ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.218C>T (p.Thr73Ile) (rs121918462)

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Total submissions: 14
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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 RCV000156985 SCV000053297 pathogenic Noonan syndrome 2019-04-06 criteria provided, single submitter clinical testing Variant summary: PTPN11 c.218C>T (p.Thr73Ile) 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 was absent in 276806 control chromosomes. c.218C>T has been reported in the literature in multiple individuals affected with Noonan Syndrome and Juvenile Myelomonocyttic Leukema (JMML) (Tartaglia_2002, Tartaglia_2003, Niihori_2005, Kratz_2005, Kosaki_2002, Jongmans_2005). These data indicate that the variant is very 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 enhanced phosphatase activity of mutant SHP-2. Five 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. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV000212891 SCV000057380 pathogenic not provided 2021-04-30 criteria provided, single submitter clinical testing Reported previously in association with Noonan spectrum disorders (Tartaglia et al., 2002); Published functional studies demonstrate the variant results in increased activity compared to wild type (Keilhack et al., 2005); Not observed 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, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28191889, 32901917, 32144894, 31560489, 31219622, 29907801, 30378271, 30050098, 26918529, 28106910, 30355600, 20383758, 15928039, 11992261, 26286251, 24718990, 24803665, 23446178, 23832011, 15987685, 32164556)
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000156985 SCV000200000 pathogenic Noonan syndrome 2016-10-12 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000212891 SCV000511497 pathogenic not provided 2016-10-28 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515312 SCV000611305 pathogenic Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000033475 SCV000821663 pathogenic Rasopathy 2019-01-25 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 73 of the PTPN11 protein (p.Thr73Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with Noonan syndrome (PMID: 11992261, 15240615, 17339163, 17020470) and has been reported to be de novo in several affected individuals (PMID: 20383758, 23446178). Additionally, this variant has been reported in several individuals affected with Noonan-syndrome associated myeloproliferative disorder and it has been reported that this variant carries a higher risk of developing hematological malignancies than other Noonan syndrome associated variants (PMID: 23832011, 14644997, 15928039). ClinVar contains an entry for this variant (Variation ID: 13334). Experimental studies have shown that this missense change functionally activates the Shp2 tyrosine phosphatase (PMID: 15987685). Additionally studies have shown that this variant leads to heart defects in zebrafish embryos (PMID: 24718990). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000014262 SCV001522576 pathogenic Noonan syndrome 1 2020-06-03 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Institute of Human Genetics, University of Leipzig Medical Center RCV000014262 SCV001934529 uncertain significance Noonan syndrome 1 2020-09-17 criteria provided, single submitter clinical testing
OMIM RCV000014262 SCV000034510 pathogenic Noonan syndrome 1 2005-04-15 no assertion criteria provided literature only
Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) RCV000014262 SCV000143816 not provided Noonan syndrome 1 no assertion provided not provided
Baylor Genetics RCV000033475 SCV000196660 pathogenic Rasopathy no assertion criteria provided clinical testing Variant classified using ACMG guidelines
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000156985 SCV000206707 pathogenic Noonan syndrome 2012-06-12 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000212891 SCV001743328 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000212891 SCV001953497 pathogenic not provided no assertion criteria provided clinical testing

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