ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.214G>T (p.Ala72Ser) (rs121918453)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212890 SCV000057376 pathogenic not provided 2021-06-01 criteria provided, single submitter clinical testing Identified in several patient patients with Noonan spectrum disorders referred for genetic testing at GeneDx and in published literature (Hakami et al., 2016); observed once apparently de novo; Published functional studies demonstrate a damaging effect; results in significantly increased tyrosine-phosphatase activity resulting in prolonged ligand-dependent ERK2 activation (Fragale et al., 2004; Oishi et al., 2006; Bocchinfuso et at., 2007); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 27535533, 32164556, 31560489, 30050098, 26918529, 24803665, 17177198, 11704759, 14974085, 16399795, 29907801, 30417923)
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000157001 SCV000061298 pathogenic Noonan syndrome 2014-05-15 criteria provided, single submitter clinical testing The Ala72Ser variant has been reported in the literature in many individuals wit h clinical features of Noonan syndrome (Zenker 2004, Tartaglia 2006, Kosaki 2002 , Bocchinfuso 2007, Fragale 2004, Hung 2007, Limal 2006, Lo 2009, Martinelli 200 6, Musante 2003, Noordam 2008, Oishi 2006). Other variants at this position (Ala 72Thr, Ala72Val) have been observed as somatic changes in hematologic malignanci es, indicating the importance of this residue in normal function of the protein (Tartaglia 2005). In summary, this variant meets our criteria to be classified a s pathogenic (
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000212890 SCV000511033 pathogenic not provided 2016-10-17 criteria provided, single submitter clinical testing
Invitae RCV000033471 SCV000659045 pathogenic Rasopathy 2020-06-22 criteria provided, single submitter clinical testing This sequence change replaces alanine with serine at codon 72 of the PTPN11 protein (p.Ala72Ser). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Noonan syndrome (PMID: 12161469, 17339163, 18678287, 26918529), including a family in which the variant segregates with disease (PMID: 11704759). ClinVar contains an entry for this variant (Variation ID: 13324). Experimental studies in flies and in vitro have shown that this missense change increases PTPN11 phosphatase activity and prolongs ERK activation (PMID: 14974085, 16399795). For these reasons, this variant has been classified as Pathogenic.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000576667 SCV000678222 pathogenic Noonan syndrome 1; LEOPARD syndrome 1 2017-08-01 criteria provided, single submitter clinical testing PTPN11 NM_002834.3 exon3 p.Ala72Ser (c.214G>T): This variant has been reported in the literature in at least 8 individuals with a diagnosis or clinical suspicion of Noonan syndrome, segregating with disease in 3 affected family members (Tartaglia 2001 PMID:11704759, Koskai 2002 PMID:12161469, Musante 2003 PMID:12634870, Fragale 2004 PMID:14974085, Zenker 2004 PMID:15001945, Limal 2006 PMID:16263833, Martinelli 2006 PMID:16631468, Oishi 2006 PMID:16399795, Hung 2007 PMID:17339163, Noordam 2008 PMID:18562489, Lo 2010 PMID:19737548). 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:13324). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, this variant occurs within the N-SH2/PTP interaction domain, a critical region for the function of this gene, and increases the likelihood that this variant is damaging (Tartaglia 2002 PMID: 11992261. Strullu 2014 PMID:25097206). In summary, this variant is classified as pathogenic based on the data above (presence in affected probands, segregation studies, absence in controls, presence in critical region/impact to protein).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000033471 SCV000698070 pathogenic Rasopathy 2019-08-26 criteria provided, single submitter clinical testing Variant summary: PTPN11 c.214G>T (p.Ala72Ser) results in a conservative amino acid change located in the first Src homology 2 (SH2) domain (IPR000980) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251856 control chromosomes (gnomAD and publication data). c.214G>T has been reported in the literature in multiple individuals affected with Noonan Syndrome (e.g. Tartaglia_2001, Kosaki_2002, Tartaglia_2006, Digilio_2013), in one of these publications the variant was reported to segregate with the disease in a family (Tartaglia_2001). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated the variant increased phosphatase activity under basal and stimulated conditions (Tartaglia_2006, Bocchinfuso_2007). Missense variants affecting the same residue (A72T, A72P, A72G) and nearby residues (F71I, F71L, T73I) have been reported in patients affected with Noonan syndrome (HGMD), suggesting these residues are critical for PTPN11 function. Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000762883 SCV000893271 pathogenic Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 2018-10-31 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000212890 SCV001746165 pathogenic not provided 2021-05-01 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000212890 SCV001762001 pathogenic not provided 2021-06-17 criteria provided, single submitter clinical testing
OMIM RCV000014252 SCV000034500 pathogenic Noonan syndrome 1 2002-08-01 no assertion criteria provided literature only
Baylor Genetics RCV000033471 SCV000196659 pathogenic Rasopathy no assertion criteria provided clinical testing Variant classified using ACMG guidelines
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000157001 SCV000206725 pathogenic Noonan syndrome 2011-05-05 no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000212890 SCV001800278 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000212890 SCV001955495 pathogenic not provided no assertion criteria provided clinical testing

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