ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.205G>C (p.Glu69Gln) (rs397507511)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000033469 SCV001192883 pathogenic Rasopathy 2019-12-05 reviewed by expert panel curation The c.205G>C (p.Glu69Gln) variant in PTPN11 has been observed in at least 25 probands diagnosed with autosomal dominant Noonan syndrome (NS) across 7 publications and 2 clinical labs (PS4; PMID: 12634870, 15001945, 20186801, 23624134, 25862627, 26607044, 31560489; Invitae internal data, SCV000659043.3; Institut Universitaire d'Hematologie internal data). This variant was identified as de novo in 6 cases and segregated with disease in 1 additional individual in 1 family (PM6_VS, PP1 not met; Institut Universitaire d'Hematologie internal data; Invitae internal data, SCV000659043.3). It has also been identified in 2 additional probands with NS for whom the cDNA change was not specified, as well as 1 de novo prenatal case (PMID: 26817465, 23321623). The p.Glu69Gln variant has also been seen by multiple clinical labs in several probands without a formal diagnosis of NS or another RASopathy. This variant was absent from large population databases (PM2; https://gnomad.broadinstitute.org). It occurs in the N-SH2 domain of the protein, which has been identified as a region important for protein function (PM1; PMID: 29493581). PTPN11 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). Computational prediction tools and conservation analyses suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Noonan syndrome. ACMG/AMP criteria applied: PM6_VS, PS4, PM1, PM2, PP2, PP3.
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.
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
Invitae RCV000033469 SCV000659043 pathogenic Rasopathy 2019-10-30 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000212889 SCV000861034 pathogenic not provided 2018-05-18 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000212889 SCV000927162 pathogenic not provided 2017-02-20 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000033469 SCV001432005 pathogenic Rasopathy 2020-08-17 criteria provided, single submitter clinical testing Variant summary: PTPN11 c.205G>C (p.Glu69Gln) results in a conservative amino acid change located in the SH2 domain (IPR000980) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251636 control chromosomes (gnomAD and publication data). c.205G>C has been reported in the literature in multiple individuals affected with Noonan Syndrome including one individual determined as de novo (Musante_2003, Zenker_2004, Pierpont_2010, Croonen_2013, Atik_2016, Chinton_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014), including one expert panel (ClinGen RASopathy Variant Curation Expert Panel), cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000033469 SCV000196658 pathogenic Rasopathy no assertion criteria provided clinical testing Variant classified using ACMG guidelines

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