Submissions for variant NM_002834.5(PTPN11):c.188A>G (p.Tyr63Cys)

gnomAD frequency: 0.00001  dbSNP: rs121918459

Total submissions: 47

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000157000	SCV000616372	pathogenic	Noonan syndrome	2017-04-03	reviewed by expert panel	curation	The c.188A>G (p.Tyr63Cys) variant in PTPN11 has been reported in the literature in at least 6 unrelated individuals and has been found to segregate with clinical features of a RASopathy in at least 15 family members (PS4, PP1_Strong; 16498234, 12634870, 12325025, 11704759). In vitro functional studies provide some evidence that the p.Tyr63Cys variant may impact protein function (PS3; PMID: 22711529). 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.Tyr63Cys variant may impact the protein (PP3). 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). 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): PP1_Strong, PS4, PS3, PM1, PP2, PP3.
GeneDx	RCV000077857	SCV000057373	pathogenic	not provided	2021-08-11	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that Y63C perturbs the autoinhibitory interaction between the N-SH2 and protein-tyrosine phosphatase domains, which is required to maintain SHP2 in its catalytically inactive state (Martinelli et al., 2012); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21407260, 12325025, 24803665, 11704759, 30055033, 30417923, 32164556, 24219368, 22711529, 12634870, 26242988, 25156961, 30692697, 30050098, 29907801, 31219622, 31560489, 32371413, 32901917, 11992261, 9491886, 16053901, 29493581)
Eurofins Ntd Llc (ga)	RCV000077857	SCV000058290	pathogenic	not provided	2013-03-01	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000157000	SCV000061294	pathogenic	Noonan syndrome	2017-04-20	criteria provided, single submitter	clinical testing	The p.Tyr63Cys variant in PTPN11 has been reported in >40 individuals with Noona n syndrome, occurred de novo in some sporadic cases and segregated with disease in numerous families (Tartaglia 2002, Kosaki 2002, Maheshwari 2002, Musante 2003 , Loh 2004, Kratz 2005, Takahashi 2006, Becker 2007, Jongmans 2011, Simsek-Kiper 2012, LMM data). In addition, this variant has been identified as a somatic var iant in one individual with chronic myelomonocytic leukemia (CMML; Loh 2004) and as a germline variant in two individuals with both clinical features of Noonan syndrome and a malignancy (precursor B-ALL and basal cell carcinoma; Jongmans 20 11). This variant has also been identified in 1/17248 East Asian chromosomes and 1/33576 Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). Moreov er, the p.Tyr63Cys variant has been classified as pathogenic on April 3, 2018 by the ClinGen-approved RASopathy Expert Panel (ClinVar SCV000616372.1). In summar y, this variant meets criteria to be classified as pathogenic for Noonan syndrom e in an autosomal dominant manner based upon presence in multiple affected indiv iduals, de novo occurrences and segregation studies. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM6_Strong.
Blueprint Genetics	RCV000157000	SCV000207167	pathogenic	Noonan syndrome	2015-01-07	criteria provided, single submitter	clinical testing
Invitae	RCV000033468	SCV000253879	pathogenic	RASopathy	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 63 of the PTPN11 protein (p.Tyr63Cys). This variant is present in population databases (rs121918459, gnomAD 0.006%). This missense change has been observed in individuals with Noonan syndrome (PMID: 11704759, 11992261, 12325025, 12960218, 16498234, 21407260). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13333). 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%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 22711529). For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	RCV000077857	SCV000265840	pathogenic	not provided	2015-09-21	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515408	SCV000611303	pathogenic	Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1	2017-05-18	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000077857	SCV000614839	pathogenic	not provided	2017-06-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588678	SCV000698066	pathogenic	Noonan syndrome 3	2016-05-02	criteria provided, single submitter	clinical testing	Variant summary: The c.188A>G variant affects a conserved nucleotide, resulting in amino acid change from Tyr to Cys. 4/4 in-silico tools predict damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is found in 1/121890 control chromosomes at a frequency of 0.0000082, which does not exceed maximal expected frequency of a pathogenic allele (0.0000625). The variant has been reported in numerous affected individuals and families in the literature and has been shown to segregate with disease in affected families. The variant is considered a common pathogenic variant. In addition, multiple reputable clinical laboratory and database classified this variant as Pathogenic. Taken together, this variant was classified as Pathogenic.
Undiagnosed Diseases Network, NIH	RCV000014261	SCV000746635	pathogenic	Noonan syndrome 1	2017-03-28	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000014261	SCV000782248	pathogenic	Noonan syndrome 1	2016-11-01	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000722014	SCV000853187	pathogenic	Lymphoma; B lymphoblastic leukemia lymphoma, no ICD-O subtype	2017-04-26	criteria provided, single submitter	clinical testing	This is a missense alteration in which an A is replaced by a G at coding nucleotide 188 and is predicted to change a Tyrosine to a Cysteine at amino acid codon 63. Classification criteria: PS1, PS3, PM1, PM2, PP3.
Baylor Genetics	RCV000014261	SCV000854621	pathogenic	Noonan syndrome 1	2021-02-12	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000077857	SCV000884430	pathogenic	not provided	2023-08-16	criteria provided, single submitter	clinical testing	The PTPN11 c.188A>G; p.Tyr63Cys variant (rs121918459) has been reported in multiple patients diagnosed with Noonan syndrome (Tartaglia 2001, Jongmans 2011, Martinelli 2012, Hashida 2013, Lepri 2014, Okamoto 2015). This variant is found on only three chromosomes (3/251010 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism, and it is listed as pathogenic in ClinVar by multiple clinical laboratories (Variation ID: 13333). The p.Tyr63Cys variant is located in a structurally important region of the catalytic N-terminal SH2 domain of PTPN11 (Hof 1998), and several additional variants in neighboring codons (p.Asp61Asn, p.Asp61Gly, p.Tyr62Asp, p.Tyr62Asn) have also been identified in individuals with Noonan syndrome (Jongmans 2011, Tartaglia 2002, Tartaglia 2006). Functional characterization of the p.Tyr63Cys variant protein indicates over-activation of p38alpha MAP kinase and phosphorERK1/2 upon growth factor signaling (Martinelli 2012, Hashida 2013), consistent with the established disease mechanisms of Noonan syndrome. Based on available information, the p.Tyr63Cys variant is classified as pathogenic. References: Hashida N et al. MAPK activation in mature cataract associated with Noonan syndrome. BMC Ophthalmol. 2013 Nov 12;13:70. PMID: 24219368 Hof P et al. Crystal structure of the tyrosine phosphatase SHP-2. Cell. 1998 Feb 20;92(4):441-50. PMID: 9491886 Jongmans M et al. Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation. Eur J Hum Genet. 2011 Aug;19(8):870-4. PMID: 21407260 Lepri et al. Diagnosis of Noonan syndrome and related disorders using target next generation sequencing. BMC Med Genet. 2014 Jan 23;15:14. PMID: 24451042 Martinelli S et al. Counteracting effects operating on Src homology 2 domain-containing protein-tyrosine phosphatase 2 (SHP2) function drive selection of the recurrent Y62D and Y63C substitutions in Noonan syndrome. J Biol Chem. 2012 Aug 3;287(32):27066-77. PMID: 22711529 Okamoto N et al. Targeted next-generation sequencing in the diagnosis of neurodevelopmental disorders. Clin Genet. 2015 Sep;88(3):288-92. PMID: 25156961 Tartaglia M et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001 Dec;29(4):465-8. PMID: 11704759 Tartaglia M et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002 Jun;70(6):1555-63. PMID: 11992261 Tartaglia M et al. Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet. 2006 Feb;78(2):279-90. PMID: 16358218
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	RCV000014261	SCV000992395	pathogenic	Noonan syndrome 1		criteria provided, single submitter	case-control
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	RCV000014261	SCV000999303	pathogenic	Noonan syndrome 1		criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000014261	SCV001190264	pathogenic	Noonan syndrome 1	2019-05-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000077857	SCV001246728	pathogenic	not provided	2023-01-01	criteria provided, single submitter	clinical testing	PTPN11: PP1:Strong, PM1, PS4:Moderate, PP2, PP3, PP4, PS3:Supporting
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	RCV001249667	SCV001423672	pathogenic	Noonan syndrome 1; Metachondromatosis; LEOPARD syndrome 1	2018-12-10	criteria provided, single submitter	clinical testing	[ACMG/AMP/ClinGen RASopathy: PS1, PS3, PS4, PP1_Strong, PM1, PP2, PP3] This alteration has an amino acid change previously established as pathogenic (regardless of nucleotide change) [PS1], 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].
Kariminejad - Najmabadi Pathology & Genetics Center	RCV000077857	SCV001755589	pathogenic	not provided	2021-07-10	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000077857	SCV001905629	pathogenic	not provided	2021-09-15	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000014261	SCV001976777	pathogenic	Noonan syndrome 1	2021-10-01	criteria provided, single submitter	clinical testing	PS3, PM1, PM2, PP2, PP3, PP5
Clinical Genetics Laboratory, Region Ostergotland	RCV000014261	SCV001984986	pathogenic	Noonan syndrome 1	2021-01-26	criteria provided, single submitter	clinical testing	PS3, PS4, PM6, PP1, PP3, PP5
3billion	RCV000014261	SCV002012314	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 observed in at least four similarly affected unrelated individuals (3billion dataset, ClinVar ID: VCV000372674.2, PMID: 11992261, 26242988, 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 observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.00001195). 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: 0.955, 3Cnet: 0.971, PP3). Patient's phenotype is considered compatible with Noonan syndrome (3billion dataset, PP4).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Centogene AG - the Rare Disease Company	RCV000014261	SCV002059442	pathogenic	Noonan syndrome 1	2018-07-12	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813198	SCV002060861	pathogenic	Noonan syndrome and Noonan-related syndrome	2020-09-14	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000515408	SCV002495907	pathogenic	Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1	2022-01-25	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in at least 10 individuals with a clinical diagnosis or suspicion of Noonan syndrome, segregating with disease in more than 15 affected family members (Selected publications: Maheshwari 2002 PMID:12325025; Musante 2003 PMID:12634870; Jongmans 2011 PMID:21407260; Athota 2020 PMID:32164556). This variant is present in 0.005% (1/18394) of East Asian alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/12-112888172-A-G?dataset=gnomad_r2_1). 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 many laboratories and the ClinGen RASopathy Variant Curation Expert Panel classifying it as pathogenic (Variation ID:13333). This variant is located at a residue directly involved in interactions between N-SH2 and PTPN domains (Gelb 2018 PMID:29493581). An in vitro functional study showed that this variant impacts protein structure, resulting in increased protein activity (Martinelli 2012 PMID:22711529). However, this study study may not accurately represent in vivo biological function. PTPN11 has a low rate of benign missense variation and pathogenic missense variation is common (Gelb 2018 PMID:29493581). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In summary, this variant is classified as pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV000077857	SCV002501823	pathogenic	not provided	2022-01-20	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000014261	SCV002581037	pathogenic	Noonan syndrome 1	2022-08-16	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000014261	SCV002768758	pathogenic	Noonan syndrome 1	2022-09-02	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 - Both loss of function and gain of function are known mechanisms of disease for this gene. Metachondromatosis (MIM#156250) and Noonan syndrome with multiple lentigines have been associated with loss of function variants, whereas Noonan syndrome 1 (MIM#163950) is caused by gain of function variants (PMIDs: 11992261, 24935154, 21533187). (I) 0107 - This gene is known to be associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 20301303). (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine. (I) 0251 - Variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and is highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (N-SH2 domain; DECIPHER). (SP) 0801 - The variant has strong previous evidence of pathogenicity in unrelated individuals with Noonan syndrome (ClinVar, DECIPHER, PMIDs: 11704759; 12325025; 12634870). (SP) 0901 - The variant has strong evidence for segregation with disease in multiple families (PMID: 12325025; 12634870). (SP) 1002 - Moderate functional evidence supporting abnormal protein function. In vitro studies showed that the variant resulted in a gain of protein function (PMID: 22711529). (SP) 1208 - Inheritance information for this variant is not currently available. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV003137518	SCV003807148	pathogenic	LEOPARD syndrome 1	2022-04-06	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 strong, PS4 strong, PM1 moderated, PP1 strong, PP2 supporting, PP3 supporting
Revvity Omics, Revvity	RCV000077857	SCV003826749	pathogenic	not provided	2022-03-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147286	SCV003835598	pathogenic	Metachondromatosis	2021-02-14	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003137518	SCV003836226	pathogenic	LEOPARD syndrome 1	2021-02-14	criteria provided, single submitter	clinical testing
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV000033468	SCV004034113	pathogenic	RASopathy	2023-07-01	criteria provided, single submitter	research
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV004528109	SCV004046310	pathogenic	PTPN11-related disorder		criteria provided, single submitter	clinical testing	This variant has been previously reported as a heterozygous change in patients with PTPN11-related disorders (PMID: 16498234, 12634870, 12325025, 11704759, 21407260). Functional studies suggest that this variant impacts protein structure, resulting in increased protein activity (PMID: 22711529). The c.188A>G (p.Tyr63Cys) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (3/251010) and thus is presumed to be rare. Based on the available evidence, the c.188A>G (p.Tyr63Cys) variant is classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004528109	SCV004103329	pathogenic	PTPN11-related disorder	2023-12-26	criteria provided, single submitter	clinical testing	The PTPN11 c.188A>G variant is predicted to result in the amino acid substitution p.Tyr63Cys. This variant has been reported in many unrelated individuals with Noonan syndrome and was found to occur de novo in several cases and segregated with disease in many families (Tartaglia et al. 2001. PubMed ID: 11704759; Maheshwari et al. 2002. PubMed ID: 12325025; Jongmans et al. 2011. PubMed ID: 21407260; Okamoto et al. 2015. PubMed ID: 25156961). Functional studies indicate that the p.Tyr63Cys variant alters the functional regulation of SHP2 protein by affecting the stability between N-SH2 and PTP domains (Martinelli et al. 2012. PubMed ID: 22711529). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000014261	SCV004176586	uncertain significance	Noonan syndrome 1	2023-02-14	criteria provided, single submitter	clinical testing	The missense c.188A>G(p.Tyr63Cys) variant in PTPN11 gene has been reported previously in heterozygous state in individual(s) affected with Noonan syndrome (Takahashi et al., 2006). Experimental studies have shown that this missense change affects PTPN11 function (Martinelli S et al., 2012). This variant is reported with the allele frequency of 0.001% in the gnomAD Exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic by multiple submitters. The amino acid Tyr at position 63 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Tyr63Cys in PTPN11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted as damaging by SIFT. For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000077857	SCV004226875	pathogenic	not provided	2022-06-02	criteria provided, single submitter	clinical testing	PP1_strong, PP2, PP3, PM1, PS3_moderate
OMIM	RCV000014261	SCV000034509	pathogenic	Noonan syndrome 1	2007-06-01	no assertion criteria provided	literature only
Baylor Genetics	RCV000033468	SCV000196657	pathogenic	RASopathy		no assertion criteria provided	clinical testing	Variant classified using ACMG guidelines
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000077857	SCV000207652	pathogenic	not provided	2015-01-15	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000077857	SCV001931284	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000077857	SCV001956732	pathogenic	not provided		no assertion criteria provided	clinical testing
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV000014261	SCV003840159	pathogenic	Noonan syndrome 1		no assertion criteria provided	research
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000014261	SCV004101114	pathogenic	Noonan syndrome 1	2023-11-02	no assertion criteria provided	clinical testing