ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.328G>A (p.Glu110Lys) (rs397507518)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000033484 SCV000057389 pathogenic not provided 2016-03-08 criteria provided, single submitter clinical testing The E110K missense variant in the PTPN11 gene has been reported in association with Noonan syndrome (Ezquieta et al., 2012). This variant has been seen previously at GeneDx in other unrelated individuals. The E110K variant lies within the highly conserved N-SH2 domain of the SHP2 protein encoded by PTPN11. This domain is the first of two sites involved in switching the protein between its inactive and active conformations. Additionally, another missense variant at this position, E110A, has been reported previously in association with autosomal dominant Noonan syndrome (Zenker et al., 2004).
Integrated Genetics/Laboratory Corporation of America RCV000589214 SCV000698075 likely pathogenic Noonan syndrome 3 2016-03-14 criteria provided, single submitter clinical testing
Invitae RCV000815390 SCV000955840 pathogenic Rasopathy 2018-08-27 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 110 of the PTPN11 protein (p.Glu110Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Noonan syndrome in the literature, including at least one individual where the variant was reported de novo (PMID: 22465605, 24150203, 24451042). ClinVar contains an entry for this variant (Variation ID: 40507). 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"). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037645 SCV000061307 pathogenic Noonan syndrome 2014-11-21 criteria provided, single submitter clinical testing The p.Glu110Lys variant in PTPN11 has been previously identified in three indivi duals with clinical features of Noonan syndrome (Ezquieta 2012, Rodriguez 2014, LMM unpublished data) and was reported to have occurred de novo in two of these individuals (Ezquieta 2012, LMM unpublished data). It was absent from large popu lation studies (http://evs.gs.washington.edu/EVS/; dbSNP rs397507518). In summar y, the p.Glu110Lys variant in PTPN11 meets our criteria to be classified as path ogenic (http://personalizedmedicine.partners.org/Laboratory-For-Molecular-Medici ne/).

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