rs28933386

chr12-112477719-A-G

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM5 PP2 PP3_Strong PP5_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. 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
• Clinical Significance: Pathogenic reviewed by expert panel P:72 O:2
• Conservation: PhyloP100: 8.89

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]

ACMG classification

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 9 benign (94%) 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
PTPN11	NM_002834.5	c.922A>G	p.Asn308Asp	missense_variant	8/16	ENST00000351677.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPN11	ENST00000351677.7	c.922A>G	p.Asn308Asp	missense_variant	8/16	1	NM_002834.5	A1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152158 Hom.: 0 Cov.: 32

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

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

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

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:72 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

Noonan syndrome 1 Pathogenic:31 Other:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 12, 2023	- -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Mar 13, 2024	Criteria applied: PS2_VSTR,PS4,PS3_MOD,PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Daryl Scott Lab, Baylor College of Medicine	Feb 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	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). (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 submitter	clinical testing	Neuberg 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 submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 01, 2021	PS3, PM1, PM5, PP2, PP3, PP4, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	UCLA Clinical Genomics Center, UCLA	Jun 03, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genesolutions, Medical Genetics Institutes, Ho Chi Minh City, Vietnam	Jun 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jun 10, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 09, 2023	- -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 01, 2023	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 06, 2013	- -
Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics, Centre for Human Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Oct 26, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Dec 20, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Lifecell 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 submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Mar 02, 2022	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM5 moderated, PM6 moderated, PP1 strong, PP2 supporting, PP3 supporting -
Pathogenic, no assertion criteria provided	research	Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital	May 31, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 19, 2022	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
not provided, no classification provided	literature only	Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Nov 15, 2021	PS2, PS3, PS4, PP1, PP2, PP3, PM1, PM5 -
Pathogenic, criteria provided, single submitter	clinical testing	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	-	- -
Pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Jul 26, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Pediatrics, The Affiliated Hospital of Qingdao University	Nov 01, 2023	- -

not provided Pathogenic:15

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Aug 18, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centro Nacional de Genética Medica "Dr. Eduardo E. Castilla", Administración Nacional de Laboratorios e Institutos de Salud	Feb 02, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	PTPN11: PP1:Strong, PS2, PM2, PP2, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jun 05, 2020	- -
Pathogenic, criteria provided, single submitter	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 12, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 26, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2019	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 11, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 11, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

LEOPARD syndrome 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Aug 12, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PP2,PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Daryl Scott Lab, Baylor College of Medicine	Aug 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 12, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Feb 26, 2019	- -

Noonan syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 24, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 10, 2015	- -
Pathogenic, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Apr 03, 2017	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

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 16, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Nov 22, 2021	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Lab, CHRU Brest	-	- -

Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Suma Genomics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Nov 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 submitter	clinical testing	Baylor Genetics	Dec 31, 2017	- -

RASopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	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; 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, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 26, 2019	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. -
Pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	-	Variant classified using ACMG guidelines -

Cardiovascular phenotype Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 01, 2022	The 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Medical University Innsbruck	-	- -

PTPN11-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 26, 2023

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 (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. -

Thrombocytopenia;C1458140:Abnormal bleeding Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Birmingham Platelet Group; University of Birmingham

May 01, 2020

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not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 24, 2019

The 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. -

Metachondromatosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

May 12, 2023

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Male infertility with azoospermia or oligozoospermia due to single gene mutation Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Laan Lab, Human Genetics Research Group, University of Tartu

Dec 01, 2023

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LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Aug 01, 2017

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

Pathogenic, criteria provided, single submitter

research

Department of Pediatric Oncology, Hematology and Clinical Immunology, University Clinics Duesseldorf

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Noonan syndrome and Noonan-related syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 07, 2021

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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

Other links and lift over

dbSNP: rs28933386; hg19: chr12-112915523; COSMIC: COSV61006575; COSMIC: COSV61006575;