ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.317A>C (p.Asp106Ala) (rs397507517)

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Total submissions: 7
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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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001282225 SCV000206748 pathogenic none provided 2020-02-07 criteria provided, single submitter clinical testing The PTPN11 c.317A>C; p.Asp106Ala variant (rs397507517) is reported in the literature in multiple individuals affected with Noonan syndrome (Bertelloni 2013, Hung 2007, Leach 2019, Pierpont 2009, Shaw 2007, Stevenson 2011, Tartaglia 2002). This variant is also reported in ClinVar (Variation ID: 40506), but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The aspartic acid at codon 106 is moderately conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: possibly damaging) predict conflicting effects of this variant on protein structure/function. Functional analyses of the variant protein show hyperactivation upon peptide addition (Keilhack 2005). Additionally, another variant at this codon (c.317A>G; p.Asp106Gly) has been reported in individuals with Noonan syndrome (Bertelloni 2013). Based on available information, the p.Asp106Ala variant is considered to be pathogenic. References: Bertelloni S et al. IGF-I generation test in prepubertal children with Noonan syndrome due to mutations in the PTPN11 gene. Hormones (Athens). 2013 Jan-Mar;12(1):86-92. Hung CS et al. Mutational analysis of PTPN11 gene in Taiwanese children with Noonan syndrome. J Formos Med Assoc. 2007 Feb;106(2):169-72. Keilhack H et al. Diverse biochemical properties of Shp2 mutants. Implications for disease phenotypes. J Biol Chem. 2005 Sep 2;280(35):30984-93. Leach NT et al. Comparative assessment of gene-specific variant distribution in prenatal and postnatal cohorts tested for Noonan syndrome and related conditions. Genet Med. 2019 Feb;21(2):417-425. Pierpont EI et al. Genotype differences in cognitive functioning in Noonan syndrome. Genes Brain Behav. 2009 Apr;8(3):275-82. Shaw AC et al. The natural history of Noonan syndrome: a long-term follow-up study. Arch Dis Child. 2007 Feb;92(2):128-32. Stevenson DA et al. Bone resorption in syndromes of the Ras/MAPK pathway. Clin Genet. 2011 Dec;80(6):566-73. Tartaglia M et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002 Jun;70(6):1555-63.
Invitae RCV000033483 SCV000549987 pathogenic Rasopathy 2020-06-02 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.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV001261998 SCV001439361 pathogenic Noonan syndrome 1 2020-07-09 criteria provided, single submitter research ACMG codes:PS3; PS4; PM1; PM2; PP2; PP3
Baylor Genetics 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

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