ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.802G>A (p.Gly268Ser) (rs397507527)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037659 SCV000061321 likely pathogenic Noonan syndrome 2015-09-29 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000159050 SCV000208992 likely pathogenic not provided 2018-06-28 criteria provided, single submitter clinical testing The G268S likely pathogenic variant has been previously reported in association with a PTPN11- related disorder (Tartaglia et al., 2006). 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. G268S 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; however, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A missense variant at the same residue (G268C) has been reported in association with Noonan syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000587886 SCV000698080 likely pathogenic Rasopathy 2016-01-13 criteria provided, single submitter clinical testing Variant summary: The c.802G>A variant affects a conserved nucleotide, resulting in amino acid change from Gly to Ser. 4/4 in-silico tools used predict damaging outcome for this variant. The variant has been reported in one family co-segregating with NS (Tartaglia_2006). It has also been reported in another NS patient (Joyce_2015). This variant is found in 1/120020 control chromosomes (including large and broad populations from ExAC) at a frequency of 0.0000083, which does not exceed the maximal expected frequency of a pathogenic allele (0.0000625) in this gene. Multiple clinical laboratories have classified this variant as likely pathogenic/pathogenic. Moreover, p.Gly268Cys has also been classified as likely pathogenic/pathogenic by multiple clinical laboratories (via ClinVar), suggesting that p.Gly268 residue is important for PTPN11 function. Taken together, this variant has currently been classified as a Proabable Disease Variant/Likely Pathogenic.

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