12-112477719-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS3PP1_StrongPM2PS2PP2PP3

This summary comes from the ClinGen Evidence Repository: The 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA220158/MONDO:0018997/004

Frequency

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

Consequence

PTPN11
NM_002834.5 missense

Scores

12
6
2

Clinical Significance

Pathogenic reviewed by expert panel P:77O: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 16 ACMG points.

PS2
For more information check the summary or visit ClinGen Evidence Repository.
PS3
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PP1
For more information check the summary or visit ClinGen Evidence Repository.
PP2
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PTPN11NM_002834.5 linkc.922A>G p.Asn308Asp missense_variant Exon 8 of 16 ENST00000351677.7 NP_002825.3 Q06124-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PTPN11ENST00000351677.7 linkc.922A>G p.Asn308Asp missense_variant Exon 8 of 16 1 NM_002834.5 ENSP00000340944.3 Q06124-2
PTPN11ENST00000635625.1 linkc.922A>G p.Asn308Asp missense_variant Exon 8 of 15 5 ENSP00000489597.1 Q06124-1

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:77Other:2
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Noonan syndrome 1 Pathogenic:35Other:2
Jan 05, 2022
DASA
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The 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. -

Jul 19, 2022
MGZ Medical Genetics Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 12, 2023
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Centogene AG - the Rare Disease Company
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP)
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

-
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Nov 15, 2021
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PS2, PS3, PS4, PP1, PP2, PP3, PM1, PM5 -

Nov 01, 2016
Center for Human Genetics, Inc, Center for Human Genetics, Inc
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 01, 2021
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PS3, PM1, PM5, PP2, PP3, PP4, PP5 -

-
Neuberg Centre For Genomic Medicine, NCGM
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

-
Lifecell International Pvt. Ltd
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

-
Molecular Genetics, Centre for Human Genetics
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jun 10, 2020
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 01, 2023
Illumina Laboratory Services, Illumina
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The 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. -

Jun 06, 2013
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Nov 01, 2023
Department of Pediatrics, The Affiliated Hospital of Qingdao University
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 03, 2014
UCLA Clinical Genomics Center, UCLA
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 31, 2019
Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Nov 30, 2023
Institute of Immunology and Genetics Kaiserslautern
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ACMG Criteria: PP1, PP2, PP3, PM2, PS3, PS2, PM5; Variant found in a heterozygous state -

Oct 26, 2018
Center of Genomic medicine, Geneva, University Hospital of Geneva
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 02, 2022
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM5 moderated, PM6 moderated, PP1 strong, PP2 supporting, PP3 supporting -

-
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 20, 2019
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 10, 2024
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Based 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). (I) 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 -

Jun 17, 2024
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Criteria applied: PS2_VSTR,PS4,PS3_MOD,PP3 -

Feb 01, 2022
Daryl Scott Lab, Baylor College of Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 22, 2022
3billion, Medical Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Same 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. -

-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Jun 22, 2022
Genesolutions, Medical Genetics Institutes, Ho Chi Minh City, Vietnam
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
NIHR Bioresource Rare Diseases, University of Cambridge
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Oct 09, 2023
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jul 26, 2023
New York Genome Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The inherited heterozygous c.922A>G, p. (Asn308Asp) in PTPN11 is reported as one of the most common variants and accounts for 25% of Noonan syndrome cases. This c.922A>G variant has previously been identified in both de novo and inherited occurrences in individuals with Noonan syndrome [PMID:20979190, 22465605, 26645620, 32164556, 34411415, 35440950, 34194850] and found to be co-segregated with disease [PMID: 11992261]. The c.922A>G variant has been classified as Pathogenic for Noonan syndrome by ClinGen RASopathy Variant Curation Expert Panel [ClinVar ID: 13326] and observed in 5 allele (~0.0011% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), suggesting it is not a common benign variant in the populations represented in those databases. The c.922A>G variant in PTPN11 is located in exon 8 of this 16-exon gene and predicted to replace an evolutionarily conserved asparagine amino acid with aspartic acid p. (Asn308Asp) in the protein tyrosine phosphatase (PTP) domain of the encoded protein and has been described as a mutational hot spot [PMID: 32164556,24628801]. In vitro functional studies demonstrated increased phosphatase activity indicating the gain-of-function effects in fibroblast cells carrying c.922A>G variant [PMID: 14974085, 15987685, 19509418, 20308328]. In silico predictions are in favor of damaging effect for p.(Asn308Asp) [(CADD v1.6 = 24.5, REVEL = 0.84)]. Other missense variants affecting the same p.(Asn308) residue have been reported in the literature (p.Asn308Ser) [PMID: 32164556] and ClinVar [ClinVar IDs: 13327] in individuals with Noonan syndrome. Based on available evidence this inherited heterozygous c.922A>G p.(Asn308Asp) in PTPN11 is classified as Pathogenic for Noonan syndrome 1. -

Oct 04, 2024
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

PS2,PS3,PP3,PM2,PP1,PM5 -

Mar 25, 2024
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

-
Juno Genomics, Hangzhou Juno Genomics, Inc
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PP2+PS2_VeryStrong+PP1_Strong+PS4+PS3 -

-
Henan Neurodevelopment Engineering Research Center for Children, Children's Hospital Affiliated to Zhengzhou University
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:17
Sep 28, 2019
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

N308D 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) -

Aug 18, 2015
Molecular Diagnostics Lab, Nemours Children's Health, Delaware
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jun 05, 2020
AiLife Diagnostics, AiLife Diagnostics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jul 25, 2024
Mayo Clinic Laboratories, Mayo Clinic
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PP2, PP3, PM1, PM6_strong, PS3 -

Aug 26, 2014
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 02, 2022
Centro Nacional de Genética Medica "Dr. Eduardo E. Castilla", Administración Nacional de Laboratorios e Institutos de Salud
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 16, 2024
Athena Diagnostics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been identified in multiple unrelated individuals with Noonan syndrome. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 12717436, 14974085, 15834506, 15987685) -

Jan 11, 2017
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 27, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The PTPN11 c.922A>G; p.Asn308Asp variant (rs28933386) 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. This variant is reported as pathogenic by an expert panel in ClinVar (Variation ID: 13326) and is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. 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. PMID: 22465605. 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. PMID: 14974085. 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. PMID: 15987685. 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. PMID: 12161469. 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. PMID: 21590266. Qiu W et al. Structural insights into Noonan/LEOPARD syndrome-related mutants of protein-tyrosine phosphatase SHP2 (PTPN11). BMC Struct Biol. 2014 14:10. PMID: 24628801. 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. PMID: 28957739 Tartaglia M et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001 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 70(6): 1555-1563. PMID: 11992261. 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. PMID: 16358218. 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. PMID: 28650561. 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. PMID: 28483241. Zenker M et al. Genotype-phenotype correlations in Noonan syndrome. J Pediatr. 2004 144(3):368-74. PMID: 15001945. -

Sep 16, 2018
Gharavi Laboratory, Columbia University
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Oct 23, 2020
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PTPN11: PS2:Very Strong, PP1:Strong, PM1, PM2, PM5, PS4:Moderate, PP3, PS3:Supporting -

May 27, 2022
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 12, 2023
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

LEOPARD syndrome 1 Pathogenic:4
Aug 12, 2019
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PP2,PP3. -

Feb 26, 2019
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 12, 2023
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 22, 2022
Daryl Scott Lab, Baylor College of Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Noonan syndrome Pathogenic:3
Nov 10, 2015
Blueprint Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 24, 2022
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.Asn308Asp variant in PTPN11 is an established pathogenic variant for Noonan syndrome and has been reported in approximately 11-20% of individuals with Noonan syndrome across multiple studies (Tartaglia 2001 PMID: 11704759, Jongmans 2005 PMID: 15723289, Tartaglia 2006 PMID: 16358218, Jongmans 2011 PMID: 21407260, Ezquieta 2012 PMID: 22465605). In addition, de novo occurrences and germline mosaicism have been described (Tartaglia 2001 PMID: 11704759, Elalaoui 2010 PMID: 20979190, Ezquieta 2012 PMID: 22465605). This variant has been identified in 0.001% (3/251440) of total chromosomes by gnomAD (http://gnomad.broadinstitute.org). Moreover, this variant has been classified as pathogenic on April 03, 2017 by the ClinGen-approved RASopathy expert panel (SCV000616374.3). In vitro functional studies provide some evidence that this variant impacts protein function (Fragale 2004 PMID: 14974085, Niihori 2005 PMID: 15834506). Additional variants involving this codon (p.Asn308Ser and p.Asn308Thr) have been identified in individuals with Noonan syndrome and are classified as pathogenic by this laboratory. In summary, this variant meets criteria to be classified as pathogenic for Noonan syndrome in an autosomal dominant manner based on its frequency in affected individuals and de novo occurrences. ACMG/AMP Criteria applied: PS4, PM6_Strong, PM5_Strong, PS3_Moderate. -

Apr 03, 2017
ClinGen RASopathy Variant Curation Expert Panel
Significance: Pathogenic
Review Status: reviewed by expert panel
Collection Method: curation

The 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. -

Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:3
Nov 22, 2021
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PTPN11 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). -

Oct 16, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Molecular Genetics Lab, CHRU Brest
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:3
-
Suma Genomics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 21, 2018
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

[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]. -

Dec 31, 2017
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

RASopathy Pathogenic:3
Jan 30, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This 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; internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13326). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) 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. -

-
Baylor Genetics
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

Variant classified using ACMG guidelines -

Nov 26, 2019
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant 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. -

Cardiovascular phenotype Pathogenic:2
-
Institute of Human Genetics, Medical University Innsbruck
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 24, 2024
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.922A>G (p.N308D) alteration is located in exon 8 (coding exon 8) of the PTPN11 gene. This alteration results from an A to G substitution at nucleotide position 922, causing the asparagine (N) at amino acid position 308 to be replaced by an aspartic acid (D). for PTPN11-related RASopathy; however, it is unlikely to be causative of Metachondromatosis. Based on data from gnomAD, the G allele has an overall frequency of 0.001% (3/251440) total alleles studied. The highest observed frequency was 0.004% (1/6136) of European (non-Finnish) individuals. The c.922A>G (p.N308D) alteration is one of the most common recurrent alterations in PTPN11 and has been reported in multiple individuals with features consistent with PTPN11-related RASopathy (Tartaglia, 2001; Tartaglia, 2005; Jongmans, 2005; Yoon, 2013); in at least one instance, this variant has been determined to be the result of a de novo mutation (Sy, 2022; Ambry internal data). Additionally, patients with PTPN11-related RASopathy and malignancies have been reported with germline p.N308D alterations, including neuroblastoma and acute myelomonocytic leukemia, chronic myelomonocytic leukemia, malignant mastocytosis, and hepatoblastoma (Matsubara, 2005; Chantrain, 2007; Yoshida, 2008; Jongmans, 2011). This amino acid position is highly conserved in available vertebrate species. The p.N308 amino acid is located in the phosphotyrosine phosphatase (PTP) domain of the PTPN11 protein (Tartaglia, 2001). 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. Functional analysis demonstrated that the p.N308D alteration leads to increased protein tyrosine phosphatase activity compared to wild-type, consistent with a gain-of-function effect (Fragale, 2004; Keilhack, 2005; Qiu, 2014). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

PTPN11-related disorder Pathogenic:1
Apr 17, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The 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 and has been interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/13326/). This variant is interpreted as pathogenic. -

Thrombocytopenia;C1458140:Abnormal bleeding Pathogenic:1
May 01, 2020
Birmingham Platelet Group; University of Birmingham
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Metachondromatosis Pathogenic:1
May 12, 2023
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Male infertility with azoospermia or oligozoospermia due to single gene mutation Pathogenic:1
Dec 01, 2023
Laan Lab, Human Genetics Research Group, University of Tartu
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:1
Aug 01, 2017
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PTPN11 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
-
Department of Pediatric Oncology, Hematology and Clinical Immunology, University Clinics Duesseldorf
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Noonan syndrome and Noonan-related syndrome Pathogenic:1
May 07, 2021
Genome Diagnostics Laboratory, The Hospital for Sick Children
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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
DEOGEN2
Pathogenic
0.96
.;.;D
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
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