ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.1505C>T (p.Ser502Leu) (rs397507544)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000033544 SCV000057449 pathogenic not provided 2018-03-08 criteria provided, single submitter clinical testing The S502L variant has been published as a pathogenic variant in association with Noonan syndrome (Bertola et al., 2006; Ko et al., 2008; Tartaglia et al., 2006). The S502L variant has also been published as a pathogenic variant in association with Noonan syndrome and acute myelogenous leukemia, acute myelogenous leukemia, and acute lymphoblastic leukemia (Aoki et al., 2008; Paulsson et al., 2008; Loh et al., 2004). The S502L variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (S502A/T) are reported in several patients with either Noonan syndrome or Noonan syndrome with myeloproliferative disorder (Tartaglia, 2006). Additionally, missense variants in the nearby residues (R498W/L, R501K, G503R/E/V/A, M504V, Q506P, T507K) have been reported in the Human Gene Mutation Database in association with Noonan-spectrum disorders (Stenson et al., 2014).
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037619 SCV000061281 pathogenic Noonan syndrome 2013-01-15 criteria provided, single submitter clinical testing The Ser502Leu variant has been reported in the literature in two individuals wit h clinical features of Noonan syndrome and/or LEOPARD syndrome (Tartaglia 2006, Ko 2008). Our laboratory has identified this variant in one proband where parent al testing was performed and showed the variant occurred de novo (LMM unpublishe d data). This variant has also been identified as a somatic variant in individua ls with hematologic malignancies including AML and ALL (Goemans 2005, Paulsson 2 007). In addition, three other amino acid changes at this location (Ser502Thr, Ser502Pro, Ser502Ala) have been associated with the clinical features of Noonan syndrome and have also been identified as somatic variants in individuals with h ematologic malignancies (Aoki 2008). The Ser502 residue is conserved across spec ies and computational analyses (biochemical amino acid properties, AlignGVGD, Po lyPhen2, and SIFT) suggest that the Ser502Leu variant may impact the normal func tion of the protein. In summary, this variant meets our criteria to be classifie d as pathogenic ( based upon the de novo occurrenc e combined with available published literature.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781773 SCV000920091 pathogenic Rasopathy 2021-05-31 criteria provided, single submitter clinical testing Variant summary: PTPN11 c.1505C>T (p.Ser502Leu) results in a non-conservative amino acid change located in the Protein-tyrosine phosphatase, catalytic domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Additionally, there are several variants associated with disease at the same codon or surrounding codons (e.g., S502A, S502T, R501K, and G503A), suggesting the region is important for protein function. Serine at position 502 interacts with Glutamate at position 76 in the SH2 domain, leading to autoinhibition of PTPN11, and mutational hotspot variants at Serine 502 or Glutamate 76 were shown to activate PTPN11 (example, Chan_2007, PMID 17053061). The variant was absent in 252092 control chromosomes. c.1505C>T has been reported in the literature in multiple individuals affected with Noonan Syndrome (example, Tartaglia_2006, Bertola_2006, Ezquieta_2012, Strullu_2014, Ko_2008, O'Halloran_2017). At-least one report of a reportedly de-novo occurrence was ascertained in the context of this evaluation (Ezquieta_2012). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no variant specific 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 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=2)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000781773 SCV000936668 likely pathogenic Rasopathy 2018-08-20 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 502 of the PTPN11 protein (p.Ser502Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with Noonan syndrome or LEOPARD syndrome (PMID: 16358218, 17020470; 19020799). ClinVar contains an entry for this variant (Variation ID: 40557). 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 within a functionally conserved  Protein kinase domain of the PTPN11 protein (PMID: 18470943) and variants that disrupt the p.Ser502 amino acid residue within this domain have been observed in affected individuals (PMID: 12325025, 18470943, 27521173, 15928039, 26242988, 23832011). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000033544 SCV001740219 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000033544 SCV001953570 pathogenic not provided no assertion criteria provided clinical testing

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