ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.179G>C (p.Gly60Ala) (rs397507509)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000033461 SCV000057366 pathogenic not provided 2019-01-11 criteria provided, single submitter clinical testing The G60A missense pathogenic variant in the PTPN11 gene has been reported previously as de novo and in association with Noonan syndrome (Roti et al., 2006; Tartaglia et al., 2002; Bertola et al., 2006; Jongmans et al., 2011). The G60A variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position in the N-SH2 domain that is conserved across species and is a hot spot for pathogenic variants as missense variants in the same residue (G60S/C) and in nearby residues (N58D/H/K, T59A, D61N/H/A/G) have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014). Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function, further supporting the functional importance of this region of the protein.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037631 SCV000061293 pathogenic Noonan syndrome 2015-07-09 criteria provided, single submitter clinical testing The p.Gly60Ala variant has been reported in >20 individuals with clinical featur es of Noonan syndrome (Tartaglia 2002, Binder 2005, Bertola 2006, Limal 2006, Ta rtaglia 2006, Roti 2006, Mutesa 2008, Noordam 2008, Jongmans 2011, Ross 2014, LM M unpublished data) but not identified in large population studies. This variant occurred de novo in at least one of the affected individuals (Roti 2006). In ad dition, this variant has been reported in two individuals with clinical features of Noonan syndrome and a central nervous system tumor (neuroblastoma, Mutesa 20 08; dysembryoplastic neuroepithelia tumor, Jongmans 2011) and as a somatic chang e in AML (Loh 2004). In summary, this variant meets our criteria to be classifie d as pathogenic for Noonan syndrome in an autosomal dominant manner based on its frequency in affected individuals, de novo occurrence, and absence from control s.
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000416546 SCV000494452 pathogenic Noonan syndrome 1 2016-06-08 criteria provided, single submitter clinical testing
Invitae RCV000459297 SCV000549986 pathogenic Rasopathy 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 60 of the PTPN11 protein (p.Gly60Ala). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals with Noonan syndrome (NS) (PMID: 11992261, 24039098, 17020470, 26817465, 18328949). In one individual with NS and acute lymphoblastic leukemia, it was reported to be de novo (not present in either parent) (PMID: 16643459). ClinVar contains an entry for this variant (Variation ID: 40493). 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: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics, Inc RCV000416546 SCV000782247 pathogenic Noonan syndrome 1 2016-11-01 criteria provided, single submitter clinical testing

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