ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.1510A>G (p.Met504Val)

dbSNP: rs397507547
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Total submissions: 32
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000156983 SCV000616376 pathogenic Noonan syndrome 2017-04-03 reviewed by expert panel curation The c.1510A>G (p.Met504Val) variant in PTPN11 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients and 3 independent occurrences in patients with clinical features of a RASopathy (PM6_Strong, PS4; GeneDx internal data; GTR Lab ID: 26957; SCV000057454.12; PMID: 15834506, 17661820, 17020470). In vitro functional studies provide some evidence that the p.Met504Val variant may impact protein function (PS3; PMID: 15834506). 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.Met504Val variant may impact the protein (PP3). 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): PS3, PM6_Strong, PS4_Moderate, PP2, PP3.
GeneDx RCV000077853 SCV000057454 pathogenic not provided 2022-01-24 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect, resulting in increased phosphatase activity (Niihori et al., 2005); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Classified as pathogenic by the ClinGen RASopathy Expert Panel (ClinVar SCV000616376.3; Gelb et al., 2018); This variant is associated with the following publications: (PMID: 24150203, 28483241, 28152038, 17661820, 15834506, 24803665, 17361219, 11704759, 26242988, 27521173, 28911804, 28607217, 29493581, 21407260, 26607044, 29703613, 29620724, 30355600, 30417923, 30050098, 29907801, 31219622, 31263281, 31560489, 31564432, 31324109, 32164556, 32824488, 31019026, 32410215, 33619735, 34006472, 33726816, 27535533)
Eurofins Ntd Llc (ga) RCV000077853 SCV000058285 pathogenic not provided 2013-03-01 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000156983 SCV000061278 pathogenic Noonan syndrome 2017-10-10 criteria provided, single submitter clinical testing The p.Met504Val variant in PTPN11 has been reported in >20 individuals with clin ical features of Noonan syndrome (Tartaglia 2002, Niihori 2005, Hung 2007, Ferre ira 2008, Ko 2008, LMM data). It has also been identified in 1/111714 European c hromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstit ute.org/; dbSNP rs397507547); however, this frequency is low enough to be consis tent with the prevalence and variable expressivity of Noonan syndrome. Computati onal prediction tools and conservation analysis suggest that the p.Met504Val var iant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that the p.Met504Val variant may impact protein function (Niihori 2005). In summary, this variant meets criteria to be classified as pathogenic for Noonan syndrome in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4, PS3, PP3, PP2.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000077853 SCV000206705 pathogenic not provided 2023-06-28 criteria provided, single submitter clinical testing The PTPN11 c.1510A>G; p.Met504Val variant (rs397507547) is reported in the literature in individuals affected with Noonan syndrome (Ferreira 2008, Ko 2008, Niihori 2005, Tartaglia 2001, Tartaglia 2002), and has been observed in familial (Hung 2007) and de novo cases (Ferreira 2005, Kingsmore 2019). This variant is also reported in the ClinVar database (Variation ID: 40562). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The variant is located in the phospho-tyrosine phosphatase domain of PTPN11 (Hof 1998, Tartaglia 2001), and implicated in the destabilizing the inactive conformation of the protein (Tartaglia 2002). The methionine at codon 504 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.945). Functional analyses of the p.Met504Val protein show increased catalytic activity upon growth factor-mediated stimulation (Niihori 2005, Tartaglia 2006), consistent with the established disease mechanisms of Noonan syndrome. Based on available information, this variant is considered to be pathogenic. References: Ferreira LV et al. PTPN11 (protein tyrosine phosphatase, nonreceptor type 11) mutations and response to growth hormone therapy in children with Noonan syndrome. J Clin Endocrinol Metab. 2005 Sep;90(9):5156-60. PMID: 15956085. Ferreira L et al. Analysis of the PTPN11 gene in idiopathic short stature children and Noonan syndrome patients. Clin Endocrinol (Oxf). 2008 69(3):426-31. PMID: 18331608. Hof P et al. Crystal structure of the tyrosine phosphatase SHP-2. Cell. 1998 92(4): 441-450. PMID: 9491886. Hung C et al. Mutational analysis of PTPN11 gene in Taiwanese children with Noonan syndrome. J Formos Med Assoc. 2007 106(2):169-72. PMID: 17339163. Kingsmore SF et al. A Randomized, Controlled Trial of the Analytic and Diagnostic Performance of Singleton and Trio, Rapid Genome and Exome Sequencing in Ill Infants. Am J Hum Genet. 2019 Oct 3;105(4):719-733. PMID: 31564432. Ko J et al. PTPN11, SOS1, KRAS, and RAF1 gene analysis, and genotype-phenotype correlation in Korean patients with Noonan syndrome. J Hum Genet. 2008 53(11-12):999-1006. PMID: 19020799. Niihori T et al. Functional analysis of PTPN11/SHP-2 mutants identified in Noonan syndrome and childhood leukemia. 2005 J Hum Genet. 50(4):192-202. PMID: 15834506. Tartaglia M et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. 2001 Nat Genet. 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 70(6): 1555-1563. PMID: 11992261. 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. PMID: 16358218.
Invitae RCV000033549 SCV000253877 pathogenic RASopathy 2024-01-18 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 504 of the PTPN11 protein (p.Met504Val). This variant is present in population databases (rs397507547, gnomAD 0.0009%). This missense change has been observed in individuals with Noonan syndrome (PMID: 11704759, 11992261, 15834506, 17339163, 19077116, 21407260, 24150203). ClinVar contains an entry for this variant (Variation ID: 40562). 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). For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostics Lab, Nemours Children's Health, Delaware RCV000077853 SCV000265847 pathogenic not provided 2015-10-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000248048 SCV000318916 pathogenic Inborn genetic diseases 2014-06-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000033549 SCV000698057 pathogenic RASopathy 2016-04-21 criteria provided, single submitter clinical testing Variant summary: The c.1510A>G variant in PTPN11 gene is a missense change that alters a highly conserved nucleotide and 3/4 in silico tools predict deleterious outcome. The variant has been reported in multiple affected individuals as de novo occurrences as well as inherited from affected parents. The mutation lies within a region of the gene coding for the highly conserved PTP domain of the protein tyrosine phosphatase 11 and was shown to increase the phosphatase activity in functional studies. The variant is absent from the large control population dataset of ExAC. Lastly, multiple reputable databases/diagnostic centers classified the variant of interest as Pathogenic. Taken together, the variant was classified as Pathogenic.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000677652 SCV000803787 pathogenic Noonan syndrome 1 2015-02-16 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000762887 SCV000893275 pathogenic Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 2018-10-31 criteria provided, single submitter clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge RCV000677652 SCV000899520 likely pathogenic Noonan syndrome 1 2019-02-01 criteria provided, single submitter research
Blueprint Genetics RCV000077853 SCV000927631 pathogenic not provided 2018-04-17 criteria provided, single submitter clinical testing
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital RCV000677652 SCV000992414 pathogenic Noonan syndrome 1 criteria provided, single submitter case-control
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000677652 SCV000996118 pathogenic Noonan syndrome 1 2018-03-16 criteria provided, single submitter clinical testing This variant has been reported multiple times as pathogenic in the literature and by clinical laboratories in the ClinVar database (Variation ID: 40562) in individuals with Noonan Syndrome (PMID: 11704759 26242988 28911804 29703613). The variant is absent from the population database gnomAD, thus presumed to be rare. The p.Met504 residue is highly conserved among eukaryotes, and in silico algorithms predict that the valine substitution will have a damaging effect on protein function. Functional characterization of the p.Met504Val demonstrated altered PTPN11 phosphatase activity compared to wild-type protein (PMID: 16358218). Based on the combined evidence, this variant is classified as pathogenic.
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München RCV000677652 SCV001149902 pathogenic Noonan syndrome 1 2019-01-22 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV001027841 SCV001190461 pathogenic Noonan syndrome 1; Metachondromatosis; LEOPARD syndrome 1 2019-10-25 criteria provided, single submitter clinical testing PTPN11 NM_002834.4 exon13 c.1510A>G p.Met504Val: This variant has been reported in the literature in multiple individuals with Noonan syndrome (Selected publications: Tartaglia 2001 PMID11704759, Jongsman 2011 PMID21407260, van Trier 2016 PMID38621173, Leach 2018 PMID 30050098). This variant is present in 0.0008% (1/113766) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/12-112926890-A-G?dataset=gnomad_r2_1). This variant is present in ClinVar, with several labs classifying this variant as pathogenic, including the ClinGen RASopathy Variant Curation Expert Panel (Variation ID: 40562). Evolutionary conservation suggests that this variant may impact the protein; computational predictive tools for this variant are unclear. In vitro functional studies support that this variant will impact the protein by causing an increase in phosphatase activity (Niihori 2005 PMID15834506). In summary, this variant is classified as pathogenic based on the data above.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000077853 SCV001447991 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000077853 SCV001713608 pathogenic not provided 2020-09-09 criteria provided, single submitter clinical testing PP2, PP3, PM6_Strong, PS3
3billion RCV000677652 SCV002012209 pathogenic Noonan syndrome 1 2021-10-02 criteria provided, single submitter clinical testing The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID:15834506, 17661820, 17020470, PS4). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 15834506, PS3). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.00000397, PM2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.843, 3Cnet: 0.995, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genetics and Molecular Pathology, SA Pathology RCV000677652 SCV002556631 pathogenic Noonan syndrome 1 2021-06-18 criteria provided, single submitter clinical testing The PTPN11 c.1510A>G variant is classified as PATHOGENIC (PP2, PS2, PS3, PS4) The PTPN11 c.1510A>G variant is a single nucleotide change in exon 13 of the PTPN11 gene, which is predicted to change the amino acid methionine at position 504 in the protein to valine. This de novo variant has been previously reported in multiple individuals with Noonan syndrome (PMID:15834506, PMID:11704759, PMID:11992261, PMID:24150203) (PS3, PS4). This variant is located within the highly conserved PTP domain of the protein and functional studies show altered (increased) phosphatase activity compared with WT protein (PMID:15834506) (PS3, PP2). This variant has been reported in dbSNP (rs397507547), and is rare in population databases (gnomAD 1/251490 alleles). The variant has been reported as pathogenic by other diagnostic laboratories (ClinVar Variation ID: 40562).
Ambry Genetics RCV002390132 SCV002705011 pathogenic Cardiovascular phenotype 2021-05-27 criteria provided, single submitter clinical testing The p.M504V pathogenic mutation (also known as c.1510A>G), located in coding exon 13 of the PTPN11 gene, results from an A to G substitution at nucleotide position 1510. The methionine at codon 504 is replaced by valine, an amino acid with highly similar properties. This mutation has been identified in multiple individuals with Noonan syndrome, including de novo occurrences (Tartaglia M et al. Nat. Genet., 2001 Dec;29:465-8; Tartaglia M et al. Am. J. Hum. Genet., 2002 Jun;70:1555-63; Ko JM et al. J. Hum. Genet., 2008 Nov;53:999-1006; Hung CS et al. J. Formos. Med. Assoc., 2007 Feb;106:169-72; izmárová M et al. Ann. Hum. Genet., 2016 Jan;80:50-62; Atik T et al. Indian J Pediatr, 2016 Jun;83:517-21; Caiazza M et al. Genes (Basel). 2020 08;11(8). In vitro analysis of this alteration demonstrated mild phosphatase activation, a three-fold increased compared to wildtype (Niihori T et al. J. Hum. Genet., 2005 Apr;50:192-202). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000677652 SCV002767130 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 Noonan syndrome (MIM#163950), LEOPARD syndrome (MIM#151100), and Metachondromatosis (MIM#156250). Gain of function variants are associated with Noonan Syndrome, while loss of function variants cause LEOPARD syndrome or metachondromatosis (PMID: 11992261, 24935154, 21533187). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from methionine to valine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) [p.(Met504Ile):1 heterozygote, 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. It is located within one of the hotspots for pathogenic or likely pathogenic missense variants (ClinVar, Decipher). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by the ClinGen RASopathy Variant Curation Expert Panel (ClinVar). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional analysis using mammalian cell lines showed a 3-fold increase in phosphatase activity in p.(Met504Val) mutant cells relative to wild-type (PMID: 15834506). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I)
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000762887 SCV003920362 pathogenic Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 2021-03-30 criteria provided, single submitter clinical testing PTPN11 NM_002834.4 exon13 c.1510A>G p.Met504Val: This variant has been reported in the literature in multiple individuals with Noonan syndrome (Selected publications: Tartaglia 2001 PMID11704759, Jongsman 2011 PMID21407260, van Trier 2016 PMID38621173, Leach 2018 PMID 30050098). This variant is present in 0.0008% (1/113766) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/12-112926890-A-G?dataset=gnomad_r2_1). This variant is present in ClinVar, with several labs classifying this variant as pathogenic, including the ClinGen RASopathy Variant Curation Expert Panel (Variation ID: 40562). Evolutionary conservation suggests that this variant may impact the protein; computational predictive tools for this variant are unclear. In vitro functional studies support that this variant will impact the protein by causing an increase in phosphatase activity (Niihori 2005 PMID15834506). In summary, this variant is classified as pathogenic based on the data above.
Preventiongenetics, part of Exact Sciences RCV003407393 SCV004115089 pathogenic PTPN11-related condition 2023-04-25 criteria provided, single submitter clinical testing The PTPN11 c.1510A>G variant is predicted to result in the amino acid substitution p.Met504Val. This variant has been identified in at least thirteen individuals with either familial or sporadic Noonan syndrome (Tartaglia et al. 2001. PubMed ID: 11704759; Tartaglia et al. 2002. PubMed ID: 11992261; Niihori et al. 2005. PubMed ID: 15834506; Tartaglia et al. 2006. PubMed ID: 16358218; Hung et al. 2007. PubMed ID: 17339163; Pierpont et al. 2009. PubMed ID: 19077116; Jongmans et al. 2011. PubMed ID: 21407260), including a de novo event in at least one individual (Table S1 - Maddirevula et al. 2018. PubMed ID: 29620724). Functional studies demonstrate increased phosphatase activity, consistent with a gain-of-function mechanism (Niihori et al. 2005. PubMed ID: 15834506; Tartaglia et al. 2006. PubMed ID: 16358218). Multiple laboratories have interpreted this variant as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/40562/). Additionally, a different amino acid substitution affecting the same amino acid (p.Met504Leu) has been reported in an individual with Noonan syndrome (Narayanan et al. 2017. PubMed ID: 28607217). This variant is interpreted as pathogenic.
CeGaT Center for Human Genetics Tuebingen RCV000077853 SCV004131973 pathogenic not provided 2023-10-01 criteria provided, single submitter clinical testing PTPN11: PS2:Very Strong, PM1, PM2, PS3:Moderate, PS4:Moderate, PP3
Baylor Genetics RCV000033549 SCV000196654 pathogenic RASopathy no assertion criteria provided clinical testing Variant classified using ACMG guidelines
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV000077853 SCV000207662 pathogenic not provided 2015-01-15 no assertion criteria provided clinical testing
Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital RCV000677652 SCV001482326 likely pathogenic Noonan syndrome 1 2019-05-31 no assertion criteria provided research
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand RCV000677652 SCV003840158 pathogenic Noonan syndrome 1 no assertion criteria provided research
Institute Of Reproduction And Development, Obstetrics and Gynecology Hospital, Fudan University RCV000677652 SCV003844103 pathogenic Noonan syndrome 1 2021-12-24 no assertion criteria provided research
Molecular Genetics, Centre for Human Genetics RCV000677652 SCV004190084 pathogenic Noonan syndrome 1 no assertion criteria provided clinical testing

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