ClinVar Miner

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

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000033502 SCV000057407 pathogenic not provided 2021-05-05 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 24803665, 16358218, 26785492, 21590266, 22465605, 28991257)
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variant in PTPN11 has been reported in two individuals with clinic al features of Noonan syndrome (Tartaglia 2006, LMM unpublished data), and is ab sent from large population studies.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.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV001265568 SCV001443727 pathogenic PTPN11 Related Disorders 2019-10-30 criteria provided, single submitter clinical testing This variant has been previously reported in at least three patients with Noonan Syndrome (PMID: 16358218, 26785492, 22465605). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (1/241992) and thus is presumed to be rare. The c.802G>T (p.Gly268Cys) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. ClinVar contains an entry for this variant (Variation ID: 40523). A different amino acid change at the same codon (p.Gly268Ser) has also been identified in individuals with Noonan Syndrome (PMID: 16358218, 26242988, 21590266). Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.802G>T (p.Gly268Cys) variant is classified as Pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens RCV001729355 SCV001976697 pathogenic Noonan syndrome 1 2021-10-01 criteria provided, single submitter clinical testing PM1, PM2, PP2, PP3, PP5

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