rs397516801

Variant names:

• chr12-112450389-A-G
• rs397516801
• NM_002834.5:c.209A>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP1 PP2 PM1 PM6 PM2 PS4

This summary comes from the ClinGen Evidence Repository: The c.2019A>G (p.Lys70Arg) variant in PTPN11 was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). It has been identified in at least 6 probands with Noonan syndrome (PS4; SCV000061296.6; PMID:29084544).One case was described as an unconfirmed de novo occurrence (PM6; PMID:29084544). It has been reported to segregate with clinical features of a RASopathy in at least 3 family members (PP1; SCV000061296.6). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID:29493581). Finally, PTPN11 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). 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): PS4, PM6, PM1, PM2, PP1, PP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA261568/MONDO:0021060/004

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 9.31
• Publications: 9 publications found

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]

PTPN11 Gene-Disease associations (from GenCC):

• LEOPARD syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Genomics England PanelApp
• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Noonan syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• metachondromatosis

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002834.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPN11	NM_002834.5	MANE Select	c.209A>G	p.Lys70Arg	missense	Exon 3 of 16	NP_002825.3
	PTPN11	NM_001330437.2		c.209A>G	p.Lys70Arg	missense	Exon 3 of 16	NP_001317366.1
	PTPN11	NM_001374625.1		c.206A>G	p.Lys69Arg	missense	Exon 3 of 16	NP_001361554.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPN11	ENST00000351677.7	TSL:1 MANE Select	c.209A>G	p.Lys70Arg	missense	Exon 3 of 16	ENSP00000340944.3
	PTPN11	ENST00000635625.1	TSL:5	c.209A>G	p.Lys70Arg	missense	Exon 3 of 15	ENSP00000489597.1
	PTPN11	ENST00000392597.5	TSL:1	c.209A>G	p.Lys70Arg	missense	Exon 3 of 11	ENSP00000376376.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461342 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726988

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000299 AC: 1 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111554

Other (OTH) AF: 0.00 AC: 0 AN: 60368

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00233887), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000571 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

Submissions by phenotype

Noonan syndrome Pathogenic:3

May 02, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Lys70Arg variant in PTPN11 has been identified in >5 individuals with clin ical features of a RASopathy, including confirmed de novo inheritance in 1 indiv idual, and segregated with disease in 3 affected relatives (LMM data, Xu 2017). This variant was absent from large population studies and is reported in ClinVar (Variation ID: 44603). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. This var iant is located in the directly interacting residues between N-SH2 and the PTPN domains, where pathogenic missense variants are common. In summary, this variant meets criteria to be classified as pathogenic for Noonan syndrome in an autosom al dominant manner based upon presence in affected individuals, de novo observat ion, segregation with disease, and absence from controls. ACMG/AMP Criteria appl ied: PS4, PM1, PM2, PM6, PP1.

Service de Génétique Moléculaire, Hôpital Robert Debré

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Dec 26, 2019

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

RASopathy Pathogenic:3

Jun 25, 2020

ClinGen RASopathy Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.2019A>G (p.Lys70Arg) variant in PTPN11 was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). It has been identified in at least 6 probands with Noonan syndrome (PS4; SCV000061296.6; PMID: 29084544).One case was described as an unconfirmed de novo occurrence (PM6; PMID: 29084544). It has been reported to segregate with clinical features of a RASopathy in at least 3 family members (PP1; SCV000061296.6). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID: 29493581). Finally, PTPN11 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). 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): PS4, PM6, PM1, PM2, PP1, PP2.

Aug 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 70 of the PTPN11 protein (p.Lys70Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 29084544). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 44603). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PTPN11 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.

Jul 08, 2020

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.209A>G (p.Lys70Arg) results in a conservative amino acid change located in the SH2 domain (IPR000980) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251054 control chromosomes (gnomAD). c.209A>G has been reported in the literature in individuals affected with and/or undergoing diagnostic evaluation for Noonan Syndrome And Related Conditions (e.g. Leach_2019, Xu_2017). At least one case of a confirmed de novo occurrence in an individual with Noonan syndrome has been reported (Xu_2017). In addition, a ClinVar submitter reports the variant in at least 5 individuals with clinical features of a RASopathy, including segregation with disease in 3 affected relatives (SCV000061296.6). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=2)/likely pathogenic (n=2). Some submitters cite overlapping evidence utilized in the context of this evaluation. Recently the ClinGen RASopathy Variant Curation Expert Panel settled on a classification of Pathogenic for this variant (personal communication, June 2020). Based on the evidence outlined above, the variant was re-classified as pathogenic.

Noonan syndrome 1 Pathogenic:2

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.67; 3Cnet: 0.73). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000044603 / PMID: 29084544). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 29084544). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc).;Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.;Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Assumed de novo, but without confirmation of paternity and maternity.

LEOPARD syndrome 1 Pathogenic:1

Nov 29, 2022

Laboratory of Medical Genetics, University of Torino

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

not provided Pathogenic:1

Sep 25, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis suggests that this missense variant does not alter protein structure/function; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34346503, 29084544, 30050098, 29907801, 32037394, 34358384, 11992261, 9491886, 16053901, 29493581)

Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:1

Apr 09, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
CardioboostCm	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.62
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Benign	1.4	L
PhyloP100		9.3
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.67
Sift	Benign	0.038	D
Sift4G	Benign	0.19	T
Polyphen		0.74	P
Vest4		0.73
MutPred		0.55		Loss of ubiquitination at K70 (P = 0.0116)
MVP		0.90
MPC		1.7
ClinPred		0.92	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.57
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397516801; hg19: chr12-112888193;