12-112450364-T-G

Position:

• chr12-112450364-T-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM6 PM2 PS4 PS3 PP3 PP2 PM1

This summary comes from the ClinGen Evidence Repository: The c.184T>G (p.Tyr62Asp) variant in PTPN11 is absent from gnomAD (PM2). This variant has been observed in multiple individuals with Noonan syndrome (PS4; SCV000659042.4, PMIDs: 26817465, 19352411, 17020470, 12325025, 11992261, 19077116, 17339163). It has also been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID:12325025). In vitro functional studies provide some evidence that the p.Tyr62Asp variant may impact protein function (PS3; PMID:22711529). 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). Computational prediction tools and conservation analysis suggest the variant may impact the protein (PP3). Additionally, the p.Tyr62Asp 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). In summary, the p.Tyr62Asp variant in PTPN11 meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM2, PS4, PM6, PS3, PM1, PP3, PP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA234749/MONDO:0021060/004

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPN11 ENST00000351677.7 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:25
• Conservation: PhyloP100: 8.01

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 16 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• 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.
• 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/exons	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.184T>G	p.Tyr62Asp	missense_variant	3/16	ENST00000351677.7	NP_002825.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.184T>G	p.Tyr62Asp	missense_variant	3/16	1	NM_002834.5	ENSP00000340944	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:25

Revision: reviewed by expert panel

Submissions by phenotype

Noonan syndrome 1 Pathogenic:6

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	Same nucleotide change resulting in same amino acid change has been previously reported as de novoo and observed in at least four similarly affected unrelated individuals (ClinVar ID: VCV000013329.17, PMID: 26817465, 19352411, 32164556, 31560489, 25533962, PS2 and PS4). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.9, 3Cnet: 0.971, PP3). Patient's phenotype is considered compatible with Noonan syndrome 1 (3billion dataset, PP4).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Jan 10, 2019	ACMG codes: PS2, PS3, PM2, PP3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	May 20, 2023	The observed missense variant c.184T>G(p.Tyr62Asp) in PTPN11 gene has been reported in heterozygous state in multiple individuals with Noonan-like/multiple giant cell syndrome and Noonan syndrome (Athota JP, et al., 2020, Chinton J, et al., 2019). Experimental studies demonstrate a profound effect on protein structure leading to re-arrangement and upregulation of its function, specifically by destabilizing the autoinhibited conformation of the SHP2 protein (Martinelli S, et al., 2012). The c.184T>G variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submissions).The amino acid Tyrosine at position 62 is changed to a Aspartic acid changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen, SIFT and MutationTaster) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Tyr62Asp 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	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 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with Metachondromatosis (MIM#156250) and Noonan syndrome 1 with or without multiple lentigines (MIM#151100, 163950), respectively (PMID: 21533187, 11992261, 24935154). (I) 0107 - This gene is associated with autosomal dominant disease. Missense variants clustered between N-SH2 and PTP domains have been reported in Noonan syndrome 1 (MIM #163950; PMID: 11992261), except variants in the active site of the PTP domain, which have been reported in Noonan syndrome with multiple lentigines (PMID: 24935154). Null variants have been reported in metachondromatosis individuals (MIM #156250; PMID: 21533187). (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 – Multiple alternative amino acid changes at the same position has been observed in gnomAD (highest allele count: 5 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER, PMID: 22711529). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It is a recurrent variant reported in Noonan syndrome 1 (MIM#163950) and classified as pathogenic by an expert panel in ClinVar (PMID: 22711529 ). (SP) 1208- Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	-	- -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 13, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Oct 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Oct 05, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 2021	Published functional studies demonstrate a profound effect on protein structure leading to re-arrangement and upregulation of its function, specifically by destabilizing the autoinhibited conformation of the SHP2 protein (Martinelli et al., 2012); The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19077116, 28607217, 25337068, 19020799, 32164556, 24033266, 16358218, 15928039, 19352411, 17020470, 12717436, 12325025, 11992261, 24803665, 25533962, 22711529, 26817465, 29555671, 29670795, 28135719, 15240615, 28191890, 28991257, 30417923, 30050098, 29907801, 31219622, 31560489, 33300679, 32901917, 32368696, 31785789) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 21, 2022	PS4, PS3, PM6 -
Pathogenic, no assertion criteria provided	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 15, 2015	- -

RASopathy Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 09, 2020	Variant summary: PTPN11 c.184T>G (p.Tyr62Asp) results in a non-conservative amino acid change located in the SH2 domain (IPR000980) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251414 control chromosomes (gnomAD). c.184T>G has been reported in the literature in multiple individuals affected with Noonan Syndrome and Related Conditions (e.g. Limal_2006, Sarkozy_2003, Tartaglia_2002). These data indicate that the variant is very likely to be associated with disease. In in vitro functional studies, the variant resulted in increased PTPN11 activity (Martinelli_2012). Nine ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2024	This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 62 of the PTPN11 protein (p.Tyr62Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan-like/multiple giant cell syndrome and Noonan syndrome (PMID: 11992261, 12325025, 15240615, 16358218, 17020470, 19020799, 19352411, 26817465). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13329). 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: 22711529). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	-	Variant classified using ACMG guidelines -
Pathogenic, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Feb 14, 2020	The c.184T>G (p.Tyr62Asp) variant in PTPN11 is absent from gnomAD (PM2). This variant has been observed in multiple individuals with Noonan syndrome (PS4; SCV000659042.4, PMIDs: 26817465, 19352411, 17020470, 12325025, 11992261, 19077116, 17339163). It has also been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID: 12325025). In vitro functional studies provide some evidence that the p.Tyr62Asp variant may impact protein function (PS3; PMID: 22711529). 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). Computational prediction tools and conservation analysis suggest the variant may impact the protein (PP3). Additionally, the p.Tyr62Asp 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). In summary, the p.Tyr62Asp variant in PTPN11 meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID: 29493581): PM2, PS4, PM6, PS3, PM1, PP3, PP2. -
Pathogenic, criteria provided, single submitter	research	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	Jul 01, 2023	- -

Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	PTPN11 NM_0002834.4 exon 3 p.Tyr62Asp (c.184T>G): This variant has been reported in the literature in several individuals with Noonan syndrome, including multiple de novo occurrences (Tartaglia 2002 PMID:11992261, Fitzgerald 2015 PMID:25533962, Jin 2017 PMID:28991257, Kosmicki 2017 PMID:28191890, McRae 2017 PMID:28135719, Szot 2018 PMID:29555671, Chinton 2019 PMID:31560489, Leach 2019 PMID:29907801, Athota 2020 PMID:32164556). This variant is not present in large control databases but is present in ClinVar, with several labs classifying this variant as pathogenic, including the ClinGen RASopathy Expert Panel (Variation ID:13329). This variant is located within the N-terminal SH2 domain, which acts as a molecular switch between the active and inactive states of SHP2 (Hof 1998 PMID: 9491886, Martinelli 2012 PMID:22711529). An in vitro functional study has shown a gain-of-function effect of this variant on the SHP2 protein product encoded by PTPN11 (Martinelli 2012 PMID:22711529). However, this study may not accurately represent in vivo biological function. In addition, evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, this variant is classified as pathogenic based on the data above. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Noonan syndrome;C0349639:Juvenile myelomonocytic leukemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 23, 2014

The p.Tyr62Asp variant in PTPN11 has been reported in many individuals with the clinical features of Noonan syndrome as well as an individual with Noonan syndro me and juvenile myelomonocytic leukemia (JMML; Tartaglia 2002, Tartaglia 2006, M aheshwari 2002, Bertola 2006, Beneteau 2009, LMM data). This variant has been re ported to have occurred de novo in an affected individual (Maheshwari 2002). In addition, this variant has not been identified in large population studies. In s ummary, the p.Tyr62Asp variant meets our criteria to be classified as pathogenic for Noonan syndrome in an autosomal dominant manner. -

PTPN11-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 26, 2023

The PTPN11 c.184T>G variant is predicted to result in the amino acid substitution p.Tyr62Asp. This variant has been reported in multiple individuals with Noonan syndrome with multiple cases where the variant arose de novo (see for example - Tartaglia et al. 2002. PubMed ID: 11992261; Szot et al. 2018. PubMed ID: 29555671). Pathogenic variants in PTPN11 act in a gain-of-function manner by causing an upregulation of the RAS pathway. Consistent with this mechanism, functional studies demonstrated this variant leads to elevated levels of ERK phosphorylation (Martinelli et al. 2012. PubMed ID: 22711529). Additionally, different missense variants affecting this residue (p.Tyr62Asn and p.Tyr62Cys) have been reported as pathogenic (Tartaglia et al. 2006. PubMed ID: 16358218; Jongmans et al. 2011. PubMed ID: 21407260). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Noonan syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 17, 2014

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 03, 2017

The p.Y62D pathogenic mutation (also known as c.184T>G), located in coding exon 3 of the PTPN11 gene, results from a T to G substitution at nucleotide position 184. The tyrosine at codon 62 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This mutation has been reported in a number of individuals with Noonan syndrome (Maheshwari M et al. Hum. Mutat., 2002 Oct;20:298-304; Tartaglia M et al. Am. J. Hum. Genet., 2002 Jun;70:1555-63; Sarkozy A et al. J. Med. Genet., 2003 Sep;40:704-8; Musante L et al. Eur. J. Hum. Genet., 2003 Feb;11:201-6; Zenker M et al. J. Pediatr., 2004 Mar;144:368-74; Kratz CP et al. Blood, 2005 Sep;106:2183-5; Binder G et al. J. Clin. Endocrinol. Metab., 2005 Sep;90:5377-81; Bertola DR et al. Genet. Test., 2006;10:186-91; Ko JM et al. J. Hum. Genet., 2008 Nov;53:999-1006; Beneteau C et al. Eur. J. Hum. Genet., 2009 Oct;17:1216-21; Ezquieta B et al. Rev Esp Cardiol (Engl Ed), 2012 May;65:447-55). Structural and in vitro functional analysis suggested that this residue is located at the PTP-interacting surface of the N-SH2 domian, and the alteration would lead to constitutively activation of PTPN11 (Martinelli S et al. J. Biol. Chem., 2012 Aug;287:27066-77). In addition, alterations affecting the same amino acid, p.Y62C and p.Y62N, have also been described in association with Noonan syndrome (Bentires-Alj M et al. Cancer Res., 2004 Dec;64:8816-20; Tartaglia M et al. Am. J. Hum. Genet., 2006 Feb;78:279-90). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Patent ductus arteriosus;C0040961:Tricuspid regurgitation;C0162770:Right ventricular hypertrophy;C0344724:Atrial septal defect, ostium secundum type;C0344974:Dysplastic pulmonary valve;C2315100:Failure to thrive Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Embryology Laboratory, Victor Chang Cardiac Research Institute

Sep 08, 2017

This variant was identified in an Australian family of South-East Asian descent. There was no family history of congenital heart disease, and the patient was identified with a novel (with respect to ExAC) de novo variant previously reported to cause Noonan syndrome. The patient exhibited typical cardiac features of Noonan syndrome, but further clinical examination was unavailable to confirm syndromic diagnosis. -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 27, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostCm	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	.;.;.;D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.66	T;T;T;T
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Uncertain	2.8	M;M;.;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.7	D;D;.;.
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0060	D;D;.;.
Sift4G	Uncertain	0.055	T;T;.;T
Polyphen		0.99	D;D;.;.
Vest4		0.91
MutPred		0.88		Loss of phosphorylation at Y62 (P = 0.0398);Loss of phosphorylation at Y62 (P = 0.0398);Loss of phosphorylation at Y62 (P = 0.0398);Loss of phosphorylation at Y62 (P = 0.0398);
MVP		0.99
MPC		2.5
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs121918460; hg19: chr12-112888168; COSMIC: COSV61011774; COSMIC: COSV61011774;