ClinVar Miner

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

dbSNP: 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, 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 2022-04-28 criteria provided, single submitter clinical testing Not observed in large population cohorts (gnomAD); 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; Identified in association with pulmonary stenosis and Noonan syndrome (Ezquieta et al., 2012; Gulec et al., 2015; Lazzaro et al., 2020); This variant is associated with the following publications: (PMID: 25804457, 22465605, 31366893, 32059087)
Laboratory for Molecular Medicine,Mass General Brigham 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 likely pathogenic RASopathy 2021-12-18 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 52 of the PTPN11 protein (p.Thr52Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Noonan syndrome (PMID: 22465605, 25804457; Invitae). ClinVar contains an entry for this variant (Variation ID: 40484). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PTPN11 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Service de Génétique Moléculaire,Hôpital Robert Debré RCV000037621 SCV001438499 uncertain significance Noonan syndrome no assertion criteria provided clinical testing

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