ClinVar Miner

Submissions for variant NM_002834.5(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
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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000157021 SCV000061306 pathogenic Noonan syndrome 2019-12-20 criteria provided, single submitter clinical testing The p.Asp106Ala variant in PTPN11 has been reported in >10 individuals with Noonan syndrome-related disorders and non-immune hydrops fetalis. It segregated with disease in 2 affected individuals from 1 family (Tartaglia 2002, Bertola 2006, Tartaglia 2006, Hung 2007, Shaw 2007, Pierpont 2009, Stevenson 2010, Leach 2019, Sparks 2019). It has additionally been observed at the Laboratory for Molecular Medicine in 7 individuals, 5 with Noonan syndrome-like features and 1 with pulmonary stenosis. The variant was found to be de novo in 1 case (LMM Data). This variant was also observed de novo in a patient with Noonan syndrome tested by GeneDx (Clinvar Variation ID: 40506, Accession: SCV000057388.14). It was absent from large population studies. In vitro functional studies provide some evidence that the p.Asp106Ala variant may impact protein function (Keilhack 2005, Chan 2008, Lee 2010). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Noonan syndrome-related disorders. ACMG/AMP Criteria applied: PS4, PM6_Strong, PM2, PP3, PS3_Supporting.
Invitae RCV000033483 SCV000549987 pathogenic Rasopathy 2019-04-28 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.
Baylor Genetics RCV000033483 SCV000196663 pathogenic Rasopathy no assertion criteria provided clinical testing Variant classified using ACMG guidelines
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000157021 SCV000206748 pathogenic Noonan syndrome 2009-10-25 no assertion criteria provided clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000157021 SCV000805101 pathogenic Noonan syndrome 2015-06-25 no assertion criteria provided clinical testing

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