ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.556C>T (p.Arg186Trp) (rs143433437)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037651 SCV000061313 uncertain significance not specified 2009-11-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000037651 SCV000918111 likely benign not specified 2018-07-30 criteria provided, single submitter clinical testing Variant summary: PTPN11 c.556C>T (p.Arg186Trp) results in a non-conservative amino acid change located in the SH2 domain (IPR000980) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.9e-05 in 276808 control chromosomes (gnomAD). The observed variant frequency is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in PTPN11 causing Noonan Syndrome and Related Conditions phenotype (6.3e-05), suggesting that the variant is benign. The variant, c.556C>T, has been reported in the literature in individuals affected with Noonan Syndrome and Related Conditions (Bertelloni_2013, Perrino_2018). These data do not allow any conclusion about variant significance since segregation analysis was not done and it is unclear if other, recently identified NS-related genes, such as MEK1, CBL, RIT1, SOS2, RRAS, LZTR1 and PPP1CB, were screened for mutations in these two patients. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx RCV001569121 SCV001793121 uncertain significance not provided 2018-11-21 criteria provided, single submitter clinical testing The majority of missense variants in this gene are considered pathogenic; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29037749, 28378436, 27884173, 23624134)
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000157018 SCV000206745 uncertain significance Noonan syndrome 2011-12-12 no assertion criteria provided clinical testing

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