ClinVar Miner

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

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Total submissions: 6
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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 2021-05-26 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26203125, 16358218, 32164556, 26242988, 24803665, 25722345, 12717436, 21590266, 18470943)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Baylor Genetics RCV001330780 SCV001522577 pathogenic LEOPARD syndrome 1 2019-09-09 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Invitae RCV000587886 SCV001592599 pathogenic Rasopathy 2020-08-26 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 268 of the PTPN11 protein (p.Gly268Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Noonan syndrome (PMID: 32164556, 26242988, 21590266). ClinVar contains an entry for this variant (Variation ID: 44614). This variant disrupts the p.Gly268 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26785492, 22465605). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV000159050 SCV001832514 likely pathogenic not provided 2020-03-11 criteria provided, single submitter clinical testing

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