ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.1510A>G (p.Met504Val) (rs397507547)

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Total submissions: 19
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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 2018-07-31 criteria provided, single submitter clinical testing The M504V missense variant has been previously reported in association with Noonan syndrome, including de novo occurrences (Tartaglia et al., 2001; Cizmarova et al., 2016; Jongmans et al., 2011; Lee et al., 2007). Additionally, this variant has been observed de novo internally in patients with clinical features of Noonan syndrome. The M504V variant is observed in 1/246266 (0.0004%) alleles in large population cohorts (Lek et al., 2016). M504V is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution lies at a position within the protein tyrosine phosphatase domain that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies of the M504V variant have shown that it results in increased phosphatase activity (Niihori et al., 2005). Missense variants in nearby residues (R501K, S502L/A/T, G503V/E/A/R/R, Q506P, T507K) have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, we interpret this variant as pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000077853 SCV000058285 pathogenic not provided 2013-03-01 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare 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 RCV000999835 SCV000206705 pathogenic not specified 2018-07-19 criteria provided, single submitter clinical testing
Invitae RCV000033549 SCV000253877 pathogenic Rasopathy 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 504 of the PTPN11 protein (p.Met504Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is not present in population databases (rs397507547, ExAC no frequency). This variant has been observed in many individuals affected with Noonan syndrome (PMID: 11704759, 11992261, 15834506, 17339163, 19077116, 21407260, 24150203). ClinVar contains an entry for this variant (Variation ID: 40562). Experimental studies have shown that this missense change alters PTPN11 phosphatase activity compared to wild-type protein (PMID: 16358218). In summary, this is a rare missense change that has been identified in several affected individuals and experimental studies demonstrate an impact on protein function. For these reasons, it has been classified as Pathogenic.
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children 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 Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Integrated Genetics/Laboratory Corporation of America 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,Klinikum rechts der Isar 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.
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

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