ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.1502G>A (p.Arg501Lys) (rs397507543)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000033541 SCV000057446 pathogenic not provided 2021-07-19 criteria provided, single submitter clinical testing Identified in several unrelated patients with Noonan syndrome in published literature (Tartaglia et al., 2002; Limal et al., 2006; Noordam et al., 2008; Jefferies et al., 2010); 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: 27535533, 31134136, 18562489, 18470943, 16263833, 11992261, 24803665, 19795160)
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037618 SCV000061280 pathogenic Noonan syndrome 2016-01-26 criteria provided, single submitter clinical testing The p.Arg501Lys variant in PTPN11 has been reported in >10 individuals with the clinical features of Noonan syndrome and segregated with disease in 1 affected r elative (Tartaglia 2002, Limal 2006, Noordam 2008, Jefferies 2010, LMM unpublish ed data). It has not been identified in large population studies. In summary, th is variant meets our criteria to be classified as pathogenic for Noonan syndrome in an autosomal dominant manner based upon presence in multiple affected indivi duals, segregation studies, and absence in the general population.
Invitae RCV000466382 SCV000549998 pathogenic Rasopathy 2020-03-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 501 of the PTPN11 protein (p.Arg501Lys). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in 4 individuals with Noonan syndrome (PMID: 16263833, 18470943, 18562489, 19795160, 11992261). ClinVar also contains an entry for this variant (Variation ID: 40555) with at least 7 additional observations of this variant in individuals with Noonan syndrome. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. However, this variant is not present in the population databases and has been observed in more than ten individuals with Noonan syndrome. For these reasons, this variant has been classified Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000466382 SCV001554571 pathogenic Rasopathy 2021-03-25 criteria provided, single submitter clinical testing Variant summary: PTPN11 c.1502G>A (p.Arg501Lys) results in a conservative amino acid change located in the PTP type protein phosphatase domain (IPR000242) 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 251492 control chromosomes. c.1502G>A has been widely reported in the literature in individuals affected with Noonan Syndrome (example, Tartaglia_2002, Limal_2006, Aoki_2008, Noordam_2008, Jefferies_2010). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories,Mayo Clinic RCV000033541 SCV001714430 pathogenic not provided 2020-07-16 criteria provided, single submitter clinical testing PS4, PM2, PP3, PP2
Institute of Human Genetics, University Hospital Muenster RCV001800333 SCV002047380 pathogenic Epicanthus; Short stature; Abnormality of cardiovascular system morphology; Abnormality of the pinna; Wide nasal bridge; Microcephaly; Depressed nasal ridge 2021-12-13 criteria provided, single submitter clinical testing ACMG categories: PM1,PM2,PP3,PP4,PP5
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000033541 SCV001977744 pathogenic not provided no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000033541 SCV001978659 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000033541 SCV001979338 pathogenic not provided no assertion criteria provided clinical testing

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