ClinVar Miner

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

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Total submissions: 9
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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
Human Genetics - Radboudumc,Radboudumc RCV000159050 SCV001979627 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000159050 SCV001980552 pathogenic not provided no assertion criteria provided clinical testing
PerkinElmer Genomics RCV000159050 SCV002019556 pathogenic not provided 2021-09-15 no assertion criteria provided clinical testing

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