ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.802G>T (p.Gly268Cys) (rs397507527)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000033502 SCV000057407 pathogenic not provided 2017-11-24 criteria provided, single submitter clinical testing The G268C missense variant has been previously reported in association with a PTPN11-related disorder (Tartaglia et al., 2006) and observed de novo in patients tested at GeneDx. It 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. G268C is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other 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. Additionally, a missense variant at the same residue (G268S) has 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 RCV000037660 SCV000061322 likely pathogenic Noonan syndrome 2014-07-15 criteria provided, single submitter clinical testing The Gly268Cys variant in PTPN11 has been reported in two individuals with clinic al features of Noonan syndrome (Tartaglia 2006, LMM unpublished data), and is ab sent from large population studies. In addition, a second variant at this codon (Gly268Ser) has been identified in three affected individuals and segregated wit h disease in one of these individuals (Tartaglia 2006, Papadopoulou 2012), sugge sting that changes to this residue are not tolerated. Furthermore, glycine (Gly) at this position is highly conserved cross evolutionarily distant species and c omputational prediction tools suggest that the Gly268Cys variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, the Gly268Cys variant is likely pathogenic.
Invitae RCV000703823 SCV000832744 pathogenic Rasopathy 2018-06-25 criteria provided, single submitter clinical testing This sequence change replaces glycine with cysteine at codon 268 of the PTPN11 protein (p.Gly268Cys). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and cysteine. This variant is present in population databases (rs397507527, ExAC 0.01%). This variant has been observed in individuals affected with Noonan syndrome (PMID: 16358218, 26785492, 22465605). In a number of these individuals, the variant was reported to be de novo (PMID: 26785492, 22465605). ClinVar contains an entry for this variant (Variation ID: 40523). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). The p.Gly268 amino acid residue in PTPN11 has been determined to be clinically significant (PMID: 21590266, 16358218). This suggests that variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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