ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.1471C>T (p.Pro491Ser) (rs397507539)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254684 SCV000057441 pathogenic not provided 2018-09-27 criteria provided, single submitter clinical testing The P491S pathogenic variant has been reported previously in the literature in patients with a clinical diagnosis of Noonan syndrome and the allelic disorder Noonan syndrome with multiple lentigines (Zenker et al., 2004; Bertola, et al., 2006; Tartaglia et al., 2006). In addition, other missense pathogenic variants altering this codon (P491T, P491L, P491H) have been reported in the literature (Ezquieta et al., 2012; Binder et al., 2005; Bertola et al., 2006). Functional studies show that this missense change results in increased phosphatase activity of the SHP-2 protein (Edwards et al., 2014). The P491S variant is not observed in large population cohorts (Lek et al., 2016). The P491S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. We interpret P491S as a pathogenic variant.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000157010 SCV000061277 pathogenic Noonan syndrome 2018-12-19 criteria provided, single submitter clinical testing The p.Pro491Ser variant in PTPN11 has been identified in at least 10 individuals with clinical features of Noonan syndrome, including one individual in whom it occurred de novo (Bertola 2006, Tartaglia 2005, LMM data). This variant has also been identified as a somatic change occurring in an individual with acute lymph oblastic leukemia (Tartaglia 2004). It has been identified in 1/111708 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinsti tute.org/; dbSNP rs397507539). Additionally, at least 2 other pathogenic missens e variants (p.Pro491Thr; p.Pro491Leu; p.Pro491His) have been previously identifi ed at this codon of PTPN11 which may indicate that this residue is critical to t he function of the protein. In summary, this variant meets our criteria to be cl assified as pathogenic. ACMG/AMP codes applied: PS4, PM5_Strong, PM6
Invitae RCV000033536 SCV000549982 pathogenic Rasopathy 2018-08-02 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 491 of the PTPN11 protein (p.Pro491Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs397507539, ExAC 0.001%). This variant has been observed to be de novo in an individual affected with Noonan syndrome (PMID: 22465605) and observed in unrelated individuals affected with this disease (PMID: 19077116, 16358218, 17020470). ClinVar contains an entry for this variant (Variation ID: 40550). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Variants that disrupt the p.Pro491 amino acid residue in PTPN11 have been observed in affected individuals (PMID: 15985475, 19621452, 22465605). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000033536 SCV000920099 pathogenic Rasopathy 2018-08-13 criteria provided, single submitter clinical testing Variant summary: PTPN11 c.1471C>T (p.Pro491Ser) results in a non-conservative amino acid change located in the Protein-tyrosine phosphatase, catalytic domain and Tyrosine specific protein phosphatases domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found in 1/246860 control chromosomes, a frequency of 4.1e-06. c.1471C>T has been reported in the literature in numerous individuals affected with Noonan Syndrome or related disorders, indicating the variant is very likely to be associated with disease. In addition, several variants causing a change at the same codon have been reported as associated with Noonan Syndrome (p.P491A, p.P491H, p.P491L, p.P491T), suggesting the proline is critical for proper gene function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery,Institute of Otolaryngology, Chinese PLA General Hospital RCV000984919 SCV000992411 pathogenic Noonan syndrome 1 criteria provided, single submitter case-control
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001000194 SCV001156694 pathogenic not specified 2019-06-26 criteria provided, single submitter clinical testing The PTPN11 c.1471C>T; p.Pro491Ser variant (rs397507539) is reported in the literature in multiple individuals affected with Noonan syndrome (Aoki 2008, Rasmussen 2008, Tartaglia 2006, van Trier 2016). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism, and it is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 40550). The proline at codon 491 is highly conserved, and functional assays suggest this variant causes increased phosphatase activity of the PTPN11 protein (Edwards 2014). Additionally, other amino acid substitutions at this codon (p.Pro491His, p.Pro491Leu, p.Pro491Phe) have been reported in individuals with Noonan syndrome and are considered disease-causing (Aoki 2008, Binder 2005, Schuettpelz 2009, Tartaglia 2006). Based on available information, the p.Pro491Ser variant is considered to be pathogenic. References: Aoki Y et al. The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders. Hum Mutat. 2008 Aug;29(8):992-1006. Binder G et al. PTPN11 mutations are associated with mild growth hormone resistance in individuals with Noonan syndrome. J Clin Endocrinol Metab. 2005 Sep;90(9):5377-81. Edwards JJ et al. A PTPN11 allele encoding a catalytically impaired SHP2 protein in a patient with a Noonan syndrome phenotype. Am J Med Genet A. 2014 Sep;164A(9):2351-5. Rasmussen KJ et al. Bile duct anomalies in a male child with Noonan syndrome: a case for ras and notch pathway synergism. Am J Med Genet A. 2008 Jan 15;146A(2):261-3. Schuettpelz LG et al. Pilocytic astrocytoma in a child with Noonan syndrome. Pediatr Blood Cancer. 2009 Dec;53(6):1147-9. 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. van Trier DC et al. Ocular Manifestations of Noonan Syndrome: A Prospective Clinical and Genetic Study of 25 Patients. Ophthalmology. 2016 Oct;123(10):2137-46.
Baylor Genetics RCV000033536 SCV000196652 pathogenic Rasopathy no assertion criteria provided clinical testing Variant classified using ACMG guidelines
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000157010 SCV000206737 pathogenic Noonan syndrome 2013-12-26 no assertion criteria provided clinical testing
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000984919 SCV001132827 pathogenic Noonan syndrome 1 2019-01-29 no assertion criteria provided clinical testing

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