ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.209A>G (p.Lys70Arg) (rs397516801)

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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 RCV000037634 SCV000061296 pathogenic Noonan syndrome 2018-05-02 criteria provided, single submitter clinical testing The p.Lys70Arg variant in PTPN11 has been identified in >5 individuals with clin ical features of a RASopathy, including confirmed de novo inheritance in 1 indiv idual, and segregated with disease in 3 affected relatives (LMM data, Xu 2017). This variant was absent from large population studies and is reported in ClinVar (Variation ID: 44603). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. This var iant is located in the directly interacting residues between N-SH2 and the PTPN domains, where pathogenic missense variants are common. In summary, this variant meets criteria to be classified as pathogenic for Noonan syndrome in an autosom al dominant manner based upon presence in affected individuals, de novo observat ion, segregation with disease, and absence from controls. ACMG/AMP Criteria appl ied: PS4, PM1, PM2, PM6, PP1.
Invitae RCV000206837 SCV000261103 likely pathogenic Rasopathy 2015-10-06 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 70 of the PTPN11 protein (p.Lys70Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. This sequence change has not been published in the literature and is not present in population databases. This change has been identified in 5 affected individuals and segregates with symptoms of Noonan syndrome in one family. ClinVar contains an entry for this variant (Variation ID: 44603). 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: "possibly damaging"; Align-GVGD: "Class C0"). This missense change is located within a functionally conserved N-SH2 domain of the PTPN11 protein (PMID: 24628801) and a significant number of previously reported PTPN11 missense mutations have been found within this domain (PMID: 16377799). These observations suggest that a novel missense substitution within this domain may affect protein function, although experiments have not been done to test this possibility. In summary, this is a rare missense change that has been reported in several individuals with Noonan syndrome and is not seen in the general population. For these reasons, it has been classified as Likely Pathogenic.
GeneDx RCV000405696 SCV000329577 likely pathogenic not provided 2018-07-13 criteria provided, single submitter clinical testing The K70R variant has been reported previously as a de novo variant in association with Noonan syndrome and in multiple probands tested at clinical laboratories (Xu et al., 2017, internal data, ClinVar: SCV000261103.1, SCV000061296.4; Landrum et al., 2016). The variant is not observed in large population cohorts (Lek et al., 2016). Missense variants in nearby residues (E69Q, F71I/L, A72P/S/G) have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. The K70R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, but in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We consider this variant to be likely pathogenic.

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