ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.227A>T (p.Glu76Val) (rs121918465)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781775 SCV000920095 pathogenic Rasopathy 2021-05-31 criteria provided, single submitter clinical testing Variant summary: PTPN11 c.227A>T (p.Glu76Val) results in a non-conservative amino acid change located in the SH2 domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on 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 251068 control chromosomes. c.227A>T has been reported in the literature as a de-novo occurrence in fetuses affected with Noonan Syndrome (example, Croonen_2013, Corsten-Janssen_2020, Normand_2018). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a constitutively activated SHP2 mutant (SHP2-E76V) that promoted the epithelial-mesenchymal transition phenotype in A549 cells as indicated by increased mRNA levels of transcriptor and mesenchymal genes (example, Li_2014). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Blueprint Genetics RCV000788241 SCV000927291 pathogenic not provided 2017-06-12 criteria provided, single submitter clinical testing
OMIM RCV000014265 SCV000034514 pathogenic Juvenile myelomonocytic leukemia 2003-06-01 no assertion criteria provided literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000788241 SCV001743129 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000788241 SCV001952852 pathogenic not provided no assertion criteria provided clinical testing

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