ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.155C>T (p.Thr52Ile) (rs397507503)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000037621 SCV000616407 likely pathogenic Noonan syndrome 2017-04-03 reviewed by expert panel curation The c.155C>T (p.Thr52Ile) variant in PTPN11 has been identified in at least 5 independent occurrences in patients with a RASopathy (PS4_Moderate; PMID: 22465605, 25804457, GeneDx, Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg internal data; GTR ID's: 26957, 21766, 506381; SCV000057357.11; SCV000061283.5). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Thr52Ile variant may impact the protein (PP3). 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). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Moderate, PM2, PP3, PP2.
GeneDx RCV000033452 SCV000057357 uncertain significance not provided 2020-06-15 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often 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: 32059087, 25804457, 22465605, 31366893)
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037621 SCV000061283 likely pathogenic Noonan syndrome 2016-02-11 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Invitae RCV000809051 SCV000949188 uncertain significance Rasopathy 2018-08-17 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 52 of the PTPN11 protein (p.Thr52Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in at least one individual with a suspected diagnosis of Noonan or Cardiofaciocutaneous (CFC) syndrome (PMID: 22465605, Collazo et al., 2012). This variant has also been reported in individuals affected with Noonan syndrome (PMID: 25804457). ClinVar contains an entry for this variant (Variation ID: 40484). 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"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Service de Génétique Moléculaire,Hôpital Robert Debré RCV000037621 SCV001438499 uncertain significance Noonan syndrome no assertion criteria provided clinical testing

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