ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.1528C>G (p.Gln510Glu) (rs397507549)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000210041 SCV000057458 pathogenic not provided 2018-08-04 criteria provided, single submitter clinical testing The Q510E pathogenic variant in the PTPN11 gene has been published in association with Noonan syndrome and NSML (also known as LEOPARD syndrome) (Takahashi et al., 2005; Digilio et al., 2006; Faienza et al., 2009; Lehmann et al., 2009; Ganigara et al., 2011; Hahn et al., 2015); all of these individuals were reported to have severe HCM, and the majority developed cardiomyopathy in infancy or prenatally. This variant has also been identified in numerous individuals at GeneDx including multiple de novo occurrences. Furthermore, Q510E is not observed in large population cohorts (Lek et al., 2016). This variant is a semi-conservative amino acid substitution located within a highly conserved portion of the gene that encodes the phosphotyrosine phosphatase (PTP) domain. Missense variants in the same residue (Q510H/R/P) and in nearby residues (T507K, Q506P, M504V, G503E/V/A/R) have been reported in the Human Gene Mutation Database in association with Noonan syndrome and NSML (Stenson et al., 2014), further supporting the functional importance of this residue and region of the protein. Moreover, newborn mice with cardiomyocyte-specific overexpression of Q510E have shown that this variant causes hypertrophic cardiomyopathy (Schramm et al., 2012). In summary, Q510E in the PTPN11 gene is interpreted as a pathogenic variant.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000824751 SCV000203937 pathogenic Noonan syndrome with multiple lentigines; Noonan syndrome 2012-06-14 criteria provided, single submitter clinical testing The p.Gln510Glu variant in PTPN11 has been reported in >10 individuals with clin ical features of RASopathy disorders (Faienza 2009, Lehmann 2009, Tartaglia 2006 , Wakabayashi 2011, Digilio 2006, Ganigara 2011, Limongelli 2008, Takahashi 2005 , and LMM data). This variant has been reported to have occurred de novo in at l east one individual (Faienza 2009). Furthermore, animal models in mice have show n that this variant causes hypertrophic cardiomyopathy (Schramm 2012). In summar y, this variant meets criteria to be classified as pathogenic for RASopathy diso rder in an autosomal dominant manner.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000210041 SCV000225834 pathogenic not provided 2015-02-14 criteria provided, single submitter clinical testing
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000210041 SCV000265845 pathogenic not provided 2015-10-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589512 SCV000698058 pathogenic Noonan syndrome 3 2016-03-07 criteria provided, single submitter clinical testing Variant summary: The c.1528C>G in a PTPN11 gene alters a highly conserved nucleotide and 4/5 in silico tools predict a damaging outcome. This variant has been reported in multiple affected individuals with NSRD with early onset HCM. The variant is absent in control dataset of ExAC. Animal model studies concluded that cardiomyocyte-specific expression of Q510E-Shp2 was sufficient to induce the HCM phenotype. In addition, other variants affecting codon Q510 have been reported in pts with NSRD. Lastly, it has been classified as pathogenic via publications and/or reputable databases/clinical laboratories. Taken together, the variant was classified as Pathogenic.
Ambry Genetics RCV000619738 SCV000739999 pathogenic Cardiovascular phenotype 2019-09-06 criteria provided, single submitter clinical testing The p.Q510E pathogenic mutation (also known as c.1528C>G), located in coding exon 13 of the PTPN11 gene, results from a C to G substitution at nucleotide position 1528. The glutamine at codon 510 is replaced by glutamic acid, an amino acid with highly similar properties. This mutation has been reported in numerous individuals with Noonan syndrome or Noonan syndrome with multiple lentigines, at least two of which are likely of de novo origin (Takahashi K et al. Eur. J. Pediatr. 2005;164:497-500; Digilio MC et al. Eur. J. Pediatr. 2006;165:803-5; Faienza MF et al. Pediatr Cardiol. 2009;30:1012-5; Ganigara M et al. Ann Pediatr Cardiol. 2011;4:74-6; Hahn A et al. Am. J. Med. Genet. A. 2015;167A:744-51; Sayeed M et al. Int J clin Cardiol. 2015;2:052-6; Chen H et al. Orphanet J Rare Dis, 2019 02;14:29). In addition, assays in both in vitro and in vivo models have demonstrated disrupted PTPN11 protein function for p.Q510E, and resultant hypertrophic cardiomyopathy (Ishida H et al. Am. J. Physiol. Heart Circ. Physiol. 2011;301:H1531-9; Schramm C et al. Am. J. Physiol. Heart Circ. Physiol. 2012;302:H231-43; Yu ZH et al. Biochemistry. 2014;53:4136-51; Noda S et al. Biochem. Biophys. Res. Commun. 2016;469:1133-9). Based on the supporting evidence, p.Q510E is interpreted as a disease-causing mutation.
Invitae RCV000033553 SCV000776867 pathogenic Rasopathy 2020-06-28 criteria provided, single submitter clinical testing This sequence change replaces glutamine with glutamic acid at codon 510 of the PTPN11 protein (p.Gln510Glu). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in individuals affected with Noonan syndrome with multiple lentigines (NSML; formerly known as LEOPARD syndrome) or Noonan syndrome (PMID: 16733669, 22190897, 25708222, 21677813, 20954246, 15889278, 19582499, 19077116). In at least one of these individuals, the variant occurred de novo (PMID: 19582499). ClinVar contains an entry for this variant (Variation ID: 40566). Experimental studies have shown that this missense change abolishes PTPN11 phosphatase activity in vitro and results in reduced RAS/MAPK phosphorylation and increased AKT/mTOR activity (PMID: 21803945, 23673659, 24935154, 26742426, 25708222). In addition, mouse models have shown that this variant upregulated mTOR signaling and altered cardiac function (PMID: 22058153). A different missense substitution at this codon (p.Gln510Pro) has been determined to be pathogenic and reported to segregate with NSML in families (PMID: 15690106, 15520399) and in individuals with NSML or Noonan syndrome (PMID: 15520399, 16358218, 20578946). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000679882 SCV000807271 pathogenic Noonan syndrome 1 2017-09-01 criteria provided, single submitter clinical testing This variant has been previously reported as disease-causing and was found once in our laboratory in a 3-month-old male with cardiovascular disease (dysplastic pulmonary valve, severe pulmonic stenosis, thickened aortic valve leaflets, abnorma mitral valve, ventricular hypertrophy), microcephaly, failure to thrive, dysmorphisms (hypertelorism, down-slanting palpebral fissures, retrgnathia, low-set posteriorly rotated ears), left pelvic kidney
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute RCV000679882 SCV001244986 pathogenic Noonan syndrome 1 2018-07-27 criteria provided, single submitter clinical testing A heterozygous missense variant, NM_002834.3(PTPN11):c.1528C>G, has been identified in exon 13 of 16 of the PTPN11 gene. The variant is predicted to result in a minor amino acid change from a glutamine to a glutamic acid at position 510 of the protein, NP_002825.3(PTPN11):p.(Gln510Glu). The glutamine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the protein tyrosine phosphatase functional domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in population databases (gnomAD, dbSNP, 1000G). The variant has previously been described multiple times as pathogenic in patients with Noonan syndrome and Noonan syndrome with multiple letigines with reported de novo cases (ClinVar). Additionally, functional analysis of cardiomyocyte cell lines demonstrated significant attenuation of myofibrillogenesis and increased proliferation, whilst mice overexpressing this variant showed increased cardiomyocyte size, heart-to-body weight ratios, interventricular septum thickness, cardiomyocyte disarray, thickened ventricular walls and depressed contractile function (Ishida, H., et al. (2011), Schramm, C., et al. (2012)). Three alternate variants in the same codon, p.(Gln510Arg), p.(Gln510Pro) and p.(Gln510His) have been reported multiple times in patients with Noonan syndrome and Noonan syndrome with multiple letigines (ClinVar). Analysis of parental samples indicated this variant to be de novo. Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000210041 SCV001247474 pathogenic not provided 2019-03-01 criteria provided, single submitter clinical testing
GeneReviews RCV000055888 SCV000086894 pathologic LEOPARD syndrome 1 2010-11-16 no assertion criteria provided curation Converted during submission to Pathogenic.
Baylor Genetics RCV000033553 SCV000196655 pathogenic Rasopathy no assertion criteria provided clinical testing Variant classified using ACMG guidelines

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