ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.1472C>T (p.Pro491Leu) (rs397507540)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254685 SCV000057443 pathogenic not provided 2018-05-22 criteria provided, single submitter clinical testing The P491L pathogenic variant in the PTPN11 gene has been reported previously in association with Noonan syndrome (Binder et al., 2005), and has been observed as a de novo change in patients referred to GeneDx for testing. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. P491L is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position within the tyrosine-protein phosphatase domain that is conserved across species. Although in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function, missense variants at the same residue (P491S/T/H) 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. Additionally, the PTPN11 gene has a low rate of benign missense variation with missense variants being a common mechanism of disease.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000156989 SCV000203905 pathogenic Noonan syndrome 2018-04-30 criteria provided, single submitter clinical testing The p.Pro491Leu variant in PTPN11 has been reported in >10 individuals with clin ical features of Noonan syndrome, including apparently de novo occurrences in 1 individual with Noonan syndrome and 1 individual with Noonan syndrome and non-Ho dgkin lymphoma (Binder 2005, Merks 2005, Chan 2006, Tartaglia 2006, Jongmans 201 1, Digilio 2012, Bertelloni 2013, LMM data, ClinVar Variation ID 40552). It also segregated in at least 3 affected relatives of two families (Binder 2005, Digil io 2012). Additionally, the p.Pro491Leu variant has been reported as a somatic c hange in individuals with acute lymphoblastic leukemia (ALL; Tartaglia 2004). Th is variant was absent from large population studies. Finally, several different variants at position 491 (p.Pro491Ala, p.Pro491Thr, p.Pro491His, p.Pro491Ser, an d p.Pro491Phe) have been identified in individuals with Noonan syndrome (LMM dat a, ClinVar), suggesting that changes at this position are not tolerated. In summ ary, this variant meets criteria to be classified as pathogenic for Noonan syndr ome in an autosomal dominant manner. ACMG/AMP criteria applied: PS4, PM5_Strong , PM2, PP1, PP2.
Invitae RCV000033538 SCV000659033 pathogenic Rasopathy 2019-12-04 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 491 of the PTPN11 protein (p.Pro491Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (rs397507540, ExAC no frequency). This variant has been reported in several families and individuals affected with Noonan syndrome (PMID: 15985475, 22781091, 23624134, 20186801, 18470943). ClinVar contains an entry for this variant (Variation ID: 40552). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Pro491Ser) has been determined to be pathogenic (PMID: 19077116, 16358218, 17020470, 22465605). This suggests that the proline residue is critical for PTPN11 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000033538 SCV000698056 pathogenic Rasopathy 2016-06-17 criteria provided, single submitter clinical testing Variant summary: The PTPN11 c.1472C>T (p.Pro491Leu) variant involves the alteration of a conserved nucleotide. 3/3 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index, Polyphen-2 not functioning at the time of scoring). This variant has been reported in numerous NS patients and is absent in 121408 control chromosomes. At least one reported de novo case has been published (Chan_2006). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Furthermore, P491S, P491T, and P491H have been classified as pathogenic in ClinVar, suggesting P491 is a mutation hot spot. Taken together, this variant is classified as pathogenic.
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery,Institute of Otolaryngology, Chinese PLA General Hospital RCV001002769 SCV000992413 pathogenic Noonan syndrome 1 criteria provided, single submitter case-control
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001490 SCV001158769 pathogenic not specified 2019-06-24 criteria provided, single submitter clinical testing The PTPN11 c.1472C>T; p.Pro491Leu variant (rs397507540) is reported in the literature in multiple individuals affected with Noonan syndrome (Aoki 2008, Ezquieta 2012, Jongmans 2011, Merks 2005, Pierpont 2010, Tartaglia 2006). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 40552), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The proline at codon 491 is highly conserved, and computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. However, other amino acid substitutions at this codon (Ser, His, Thr, Phe) have been reported in individuals with Noonan syndrome and are considered pathogenic (Aoki 2008, Ezquieta 2012, Jongmans 2011, Pierpont 2010, Tartaglia 2006). Based on available information, this 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. Ezquieta B et al. Alterations in RAS-MAPK genes in 200 Spanish patients with Noonan and other neuro-cardio-facio-cutaneous syndromes. Genotype and cardiopathy. Rev Esp Cardiol (Engl Ed). 2012 May;65(5):447-55. Jongmans MC et al. Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation. Eur J Hum Genet. 2011 Aug;19(8):870-4. Merks JH et al. High incidence of malformation syndromes in a series of 1,073 children with cancer. Am J Med Genet A. 2005 Apr 15;134A(2):132-43. Pierpont EI et al. Effects of germline mutations in the Ras/MAPK signaling pathway on adaptive behavior: cardiofaciocutaneous syndrome and Noonan syndrome. Am J Med Genet A. 2010 Mar;152A(3):591-600. 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000156989 SCV000206712 pathogenic Noonan syndrome 2011-08-20 no assertion criteria provided clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000156989 SCV000805104 pathogenic Noonan syndrome 2016-02-24 no assertion criteria provided clinical testing

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