ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.214G>T (p.Ala72Ser) (rs121918453)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000157001 SCV000206725 pathogenic Noonan syndrome 2011-05-05 no assertion criteria provided clinical testing
Baylor Miraca Genetics Laboratories, RCV000033471 SCV000196659 pathogenic Rasopathy no assertion criteria provided clinical testing Variant classified using ACMG guidelines
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).
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
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
GeneDx RCV000212890 SCV000057376 pathogenic not provided 2018-02-22 criteria provided, single submitter clinical testing The A72S variant in the PTPN11 gene has been reported previously in patients with Noonan syndrome (Tartaglia et al., 2001; Hakami et al., 2016). Functional studies of the A72S variant have shown that it 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). The A72S variant is not observed in large population cohorts (Lek et al., 2016). The A72S 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. Missense variants at this same codon (A72P, A72G) as well as missense variants in neighboring codons (E69Q, F71L, F71I, T73I) have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret A72S as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000033471 SCV000698070 pathogenic Rasopathy 2017-02-20 criteria provided, single submitter clinical testing Variant summary: The PTPN11 c.214G>T (p.Ala72Ser) variant involves the alteration of a conserved nucleotide and is located in SH2 domain. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant has been reported in multiple patients with Noonan syndrome or Leopard syndrome (Tartaglia_2001, Tartaglia_2006, Kosaki_2002, Digilio_2013) and is absent in 122200 control chromosomes. Functional study showed PTPN11 A72S had increased phosphatase activity under basal and stimulated conditions (Tartaglia_2006). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Missese variants affecting the same residue (A72T, A72P, A72G) and nearby residues (F71I, F71L, T73I) have been shown to associate with Noonan syndrome, suggesting these residues are critical for PTPN11 function. Taken together, this variant is classified as pathogenic.
Invitae RCV000033471 SCV000659045 pathogenic Rasopathy 2018-10-14 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.
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 (http://pcpgm.partners.org/LMM).
OMIM RCV000014252 SCV000034500 pathogenic Noonan syndrome 1 2002-08-01 no assertion criteria provided literature only

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