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rs28933386

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM5PP2PP3_StrongPP5_Very_Strong

The NM_002834.5(PTPN11):c.922A>G(p.Asn308Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,612,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N308S) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

PTPN11
NM_002834.5 missense

Scores

11
6
2

Clinical Significance

Pathogenic reviewed by expert panel P:70O:2

Conservation

PhyloP100: 8.89
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 17 ACMG points.

PM1
In a domain Tyrosine-protein phosphatase (size 270) in uniprot entity PTN11_HUMAN there are 130 pathogenic changes around while only 10 benign (93%) in NM_002834.5
PM5
Other missense variant is known to change same aminoacid residue: Variant chr12-112477720-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 13327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
Missense variant where missense usually causes diseases, PTPN11
PP3
MetaRNN computational evidence supports a deleterious effect, 0.968
PP5
Variant 12-112477719-A-G is Pathogenic according to our data. Variant chr12-112477719-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 13326.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-112477719-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.922A>G p.Asn308Asp missense_variant 8/16 ENST00000351677.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PTPN11ENST00000351677.7 linkuse as main transcriptc.922A>G p.Asn308Asp missense_variant 8/161 NM_002834.5 A1Q06124-2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152158
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:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251440
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135888
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.00000753
AC:
11
AN:
1460034
Hom.:
0
Cov.:
32
AF XY:
0.00000964
AC XY:
7
AN XY:
726478
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000766
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000374
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152158
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74334
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:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:70Other:2
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Noonan syndrome 1 Pathogenic:30Other:2
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaSep 01, 2023The PTPN11 c.922A>G (p.Asn308Asp) missense variant is one of the most common pathogenic variants associated with Noonan syndrome. In most cases, this variant occurs as the result of a de novo event, but also has been shown to segregate with disease in affected individuals within families (PMID: 11992261; 19352411; 20301303; 20979190; 22465605). This variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Functional studies demonstrate that this variant impacts protein function (PMID: 15987685; 19509418). This variant has been classified as pathogenic in ClinVar by several submitters, including the ClinGen RASopathy Expert Panel. This variant was identified in a de novo state. Based on the available evidence, the c.922A>G (p.Asn308Asp) variant is classified as pathogenic for Noonan syndrome. -
Pathogenic, criteria provided, single submitterclinical testingLaboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert EinsteinMar 02, 2022ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM5 moderated, PM6 moderated, PP1 strong, PP2 supporting, PP3 supporting -
Pathogenic, criteria provided, single submitterclinical testingKasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India-- -
Pathogenic, criteria provided, single submitterclinical testingEquipe Genetique des Anomalies du Developpement, Université de BourgogneDec 20, 2019- -
Pathogenic, criteria provided, single submitterclinical testingGenesolutions, Medical Genetics Institutes, Ho Chi Minh City, VietnamJun 22, 2022- -
Pathogenic, no assertion criteria providedclinical testingZotz-Klimas Genetics Lab, MVZ Zotz KlimasOct 09, 2023- -
Pathogenic, criteria provided, single submitterclinical testingCenter of Genomic medicine, Geneva, University Hospital of GenevaOct 26, 2018- -
Pathogenic, criteria provided, single submitterclinical testingDaryl Scott Lab, Baylor College of MedicineFeb 01, 2022- -
Pathogenic, criteria provided, single submitterclinical testingUCLA Clinical Genomics Center, UCLAJun 03, 2014- -
Pathogenic, no assertion criteria providedresearchBeijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College HospitalMay 31, 2019- -
Pathogenic, no assertion criteria providedresearchNIHR Bioresource Rare Diseases, University of Cambridge-- -
Pathogenic, no assertion criteria providedresearchDivision of Human Genetics, National Health Laboratory Service/University of the Witwatersrand-- -
Pathogenic, criteria provided, single submitterclinical testingLifecell International Pvt. Ltd-A Heterozygous Missense variant c.922A>G in Exon 8 of the PTPN11 gene that results in the amino acid substitution p.Asn308Asp was identified. The observed variant has a maximum allele frequency of 0.00001% in gnomAD exomes and novel in 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. ClinVar has also classified this variant as Pathogenic [Variation ID:13326]. This variant has previously been reported for Noonan syndrome by Jeevana PA et al., 2020. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingDepartment of Pediatrics, The Affiliated Hospital of Qingdao UniversityNov 01, 2023- -
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteFeb 02, 2022Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss- 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). (N) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene associated with Noonan syndrome are known to have variable expressivity (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants in the protein tyrosine phosphatase domain (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is well established as a pathogenic variant for Noonan syndrome (ClinVar). (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitterclinical testing3billionMay 22, 2022Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013326). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 11704759,20979190,22465605) and co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID:11992261). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:14974085, 15987685, 19509418, 20308328). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.84; 3Cnet: 0.98). Different missense changes at the same codon (p.Asn308Ser, p.Asn308Thr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013327, VCV000040535). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria providedclinical testingMolecular Genetics, Centre for Human Genetics-- -
Pathogenic, criteria provided, single submitterclinical testingCenter for Human Genetics, Inc, Center for Human Genetics, IncNov 01, 2016- -
Pathogenic, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGM-The PTPN11 c.922A>G (p.Asn308Asp) variant has been reported to segregate with disease in many families with Noonan syndrome and related conditions (Tartaglia M et al). Experimental studies have shown that this missense change is located in the conserved protein-tyrosine phosphatase domain of the PTPN11 protein and results in higher levels of activity (Tartaglia M et al). This variant is reported with the allele frequency (0.0012%) in the gnomAD and novel in 1000 genome database. It has been submitted to ClinVar Pathogenic. The amino acid Asn at position 308 is changed to a Asp changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Asn308Asp in PTPN11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingDASAJan 05, 2022The c.922A>G;p.(Asn308Asp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 13326; PMID: 11992261; 14974085; 15987685; 19509418; 20308328; 20979190; 11704759; 22465605) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID:14974085, 15987685, 19509418, 20308328) - PS3. The variant was observed to have arisen de novo (paternity confirmed) in a patient with the disease and no family history (PMID: 20979190; 11704759; 22465605) - PS2.The variant is present at low allele frequencies population databases (rs28933386– gnomAD 0.00006572%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The variant co-segregated with disease in multiple affected family members (PMID: 11992261) - PP1_strong. Missense variant in PTPN11 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, no assertion criteria providedliterature onlyOMIMJun 06, 2013- -
Pathogenic, criteria provided, single submitterclinical testingInstitute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu MünchenJun 10, 2020- -
Pathogenic, criteria provided, single submitterclinical testingCentre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille-- -
not provided, no classification providedliterature onlyInstitute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP)-- -
Pathogenic, criteria provided, single submitterresearchCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterMar 25, 2024- -
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterMar 01, 2024Criteria applied: PS2_VSTR,PS4,PS3_MOD,PP3 -
Pathogenic, criteria provided, single submitterclinical testingGreenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic CenterNov 15, 2021PS2, PS3, PS4, PP1, PP2, PP3, PM1, PM5 -
Pathogenic, criteria provided, single submitterclinical testingCentogene AG - the Rare Disease Company-- -
Pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterJul 19, 2022- -
Pathogenic, criteria provided, single submitterclinical testingLaboratory of Medical Genetics, National & Kapodistrian University of AthensOct 01, 2021PS3, PM1, PM5, PP2, PP3, PP4, PP5 -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMay 12, 2023- -
not provided Pathogenic:15
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, criteria provided, single submitterclinical testingAthena Diagnostics IncJul 11, 2017- -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicMay 07, 2021- -
Pathogenic, criteria provided, single submitterclinical testingCentro Nacional de Genética Medica "Dr. Eduardo E. Castilla", Administración Nacional de Laboratorios e Institutos de SaludFeb 02, 2022- -
Pathogenic, criteria provided, single submitterclinical testingMolecular Diagnostics Lab, Nemours Children's Health, DelawareAug 18, 2015- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenAug 01, 2022PTPN11: PP1:Strong, PS2, PM2, PP2, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityMay 12, 2023- -
Pathogenic, criteria provided, single submitterresearchGharavi Laboratory, Columbia UniversitySep 16, 2018- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenOct 23, 2020- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jan 11, 2017- -
Pathogenic, criteria provided, single submitterclinical testingAiLife Diagnostics, AiLife DiagnosticsJun 05, 2020- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxSep 28, 2019N308D is the most common variant causing Noonan syndrome (Tartaglia et al., 2002); Most individuals have mild or no cognitive impairment (Pierpont et al., 2009; Tartaglia et al., 2002); Published functional studies indicate altered local hydrogen bond network of the PTPN11 protein and increased basal phosphatase activity compared to wild-type protein (Qiu et al., 2014; Fragale et al., 2004); Classified as pathogenic by the ClinGen RASopathy Expert Panel (ClinVar SCV000616374.3; Gelb et al., 2018); This variant is associated with the following publications: (PMID: 20308328, 16399795, 26607044, 21567923, 26377682, 27521173, 11704759, 20979190, 30294303, 28991257, 19352411, 21407260, 14974085, 15987685, 19509418, 25912702, 24628801, 11992261, 24803665, 26918529, 23726368, 24072241, 22822385, 19077116, 26785492, 21340158, 28135719, 28957739, 28650561, 28483241, 18253957, 29214238, 30355600, 26645620, 29848529, 30417923, 30050098, 29263817, 30287924, 29907801, 31219622, 31637070, 31560489, 32164556, 32054441, 32935436, 32150461, 32369273, 31216405, 32371413, 32581362, 31589614, 33300679, 33258288) -
Pathogenic, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsAug 26, 2014- -
Pathogenic, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
LEOPARD syndrome 1 Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterFeb 26, 2019- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMay 12, 2023- -
Pathogenic, criteria provided, single submitterclinical testingDaryl Scott Lab, Baylor College of MedicineAug 22, 2022- -
Pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaAug 12, 2019This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PP2,PP3. -
Noonan syndrome Pathogenic:3
Pathogenic, reviewed by expert panelcurationClinGen RASopathy Variant Curation Expert PanelApr 03, 2017The c.922A>G (p.Asn308Asp) variant in PTPN11 has been reported in the literature as a confirmed and unconfirmed de novo occurrence in 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 20979190, and 11704759, 22465605). The variant has co-segregated with disease in more than 7 family members (PP1_Strong; PMID: 11992261). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). 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.Asn308Asp variant may impact the protein (PP3). Additionally, at least 2 functional studies have been concordant in showing that this variant may be deleterious to the protein (PS3; PMID 14974085, 15987685, 19509418, 20308328). 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): PP2, PP3, PM2, PP1_Strong, PS2_VeryStrong, PS3. -
Pathogenic, criteria provided, single submitterclinical testingBlueprint GeneticsNov 10, 2015- -
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineOct 10, 2017The p.Asn308Asp variant in PTPN11 is an established pathogenic variant for Noona n syndrome and has been reported in approximately 11-20% of individuals with Noo nan syndrome across multiple studies (Tartaglia 2001, Jongmans 2005, Tartaglia 2 006, Jongmans 2011, Ezquieta 2012). In addition, de novo occurrences and germlin e mosaicism have been described (Tartaglia 2001, Elalaoui 2010, Ezquieta 2012). This variant has been identified in 3/246202 total chromosomes by the Genome Agg regation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs28933386). In summary, this variant meets criteria to be classified as pathogenic for Noon an syndrome in an autosomal dominant manner based on its frequency in affected i ndividuals and de novo occurrences. ACMG/AMP Criteria applied: PS4, PM6_Strong. -
Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomics, Ann and Robert H. Lurie Children's Hospital of ChicagoNov 22, 2021PTPN11 NM_002834 exon 8 p.Asn308Asp (c.922A>G): This variant is one of the most common and well established pathogenic variants for Noonan syndrome. This variant has been identified in >20 probands with Noonan syndrome and segregating with disease in at least 7 affected relatives (Tartaglia 2001 PMID:11704759, Tartaglia 2002 PMID:11992261, Brasil 2010 PMID:21340158, Jongmans 2011 PMID:21407260, Prada 2011 PMID:21567923, Ejarque 2015 PMID:25912702, van Trier 2016 PMID:27521173, van Nierop 2017 PMID:28483241). This variant is present in 3/246202 individuals of different ethnicities in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs28933386). 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 several labs classifying this variant as pathogenic (Variation ID:13326). Evolutionary conservation and computational predictive tools for this variant are unclear. However, functional studies have shown a deleterious effect of this variant on the protein (Fragale 2004 PMID:14974085, Oishi 2006 PMID:16399795, Qiu 2014 PMID:24628801). Of note, at least one other variant at this position (p.Asn308Ser) has been associated with disease at this position, supporting that this region is functionally significant. In summary, this variant is classified as pathogenic (high presence of affected probands, segregation studies, absence from controls, functional studies). -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 16, 2021- -
Pathogenic, criteria provided, single submitterclinical testingMolecular Genetics Lab, CHRU Brest-- -
Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingInstitute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's HospitalNov 21, 2018[ACMG/AMP/ClinGen RASopathy: PS2_VeryStrong, PS3, PS4, PP1_Strong, PM1, PP2, PP3] This alteration is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2_VeryStrong], 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]. -
Pathogenic, criteria provided, single submitterclinical testingSuma Genomics-- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsDec 31, 2017- -
RASopathy Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpNov 26, 2019Variant summary: PTPN11 c.922A>G (p.Asn308Asp) results in a conservative amino acid change located in the PTP type protein phosphatase of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251830 control chromosomes. c.922A>G has been reported in the literature in numerous individuals affected with Noonan Syndrome. These data indicate that the variant is very likely to be associated with disease. Residue 308 is located in the PTP domain and is reported as the most common residue affected in NS patients (N308D and N308S). Functional studies showed that this variant leads to a mild activation of the protein's catalytic activity (about 3-fold higher than WT; Keilhack_2005). 16 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. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 26, 2024This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 308 of the PTPN11 protein (p.Asn308Asp). This variant is present in population databases (rs28933386, gnomAD 0.004%). This missense change has been observed in individual(s) with Noonan syndrome and related conditions (PMID: 11704759, 16358218, 21340158, 21567923; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13326). 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: 16358218, 19509418, 20308328). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria providedclinical testingBaylor Genetics-Variant classified using ACMG guidelines -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJun 05, 2014- -
Thrombocytopenia;C1458140:Abnormal bleeding Pathogenic:1
Likely pathogenic, no assertion criteria providedresearchBirmingham Platelet Group; University of BirminghamMay 01, 2020- -
not specified Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesJan 24, 2019The PTPN11 p.Asn308Asp variant (rs28933386, ClinVar variant ID 13326) is frequently found in patients diagnosed with Noonan syndrome (Ezquita 2012, Jongmans 2005, Kosaki 2002, Papadopoulou 2012, Tafazoli 2018, Tartaglia 2001, Tartaglia 2002, Tartaglia 2006, Ueda 2017, van Nierop 2017, Zenker 2004), and co-segregates with affected individuals (Tartaglia 2002). The variant is located in the phospho-tyrosine phosphatase domain of PTPN11 (Qiu 2014, Tartaglia 2001), and additional missense variants at this residue have also been associated with Noonan syndrome (Tartaglia 2002, Tartaglia 2006). Functional characterization of the p.Asn308Asp protein indicates increased catalytic activity (Fragale 2004, Keilhack 2005, Qui 2014, Tartaglia 2006) due to stabilization of the active enzyme (Qiu 2014). This leads to over-activation of phospho-MEK and phospho-ERK signaling (Fragale 2004), consistent with the established disease mechanisms of Noonan syndrome. The p.Asn308Asp variant is therefore classified as pathogenic. References: Ezquieta B et al. Alterations in RAS-MAPK genes in 200 Spanish patients with Noonan and other neuro-cardio-facio-cutaneous syndromes. Genotype and cardiopathy. Rev Esp Cardiol (Engl Ed). 2012 65(5):447-55. Fragale A et al. Noonan syndrome-associated SHP2/PTPN11 mutants cause EGF-dependent prolonged GAB1 binding and sustained ERK2/MAPK1 activation. Hum Mutat 2004 23(3):267-77. Jongmans M et al. Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation. Eur J Hum Genet. 2011 19(8):870-4. Keilhack H et al. Diverse biochemical properties of Shp2 mutants. Implications for disease phenotypes. J Biol Chem. 2005 280(35):30984-93. Kosaki K et al. PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) mutations in seven Japanese patients with Noonan syndrome. J Clin Endocrinol Metab. 2002 87(8):3529-33. Papadopoulou A et al. Phenotypic spectrum of 80 Greek patients referred as Noonan syndrome and PTPN11 mutation analysis: the value of initial clinical assessment. Eur J Pediatr. 2012 171(1):51-8. Qiu W et al. Structural insights into Noonan/LEOPARD syndrome-related mutants of protein-tyrosine phosphatase SHP2 (PTPN11). BMC Struct Biol. 2014 14:10. Tafazoli A et al. Novel mutations and their genotype-phenotype correlations in patients with Noonan syndrome, using next-generation sequencing. Adv Med Sci. 2018 Mar;63(1):87-93. Tartaglia M et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001 29(4):465-8. Tartaglia M et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002 70(6): 1555-1563. Tartaglia M et al. Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet. 2006 78(2): 279-290. Ueda K et al. Craniosynostosis in patients with RASopathies: Accumulating clinical evidence for expanding the phenotype. Am J Med Genet A. 2017 Sep;173(9):2346-2352. van Nierop JWI et al. Cochlear implantation and clinical features in patients with Noonan syndrome and Noonan syndrome with multiple lentigines caused by a mutation in PTPN11. Int J Pediatr Otorhinolaryngol. 2017 Jun;97:228-234. Zenker M et al. Genotype-phenotype correlations in Noonan syndrome. J Pediatr. 2004 144(3):368-74. -
PTPN11-related condition Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesDec 26, 2023The PTPN11 c.922A>G variant is predicted to result in the amino acid substitution p.Asn308Asp. This variant has been well documented to be causative for Noonan syndrome (see for example - Tartaglia et al. 2001. PubMed ID: 11704759). At PreventionGenetics, we identified this variant previously in several other patients with Noonan spectrum disorders. Functional studies demonstrate increased protein tyrosine phosphatase activity, consistent with a gain-of-function mechanism that results in the hyperactivation of the RAS pathway (Fragale et al. 2004. PubMed ID: 14974085). Additionally, different amino acid substitutions affecting the same amino acid (p.Asn308Thr and p.Asn308Ser) have been reported in individuals with Noonan syndrome (Wilbe et al. 2017. PubMed ID: 28921562; Tartaglia et al. 2002. PubMed ID: 11992261). This variant is reported in 0.0046% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-112915523-A-G) and has been interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/13326/). This variant is interpreted as pathogenic. -
Metachondromatosis Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMay 12, 2023- -
LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomics, Ann and Robert H. Lurie Children's Hospital of ChicagoAug 01, 2017PTPN11 NM_002834 exon 8 p.Asn308Asp (c.922A>G): This variant is one of the most common and well established pathogenic variants for Noonan syndrome. This variant has been identified in >20 probands with Noonan syndrome and segregating with disease in at least 7 affected relatives (Tartaglia 2001 PMID:11704759, Tartaglia 2002 PMID:11992261, Brasil 2010 PMID:21340158, Jongmans 2011 PMID:21407260, Prada 2011 PMID:21567923, Ejarque 2015 PMID:25912702, van Trier 2016 PMID:27521173, van Nierop 2017 PMID:28483241). This variant is present in 3/246202 individuals of different ethnicities in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs28933386). 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 several labs classifying this variant as pathogenic (Variation ID:13326). Evolutionary conservation and computational predictive tools for this variant are unclear. However, functional studies have shown a deleterious effect of this variant on the protein (Fragale 2004 PMID:14974085, Oishi 2006 PMID:16399795, Qiu 2014 PMID:24628801). Of note, at least one other variant at this position (p.Asn308Ser) has been associated with disease at this position, supporting that this region is functionally significant. In summary, this variant is classified as pathogenic (high presence of affected probands, segregation studies, absence from controls, functional studies). -
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterresearchDepartment of Pediatric Oncology, Hematology and Clinical Immunology, University Clinics Duesseldorf-- -
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsFeb 01, 2022The p.N308D pathogenic mutation (also known as c.922A>G), located in coding exon 8 of the PTPN11 gene, results from an A to G substitution at nucleotide position 922. The asparagine at codon 308 is replaced by aspartic acid, an amino acid with highly similar properties. This alteration was first reported in three families and one sporadic proband with Noonan syndrome; however, specific diagnostic criteria were not strictly defined in this study (Tartaglia M et al. Nat. Genet., 2001 Dec;29:465-8). The Asn308 residue is located in the PTP (protein tyrosine phosphate) domain, and it has been described as a mutational hot spot, with p.N308D referred to as the most common Noonan syndrome mutation accounting for 25% of cases. In the same studies, functional in vitro analyses revealed that this alteration increases protein tyrosine phosphatase activity in the catalytic domain compared to wild type due to gain-of-function effects (Fragale A et al. Hum. Mutat., 2004 Mar;23:267-77; Qiu W et al. BMC Struct. Biol., 2014 Mar;14:10). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Noonan syndrome and Noonan-related syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenMay 07, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
CardioboostCm
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Pathogenic
0.14
Cadd
Pathogenic
26
Dann
Uncertain
1.0
Eigen
Uncertain
0.46
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Benign
0.76
T;T;T
M_CAP
Pathogenic
0.78
D
MetaRNN
Pathogenic
0.97
D;D;D
MetaSVM
Pathogenic
1.2
D
MutationAssessor
Pathogenic
3.9
H;H;H
MutationTaster
Benign
1.0
A;A
PrimateAI
Pathogenic
0.88
D
PROVEAN
Uncertain
-4.4
D;D;.
REVEL
Pathogenic
0.84
Sift
Uncertain
0.016
D;D;.
Sift4G
Uncertain
0.031
D;D;D
Polyphen
0.35
B;B;.
Vest4
0.96
MVP
0.97
MPC
0.93
ClinPred
0.58
D
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.87
gMVP
0.84

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs28933386; hg19: chr12-112915523; COSMIC: COSV61006575; COSMIC: COSV61006575; API