of pathogenicity in unrelated individuals with Noonan syndrome (ClinVar, DECIPHER, PMIDs: 11704759; 12325025; 12634870). (SP) 0901 - The variant has strong evidence for segregation with disease in multiple families (PMID: 12325025; 12634870). (SP) 1002 - Moderate functional evidence supporting abnormal protein function. In vitro studies showed that the variant resulted in a gain of protein function (PMID: 22711529). (SP) 1208 - Inheritance information for this variant is not currently available. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterAug 16, 2022- -
Pathogenic, criteria provided, single submitterclinical testingUndiagnosed Diseases Network, NIHMar 28, 2017- -
Pathogenic, criteria provided, single submitterclinical testingCenter for Human Genetics, Inc, Center for Human Genetics, IncNov 01, 2016- -
Pathogenic, criteria provided, single submitterclinical testingEquipe Genetique des Anomalies du Developpement, Université de BourgogneMay 23, 2019- -
Pathogenic, criteria provided, single submitterclinical testingInstitute for Genomic Statistics and Bioinformatics, University Hospital Bonn-- -
Pathogenic, no assertion criteria providedclinical testingZotz-Klimas Genetics Lab, MVZ Zotz KlimasNov 02, 2023- -
Pathogenic, criteria provided, single submittercase-controlGenetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital-- -
Pathogenic, no assertion criteria providedliterature onlyOMIMJun 01, 2007- -
Pathogenic, criteria provided, single submitterclinical testingCentogene AG - the Rare Disease CompanyJul 12, 2018- -
Pathogenic, criteria provided, single submitterclinical testingLaboratory of Medical Genetics, National & Kapodistrian University of AthensOct 01, 2021PS3, PM1, PM2, PP2, PP3, PP5 -
Pathogenic, criteria provided, single submitterclinical testingClinical Genetics Laboratory, Region OstergotlandJan 26, 2021PS3, PS4, PM6, PP1, PP3, PP5 -
Pathogenic, criteria provided, single submitterclinical testing3billionOct 02, 2021Same nucleotide change resulting in same amino acid change has been previously observed in at least four similarly affected unrelated individuals (3billion dataset, ClinVar ID: VCV000372674.2, PMID: 11992261, 26242988, PS4). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.00001195). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.955, 3Cnet: 0.971, PP3). Patient's phenotype is considered compatible with Noonan syndrome (3billion dataset, PP4).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria providedresearchDivision of Human Genetics, National Health Laboratory Service/University of the Witwatersrand-- -
Uncertain significance, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGMFeb 14, 2023The missense c.188A>G(p.Tyr63Cys) variant in PTPN11 gene has been reported previously in heterozygous state in individual(s) affected with Noonan syndrome (Takahashi et al., 2006). Experimental studies have shown that this missense change affects PTPN11 function (Martinelli S et al., 2012). This variant is reported with the allele frequency of 0.001% in the gnomAD Exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic by multiple submitters. The amino acid Tyr at position 63 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Tyr63Cys in PTPN11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted as damaging by SIFT. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsFeb 12, 2021- -
not provided Pathogenic:14
Pathogenic, criteria provided, single submitterclinical testingGeneDxAug 11, 2021Published functional studies demonstrate that Y63C perturbs the autoinhibitory interaction between the N-SH2 and protein-tyrosine phosphatase domains, which is required to maintain SHP2 in its catalytically inactive state (Martinelli et al., 2012); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); 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: 21407260, 12325025, 24803665, 11704759, 30055033, 30417923, 32164556, 24219368, 22711529, 12634870, 26242988, 25156961, 30692697, 30050098, 29907801, 31219622, 31560489, 32371413, 32901917, 11992261, 9491886, 16053901, 29493581) -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Mar 01, 2013- -
Pathogenic, no assertion criteria providedclinical testingGreenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic CenterJan 15, 2015- -
Pathogenic, criteria provided, single submitterclinical testingAthena DiagnosticsJun 15, 2017- -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesAug 16, 2023The PTPN11 c.188A>G; p.Tyr63Cys variant (rs121918459) has been reported in multiple patients diagnosed with Noonan syndrome (Tartaglia 2001, Jongmans 2011, Martinelli 2012, Hashida 2013, Lepri 2014, Okamoto 2015). This variant is found on only three chromosomes (3/251010 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism, and it is listed as pathogenic in ClinVar by multiple clinical laboratories (Variation ID: 13333). The p.Tyr63Cys variant is located in a structurally important region of the catalytic N-terminal SH2 domain of PTPN11 (Hof 1998), and several additional variants in neighboring codons (p.Asp61Asn, p.Asp61Gly, p.Tyr62Asp, p.Tyr62Asn) have also been identified in individuals with Noonan syndrome (Jongmans 2011, Tartaglia 2002, Tartaglia 2006). Functional characterization of the p.Tyr63Cys variant protein indicates over-activation of p38alpha MAP kinase and phosphorERK1/2 upon growth factor signaling (Martinelli 2012, Hashida 2013), consistent with the established disease mechanisms of Noonan syndrome. Based on available information, the p.Tyr63Cys variant is classified as pathogenic. References: Hashida N et al. MAPK activation in mature cataract associated with Noonan syndrome. BMC Ophthalmol. 2013 Nov 12;13:70. PMID: 24219368 Hof P et al. Crystal structure of the tyrosine phosphatase SHP-2. Cell. 1998 Feb 20;92(4):441-50. PMID: 9491886 Jongmans M et al. Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation. Eur J Hum Genet. 2011 Aug;19(8):870-4. PMID: 21407260 Lepri et al. Diagnosis of Noonan syndrome and related disorders using target next generation sequencing. BMC Med Genet. 2014 Jan 23;15:14. PMID: 24451042 Martinelli S et al. Counteracting effects operating on Src homology 2 domain-containing protein-tyrosine phosphatase 2 (SHP2) function drive selection of the recurrent Y62D and Y63C substitutions in Noonan syndrome. J Biol Chem. 2012 Aug 3;287(32):27066-77. PMID: 22711529 Okamoto N et al. Targeted next-generation sequencing in the diagnosis of neurodevelopmental disorders. Clin Genet. 2015 Sep;88(3):288-92. PMID: 25156961 Tartaglia M et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001 Dec;29(4):465-8. PMID: 11704759 Tartaglia M et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002 Jun;70(6):1555-63. PMID: 11992261 Tartaglia M et al. Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet. 2006 Feb;78(2):279-90. PMID: 16358218 -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenSep 15, 2021- -
Pathogenic, criteria provided, single submitterclinical testingKariminejad - Najmabadi Pathology & Genetics CenterJul 10, 2021- -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityMar 18, 2022- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJan 01, 2023PTPN11: PP1:Strong, PM1, PS4:Moderate, PP2, PP3, PP4, PS3:Supporting -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, criteria provided, single submitterclinical testingMolecular Diagnostics Lab, Nemours Children's Health, DelawareSep 21, 2015- -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Pathogenic, criteria provided, single submitterclinical testingAiLife Diagnostics, AiLife DiagnosticsJan 20, 2022- -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicJun 02, 2022PP1_strong, PP2, PP3, PM1, PS3_moderate -
Noonan syndrome Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingBlueprint GeneticsJan 07, 2015- -
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineApr 20, 2017The p.Tyr63Cys variant in PTPN11 has been reported in >40 individuals with Noona n syndrome, occurred de novo in some sporadic cases and segregated with disease in numerous families (Tartaglia 2002, Kosaki 2002, Maheshwari 2002, Musante 2003 , Loh 2004, Kratz 2005, Takahashi 2006, Becker 2007, Jongmans 2011, Simsek-Kiper 2012, LMM data). In addition, this variant has been identified as a somatic var iant in one individual with chronic myelomonocytic leukemia (CMML; Loh 2004) and as a germline variant in two individuals with both clinical features of Noonan syndrome and a malignancy (precursor B-ALL and basal cell carcinoma; Jongmans 20 11). This variant has also been identified in 1/17248 East Asian chromosomes and 1/33576 Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). Moreov er, the p.Tyr63Cys variant has been classified as pathogenic on April 3, 2018 by the ClinGen-approved RASopathy Expert Panel (ClinVar SCV000616372.1). In summar y, this variant meets criteria to be classified as pathogenic for Noonan syndrom e in an autosomal dominant manner based upon presence in multiple affected indiv iduals, de novo occurrences and segregation studies. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM6_Strong. -
Pathogenic, reviewed by expert panelcurationClinGen RASopathy Variant Curation Expert PanelApr 03, 2017The c.188A>G (p.Tyr63Cys) variant in PTPN11 has been reported in the literature in at least 6 unrelated individuals and has been found to segregate with clinical features of a RASopathy in at least 15 family members (PS4, PP1_Strong; 16498234, 12634870, 12325025, 11704759). In vitro functional studies provide some evidence that the p.Tyr63Cys variant may impact protein function (PS3; PMID: 22711529). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Tyr63Cys variant may impact the protein (PP3). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP1_Strong, PS4, PS3, PM1, PP2, PP3. -
RASopathy Pathogenic:3
Pathogenic, no assertion criteria providedclinical testingBaylor Genetics-Variant classified using ACMG guidelines -
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 25, 2024This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 63 of the PTPN11 protein (p.Tyr63Cys). This variant is present in population databases (rs121918459, gnomAD 0.006%). This missense change has been observed in individuals with Noonan syndrome (PMID: 11704759, 11992261, 12325025, 12960218, 16498234, 21407260). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13333). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PTPN11 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 22711529). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterresearchDivision of Human Genetics, National Health Laboratory Service/University of the WitwatersrandJul 01, 2023- -
LEOPARD syndrome 1 Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingLaboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert EinsteinApr 06, 2022ACMG classification criteria: PS3 strong, PS4 strong, PM1 moderated, PP1 strong, PP2 supporting, PP3 supporting -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsFeb 14, 2021- -
PTPN11-related disorder Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesDec 26, 2023The PTPN11 c.188A>G variant is predicted to result in the amino acid substitution p.Tyr63Cys. This variant has been reported in many unrelated individuals with Noonan syndrome and was found to occur de novo in several cases and segregated with disease in many families (Tartaglia et al. 2001. PubMed ID: 11704759; Maheshwari et al. 2002. PubMed ID: 12325025; Jongmans et al. 2011. PubMed ID: 21407260; Okamoto et al. 2015. PubMed ID: 25156961). Functional studies indicate that the p.Tyr63Cys variant alters the functional regulation of SHP2 protein by affecting the stability between N-SH2 and PTP domains (Martinelli et al. 2012. PubMed ID: 22711529). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingRady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego-This variant has been previously reported as a heterozygous change in patients with PTPN11-related disorders (PMID: 16498234, 12634870, 12325025, 11704759, 21407260). Functional studies suggest that this variant impacts protein structure, resulting in increased protein activity (PMID: 22711529). The c.188A>G (p.Tyr63Cys) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (3/251010) and thus is presumed to be rare. Based on the available evidence, the c.188A>G (p.Tyr63Cys) variant is classified as Pathogenic. -
Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomics, Ann and Robert H. Lurie Children's Hospital of ChicagoJan 25, 2022This variant has been reported in the literature in at least 10 individuals with a clinical diagnosis or suspicion of Noonan syndrome, segregating with disease in more than 15 affected family members (Selected publications: Maheshwari 2002 PMID:12325025; Musante 2003 PMID:12634870; Jongmans 2011 PMID:21407260; Athota 2020 PMID:32164556). This variant is present in 0.005% (1/18394) of East Asian alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/12-112888172-A-G?dataset=gnomad_r2_1). Please note, disease-causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar, with many laboratories and the ClinGen RASopathy Variant Curation Expert Panel classifying it as pathogenic (Variation ID:13333). This variant is located at a residue directly involved in interactions between N-SH2 and PTPN domains (Gelb 2018 PMID:29493581). An in vitro functional study showed that this variant impacts protein structure, resulting in increased protein activity (Martinelli 2012 PMID:22711529). However, this study study may not accurately represent in vivo biological function. PTPN11 has a low rate of benign missense variation and pathogenic missense variation is common (Gelb 2018 PMID:29493581). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In summary, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 18, 2017- -
Metachondromatosis Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsFeb 14, 2021- -
Lymphoma;CN257934:B lymphoblastic leukemia lymphoma, no ICD-O subtype Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingSt. Jude Molecular Pathology, St. Jude Children's Research HospitalApr 26, 2017This is a missense alteration in which an A is replaced by a G at coding nucleotide 188 and is predicted to change a Tyrosine to a Cysteine at amino acid codon 63. Classification criteria: PS1, PS3, PM1, PM2, PP3. -
Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInstitute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's HospitalDec 10, 2018[ACMG/AMP/ClinGen RASopathy: PS1, PS3, PS4, PP1_Strong, PM1, PP2, PP3] This alteration has an amino acid change previously established as pathogenic (regardless of nucleotide change) [PS1], is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], has a prevalence that is significantly increased compared with controls (RR/OR > 5; CI does not include 1.0) [PS4], has been shown to cosegregate with disease in multiple affected family members [PP1_Strong], is located in a mutational hotspot and/or critical and well-established functional domain [PM1], is a missense variant in a gene in which missense variants are a common mechanism of disease [PP2], is predicted to be damaging by multiple functional prediction tools [PP3]. -
Noonan syndrome 3 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 02, 2016Variant summary: The c.188A>G variant affects a conserved nucleotide, resulting in amino acid change from Tyr to Cys. 4/4 in-silico tools predict damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is found in 1/121890 control chromosomes at a frequency of 0.0000082, which does not exceed maximal expected frequency of a pathogenic allele (0.0000625). The variant has been reported in numerous affected individuals and families in the literature and has been shown to segregate with disease in affected families. The variant is considered a common pathogenic variant. In addition, multiple reputable clinical laboratory and database classified this variant as Pathogenic. Taken together, this variant was classified as Pathogenic. -
Noonan syndrome and Noonan-related syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenSep 14, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
CardioboostCm
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.38
D
BayesDel_noAF
Pathogenic
0.48
Cadd
Pathogenic
31
Dann
Uncertain
1.0
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.93
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.89
D;D;D;D
M_CAP
Pathogenic
0.38
D
MetaRNN
Pathogenic
0.98
D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.3
M;M;.;M
MutationTaster
Benign
1.0
A;A
PrimateAI
Pathogenic
0.92
D
PROVEAN
Pathogenic
-7.5
D;D;.;.
REVEL
Pathogenic
0.95
Sift
Pathogenic
0.0
D;D;.;.
Sift4G
Uncertain
0.0030
D;D;.;D
Polyphen
1.0
D;D;.;.
Vest4
0.93
MutPred
0.94
Loss of phosphorylation at Y63 (P = 0.048);Loss of phosphorylation at Y63 (P = 0.048);Loss of phosphorylation at Y63 (P = 0.048);Loss of phosphorylation at Y63 (P = 0.048);
MVP
0.98
MPC
2.1
ClinPred
1.0
D
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.97
gMVP
0.87

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121918459; hg19: chr12-112888172; COSMIC: COSV61007856; COSMIC: COSV61007856; API