ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.836A>G (p.Tyr279Cys) (rs121918456)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000617951 SCV000739978 pathogenic Cardiovascular phenotype 2018-03-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Confirmed de novo alteration in the setting of a new disease (appropriate phenotype) in the family,Deficient protein function in appropriate functional assay(s),Well-characterized mutation at same position
Baylor Genetics RCV000033504 SCV000196665 pathogenic Rasopathy no assertion criteria provided clinical testing Variant classified using ACMG guidelines
Baylor Genetics RCV000577894 SCV000854622 pathogenic Noonan syndrome 1 2018-11-18 no assertion criteria provided clinical testing
Blueprint Genetics RCV000077859 SCV000927420 pathogenic not provided 2017-10-03 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768062 SCV000898916 pathogenic Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 2018-07-18 criteria provided, single submitter clinical testing PTPN11 NM_002834.4 exon 7 p.Tyr279Cys (c.836A>G): This variant is a well established and commonly reported pathogenic variant in the literature, identified in several individuals with Noonan syndrome/LEOPARD syndrome, including a GeneReviews entry. This variant has been published as segregating with disease in multiple affected family members, and as a de novo occurence (Legius 2002 PMID:12161596, Tartaglia 2002 PMID:11992261, Kalev 2010 PMID:19768645, Begic 2014 PMID:24401936, Gelb 2015 PMID:20301557). This variant is not present in large control databases. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:13328). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In addition, functional studies (including a drosophila model) have shown a deleterious effect of this variant (Kontaridis 2006 PMID: 16377799, Martinelli 2008 PMID:18372317, Oishi 2009 PMID:18849586). In summary, this variant is classified as pathogenic.
Center for Human Genetics, Inc RCV000055890 SCV000782250 pathogenic LEOPARD syndrome 1 2016-11-01 criteria provided, single submitter clinical testing
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000055890 SCV000268512 pathogenic LEOPARD syndrome 1 2016-03-17 criteria provided, single submitter clinical testing This de novo mutation identified in the PTPN11 gene is one of the well-described mutations causing the LEOPARD syndrome.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000077859 SCV000058294 pathogenic not provided 2013-03-01 criteria provided, single submitter clinical testing
GeneDx RCV000077859 SCV000057409 pathogenic not provided 2019-01-14 criteria provided, single submitter clinical testing The Y279C pathogenic variant in the PTPN11 gene has been reported previously in many individuals with a clinical diagnosis of Noonan Syndrome with multiple lentigines (formerly known as LEOPARD syndrome) and Noonan syndrome, both in familial and sporadic cases (Legius et al., 2002; Digilio et al., 2002; Tartaglia et al., 2002; Keren et al., 2004; Sarkozy et al., 2004). The Y279C variant has been noted to be pathogenic by multiple other clinical laboratories in the ClinVar database (Landrum et al., 2014) and is not observed in large population cohorts (Lek et al., 2016). The Y279C 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. Moreover, the Y279C pathogenic variant is located within the PTP domain and functional studies suggest this variant is associated with weakened interactions between the N-SH2 and PTP domains leading to sustained RAS-ERK1/2 activation (Yu et al., 2014). Additionally, another missense variant in this same residue (Y279S) and missense variants in nearby residues (I282V, F285L, F285I, F285C, F285S) have been reported in the Human Gene Mutation Database in association with PTPN11-related disorders (Stenson et al., 2014). In summary, Y279C in the PTPN11 gene is interpreted as a pathogenic variant.
GeneReviews RCV000055890 SCV000086896 pathologic LEOPARD syndrome 1 2010-11-16 no assertion criteria provided curation Converted during submission to Pathogenic.
Institute of Human Genetics,Klinikum rechts der Isar RCV000577894 SCV000680351 pathogenic Noonan syndrome 1 2017-12-18 criteria provided, single submitter clinical testing
Institute of Molecular Biology and Genetics,Federal Almazov North-West Medical Research Centre RCV000492270 SCV000494671 pathogenic Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia 2014-12-30 criteria provided, single submitter research The variant was detected in a neonate with congenital intrauterine revealed myocardial hypertrophy. The main clinical sign was myocardial hypertrophy and cardiac output deficit due to reduced LV cavity. No morphological signs of Noonan syndrome were observed. The variant was detected in combination with CBL NM_005188: exon11: c.G1754T :p.R585L variant in RAS-pathway (PMID 25731833).
Integrated Genetics/Laboratory Corporation of America RCV000030620 SCV000053298 pathogenic LEOPARD syndrome 1; Noonan syndrome 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
Invitae RCV000033504 SCV000287695 pathogenic Rasopathy 2019-01-05 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 279 of the PTPN11 protein (p.Tyr279Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with Noonan syndrome with multiple lentigines (NSML; also known as LEOPARD syndrome) in a single family (PMID: 24401936) and has also been reported in many unrelated individuals with NSML (PMID: 25917897, 24820750, 22822385, 15520399, 17020470, 22681964). ClinVar contains an entry for this variant (Variation ID: 13328). Experimental studies have shown that this missense change abolishes the enzymatic activity of PTPN11 in vitro and increases the activity of AKT and mTOR in cell culture (PMID: 16377799, 16638574, 23673659, 18372317, 21339643). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000824744 SCV000200016 pathogenic Noonan syndrome with multiple lentigines; Noonan syndrome 2013-04-09 criteria provided, single submitter clinical testing The p.Tyr279Cys variant in PTPN11 has previously been reported in several indivi duals with clinical features of Noonan or LEOPARD syndrome, segregated with dis ease in multiple families, and occured as a de novo variant in sporadic cases (F roster 2003, Tartaglia 2006, Martinelli 2008, Tang 2009, Digilio 2002, Kalev 200 9, Legius 2002, Legius 2002, Oishi 2009). It was absent from large population st udies. In summary, this variant meets our criteria to be classified as pathogeni c for Noonan syndrome and LEOPARD syndrome in an autosomal dominant manner (http ://www.partners.org/personalizedmedicine/LMM).
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000577894 SCV000583577 likely pathogenic Noonan syndrome 1 2017-06-01 criteria provided, single submitter research
OMIM RCV000055890 SCV000034504 pathogenic LEOPARD syndrome 1 2010-05-01 no assertion criteria provided literature only

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