ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.178G>A (p.Gly60Ser) (rs397507507)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000157700 SCV000057363 pathogenic not provided 2019-12-30 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 22465605, 23624134)
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000151684 SCV000199992 pathogenic Noonan syndrome 2017-07-31 criteria provided, single submitter clinical testing The p.Gly60Ser variant in PTPN11 has been previously identified in three individ uals with clinical features of Noonan syndrome (Ezquieta 2012, LMM unpublished d ata), was noted to have occurred de novo in one individual, and was absent from large population studies. In addition, several other amino acid changes at this position (p.Gly60Ala, p.Gly60Cys, p.Gly60Val) have been observed in individuals with clinical features of Noonan syndrome, suggesting that changes to this resid ue are not tolerated. In summary, this variant meets our criteria to be classifi ed as pathogenic for Noonan syndrome in an autosomal dominant manner based on it s de novo occurrence, absence from large population databases and multiple varia nts affecting this codon in individuals with features of Noonan syndrome.
Invitae RCV001219186 SCV001391111 pathogenic Rasopathy 2019-05-17 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 60 of the PTPN11 protein (p.Gly60Ser). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with clinical features of Noonan syndrome (PMID: 22465605). ClinVar contains an entry for this variant (Variation ID: 40490). 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). This variant disrupts the p.Gly60 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16643459, 11992261, 24039098, 17020470, 26817465). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Greenwood Genetic Center Diagnostic Laboratories,Greenwood Genetic Center RCV000157700 SCV000207686 likely pathogenic not provided 2015-01-15 no assertion criteria provided clinical testing

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