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

dbSNP: rs397507503

Total submissions: 6

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	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	2023-01-15	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 40484). 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. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTPN11 function. This missense change has been observed in individuals with clinical features of Noonan syndrome (PMID: 22465605, 25804457; Invitae). This variant is not present in population databases (gnomAD no frequency). 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).
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	RCV002287349	SCV002578163	likely pathogenic	Noonan syndrome 1	2022-09-27	criteria provided, single submitter	clinical testing
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV000037621	SCV001438499	uncertain significance	Noonan syndrome		no assertion criteria provided	clinical testing