ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.844A>G (p.Ile282Val) (rs397507529)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000077860 SCV000057410 pathogenic not provided 2018-12-07 criteria provided, single submitter clinical testing The I282V variant in the PTPN11 gene has been reported previously in multiple unrelated individuals with Noonan syndrome (Tartaglia et al., 2001; Jongmans et al., 2011). In addition, I282V has been observed several times at GeneDx as de novo. The I282V variant is not observed in large population cohorts (Lek et al., 2016). This variant occurs within the highly conserved phosphotyrosine phosphatase (PTP) domain, and in vitro studies show that I282V exhibits a gain-of-function effect on the protein (Fragale et al., 2004; Martinelli et al., 2008). Other pathogenic variants in this residue (I282T, I282M) and in nearby residues (Y279C, Y279S, F285L, F285I, F285C, F285S) have been reported in the Human Gene Mutation Database in association with PTPN11-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpretI282V as a pathogenic variant
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000824745 SCV000204070 pathogenic Noonan syndrome with multiple lentigines; Noonan syndrome 2014-05-09 criteria provided, single submitter clinical testing The p.Ile282Val variant in PTPN11 has been reported in >20 individuals with clin ical features of Noonan syndrome or LEOPARD syndrome (Tartaglia 2001, Tartaglia 2002, Mustane 2003, Binder 2005, Tartaglia 2006, Jongmans 2011, LMM unpublished data), and is absent from large population studies. In addition, functional evid ence suggests that this variant increases the activity of the PTPN11 protein, wh ich is consistent with other pathogenic variants in PTPN11 (Fragale 2004, Tartag lia 2006, Martinelli 2008). In summary, this variant meets our criteria to be cl assified as pathogenic for Noonan syndrome and LEOPARD syndrome in an autosomal dominant manner (http://www.partners.org/personalizedmedicine/LMM).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000077860 SCV000232165 pathogenic not provided 2015-01-09 criteria provided, single submitter clinical testing
Invitae RCV000033505 SCV000549995 pathogenic Rasopathy 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 282 of the PTPN11 protein (p.Ile282Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in many individuals with Noonan syndrome (PMID: 11704759, 21407260, 15834506, 19077116). ClinVar contains an entry for this variant (Variation ID: 40525). Multiple experimental studies have demonstrated that this missense change mildly decreases the stability of the inhibitory N-SH2/PTP intramolecular interaction, and significantly increases the basal phosphatase activity, thereby resulting in a constitutively activated PTPN11 protein (PMID: 14974085, 18372317, 15834506). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000033505 SCV000698081 pathogenic Rasopathy 2016-04-25 criteria provided, single submitter clinical testing Variant summary: The PTPN11 c.844A>G variant affects a conserved nucleotide, resulting in an amino acid change from Ile to Val in functionally important protein tyrosine phosphatase (PTP) domain. 2/4 in-silico tools predict this variant to be damaging, and published functional studies are consistent with the variant being an activating mutation; gain of function is a known molecular mechanism in Noonan Syndrome. This variant was not found in approximately 118834 control chromosomes; however, the variant is a known recurrent pathogenic mutation causing Noonan Syndrome reported in the literature. It has been reported in sporadic as well as familial Noonan cases. Additionally, multiple clinical laboratories have classified this variant as pathogenic. Taken together, this variant has been classified as a Disease Variant/Pathogenic.
Ambry Genetics RCV000624312 SCV000742053 pathogenic Inborn genetic diseases 2016-12-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Blueprint Genetics RCV000077860 SCV000927936 pathogenic not provided 2018-09-14 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000077860 SCV001246731 pathogenic not provided 2018-10-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197977 SCV001368762 pathogenic Rare genetic syndrome 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS3,PM2,PP5. This variant was detected in homozygous state.

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