ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.205G>C (p.Glu69Gln) (rs397507511)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Miraca Genetics Laboratories, RCV000033469 SCV000196658 pathogenic Rasopathy no assertion criteria provided clinical testing Variant classified using ACMG guidelines
Blueprint Genetics RCV000212889 SCV000927162 pathogenic not provided 2017-02-20 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000212889 SCV000861034 pathogenic not provided 2018-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000212889 SCV000057374 pathogenic not provided 2018-07-23 criteria provided, single submitter clinical testing The E69Q missense change in the PTPN11 gene has been reported previously in association with Noonan syndrome and observed de novo in one family (Musante et al., 2003; Bertelloni et al., 2013; Croonen et al., 2013). This variant has also been observed de novo in patients tested at GeneDx. The E69Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). It is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants at the same (E69V) and in nearby residues (F71I/L, A72P, T73I) have been reported in the Human Gene Mutation Database in association with Noonan syndrome(Stenson et al., 2014), supporting the functional importance of this region of the protein.
Invitae RCV000033469 SCV000659043 pathogenic Rasopathy 2018-07-30 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glutamine at codon 69 of the PTPN11 protein (p.Glu69Gln). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and glutamine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in individuals affected with Noonan syndrome (PMID: 12634870, 26817465, 15001945, 23624134, 23321623, 20186801). In one of these individuals, it was determined to be de novo (PMID: 23321623). ClinVar contains an entry for this variant (Variation ID: 40498). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Glu69Val) has been reported in individuals affected with Noonan syndrome (PMID: 19077116, 20578946, 20186801). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037633 SCV000061295 pathogenic Noonan syndrome 2016-02-11 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory

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