Submissions for variant NM_002834.5(PTPN11):c.184T>G (p.Tyr62Asp)

dbSNP: rs121918460

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000033466	SCV001335317	pathogenic	RASopathy	2020-02-14	reviewed by expert panel	curation	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.
GeneDx	RCV000153794	SCV000057371	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing	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)
Eurofins Ntd Llc (ga)	RCV000153794	SCV000203372	pathogenic	not provided	2018-02-13	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000824739	SCV000204059	pathogenic	Juvenile myelomonocytic leukemia; Noonan syndrome	2014-05-23	criteria provided, single submitter	clinical testing	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.
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	RCV000153794	SCV000265849	pathogenic	not provided	2015-10-05	criteria provided, single submitter	clinical testing
Invitae	RCV000033466	SCV000659042	pathogenic	RASopathy	2024-01-09	criteria provided, single submitter	clinical testing	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.
Embryology Laboratory, Victor Chang Cardiac Research Institute	RCV000590972	SCV000680457	pathogenic	Failure to thrive; Atrial septal defect, ostium secundum type; Tricuspid regurgitation; Right ventricular hypertrophy; Dysplastic pulmonary valve; Patent ductus arteriosus	2017-09-08	criteria provided, single submitter	research	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000033466	SCV000698065	pathogenic	RASopathy	2020-04-09	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV000762882	SCV000893270	pathogenic	Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1	2018-10-31	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000153794	SCV000927995	pathogenic	not provided	2018-10-16	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000014257	SCV000992537	pathogenic	Noonan syndrome 1	2019-01-10	criteria provided, single submitter	research	ACMG codes: PS2, PS3, PM2, PP3, PP5
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	RCV000014257	SCV000999301	pathogenic	Noonan syndrome 1		criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000153794	SCV001714421	pathogenic	not provided	2022-02-21	criteria provided, single submitter	clinical testing	PS4, PS3, PM6
3billion	RCV000014257	SCV002012325	pathogenic	Noonan syndrome 1	2021-10-02	criteria provided, single submitter	clinical testing	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.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813195	SCV002060839	pathogenic	Noonan syndrome and Noonan-related syndrome	2019-05-27	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000762882	SCV002495905	pathogenic	Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1	2021-03-30	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV002408460	SCV002717120	pathogenic	Cardiovascular phenotype	2017-08-03	criteria provided, single submitter	clinical testing	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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000014257	SCV002768634	pathogenic	Noonan syndrome 1	2022-02-02	criteria provided, single submitter	clinical testing	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
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV000033466	SCV004034101	pathogenic	RASopathy	2023-07-01	criteria provided, single submitter	research
PreventionGenetics, part of Exact Sciences	RCV004532340	SCV004120665	pathogenic	PTPN11-related disorder	2023-02-26	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000014257	SCV000034505	pathogenic	Noonan syndrome 1	2002-10-01	no assertion criteria provided	literature only
Baylor Genetics	RCV000033466	SCV000196656	pathogenic	RASopathy		no assertion criteria provided	clinical testing	Variant classified using ACMG guidelines
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000156993	SCV000206716	pathogenic	Noonan syndrome	2014-01-17	no assertion criteria provided	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000153794	SCV000207651	pathogenic	not provided	2015-01-15	no assertion criteria provided	clinical testing