ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.209A>G (p.Lys70Arg) (rs397516801)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000206837 SCV001424748 pathogenic Rasopathy 2020-06-25 reviewed by expert panel curation The c.2019A>G (p.Lys70Arg) variant in PTPN11 was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). It has been identified in at least 6 probands with Noonan syndrome (PS4; SCV000061296.6; PMID: 29084544).One case was described as an unconfirmed de novo occurrence (PM6; PMID: 29084544). It has been reported to segregate with clinical features of a RASopathy in at least 3 family members (PP1; SCV000061296.6). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID: 29493581). Finally, PTPN11 has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4, PM6, PM1, PM2, PP1, PP2.
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 pathogenic Rasopathy 2019-09-09 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 moderately conserved and there is a small physicochemical difference between lysine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with Noonan syndrome (PMID: 29084544). ClinVar contains an entry for this variant (Variation ID: 44603). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This missense change is located in a region of the PTPN11 protein where a significant number of previously reported PTPN11 missense mutations are found (PMID: 16377799). These observations suggest that a previously unreported missense substitution within this region may affect protein function, but experiments have not been done to test this possibility. For these reasons, this variant has been classified as 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.
Integrated Genetics/Laboratory Corporation of America RCV000206837 SCV001426844 pathogenic Rasopathy 2020-07-08 criteria provided, single submitter clinical testing Variant summary: PTPN11 c.209A>G (p.Lys70Arg) results in a conservative amino acid change located in the SH2 domain (IPR000980) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251054 control chromosomes (gnomAD). c.209A>G has been reported in the literature in individuals affected with and/or undergoing diagnostic evaluation for Noonan Syndrome And Related Conditions (e.g. Leach_2019, Xu_2017). At least one case of a confirmed de novo occurrence in an individual with Noonan syndrome has been reported (Xu_2017). In addition, a ClinVar submitter reports the variant in at least 5 individuals with clinical features of a RASopathy, including segregation with disease in 3 affected relatives (SCV000061296.6). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=2)/likely pathogenic (n=2). Some submitters cite overlapping evidence utilized in the context of this evaluation. Recently the ClinGen RASopathy Variant Curation Expert Panel settled on a classification of Pathogenic for this variant (personal communication, June 2020). Based on the evidence outlined above, the variant was re-classified as pathogenic.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000037634 SCV001132685 likely pathogenic Noonan syndrome 2019-12-26 no assertion criteria provided clinical testing

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