ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.317A>C (p.Asp106Ala) (rs397507517)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000157021 SCV000206748 pathogenic Noonan syndrome 2009-10-25 no assertion criteria provided clinical testing
Baylor Miraca Genetics Laboratories, RCV000033483 SCV000196663 pathogenic Rasopathy no assertion criteria provided clinical testing Variant classified using ACMG guidelines
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000157021 SCV000805101 pathogenic Noonan syndrome 2015-06-25 no assertion criteria provided clinical testing
GeneDx RCV000212893 SCV000057388 pathogenic not provided 2018-10-11 criteria provided, single submitter clinical testing The D106A missense variant in the PTPN11 gene has been reported previously in association with Noonan syndrome (Tartaglia et al., 2002). Additionally, this variant was observed as apparently de novo in a patient with a clinical diagnosis of Noonan syndrome previously tested at GeneDx. This variant is not observed in large population cohorts (Lek et al., 2016). The D106A variant lies in the linker region between the NSH2 and C-SH2 domains 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. Functional studies have shown D106A increases the activated activity level of the PTPN11 protein in comparison to wild-type (Keilhack et al., 2005). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. In summary, we consider this variant to be pathogenic.
Invitae RCV000033483 SCV000549987 pathogenic Rasopathy 2018-05-14 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with alanine at codon 106 of the PTPN11 protein (p.Asp106Ala). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been identified in 2-5% of all individuals reported in the literature with Noonan syndrome (PMID: 18470943, 12717436). ClinVar contains an entry for this variant (Variation ID: 40506). Experimental studies and structural modeling of the PTPN11 protein indicate that this missense change increases activity most likely due to misfolding of the inter-SH2 domain linker (PMID: 15987685, 18286234). In summary, this variant is a rare missense change that is preferentially found in patients with disease and has been demonstrated to increase activity of the PTPN11 protein. For these reasons, it has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000157021 SCV000061306 pathogenic Noonan syndrome 2017-05-16 criteria provided, single submitter clinical testing p.Asp106Ala, c.317A>C (PTPN11; NM_002834.3; Chr12g.112888301A>C; GRCh37): The p. Asp106Ala variant in PTPN11 has been reported in >10 individuals with clinical f eatures of Noonan syndrome with or without multiple giant-cell lesions (Tartagli a 2002, Bertola 2006, Tartaglia 2006, Hung 2007, Shaw 2007, Pierpont 2009, Steve nson 2010, LMM data). It has not been identified in large population studies. In vitro functional studies provide some evidence that the p.Asp106Ala variant may impact protein function (Keilhack 2005, Lee 2010). In summary, this variant mee ts criteria to be classified as pathogenic for Noonan syndrome in an autosomal d ominant manner based upon prevalence in affected individuals, extremely low freq uency in the general population, and supportive functional evidence.

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