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

dbSNP: rs397507549

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000210041	SCV000057458	pathogenic	not provided	2023-05-21	criteria provided, single submitter	clinical testing	Published functional studies demonstrate newborn mice with cardiomyocyte-specific overexpression of Q510E develop hypertrophic cardiomyopathy (Schramm et al., 2012); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29696744, 30732632, 30384889, 35050212, 25708222, 21803945, 22058153, 21677813, 24935154, 19582499, 26742426, 15889278, 23673659, 16733669, 19273734, 16358218, 18241070, 28973083, 21910226, 20954246, 25724491, 25359717, 30050098, 29907801, 31219622, 31712860, 32164556, 31965297, 31370276, 32573669, 33318624)
Laboratory for Molecular Medicine, Mass General Brigham 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.
Eurofins Ntd Llc (ga)	RCV000210041	SCV000225834	pathogenic	not provided	2015-02-14	criteria provided, single submitter	clinical testing
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	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	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 510 of the PTPN11 protein (p.Gln510Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome and/or Noonan syndrome with multiple lentigines (NSML, formerly known as LEOPARD syndrome) (PMID: 15889278, 16733669, 19077116, 19582499, 20954246, 21677813, 22190897, 25708222). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40566). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTPN11 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 21803945, 22058153, 23673659, 24935154, 25708222, 26742426). This variant disrupts the p.Gln510 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2057894, 15520399, 15690106, 16358218). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 Center for Human Genetics Tuebingen	RCV000210041	SCV001247474	pathogenic	not provided	2019-03-01	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251945	SCV002523897	pathogenic	See cases	2020-12-15	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS2, PS4, PM2, PP2, PP3
Clinical Genetics Laboratory, Region Ostergotland	RCV000679882	SCV003925556	pathogenic	Noonan syndrome 1	2023-03-23	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003335060	SCV004046160	pathogenic	PTPN11 Related Disorders		criteria provided, single submitter	clinical testing	This variant has been reported in the literature in individuals affected with Noonan syndrome with multiple lentigines (NSML, also referred to as LEOPARD syndrome) or Noonan syndrome, also as a de novo alteration (PMID: 16733669, 22190897, 25708222, 21677813, 20954246, 15889278, 19582499, 19077116). In-vitro studies have shown that this missense change abolishes PTPN11 phosphatase activity (PMID: 21803945, 23673659, 24935154, 26742426, 25708222), and mouse models have demonstrated altered cardiac function (PMID: 22058153). The c.1528C>G (p.Gln510Glu) variant is absent from the gnomAD population database and thus is presumed to be rare. The c.1528C>G (p.Gln510Glu) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Different missense variants affecting the same amino acid residue, including a c.1530G>T (p.Gln510His), have been reported individuals with NSML or Noonan syndrome (PMID: 27193571, 21910226, 15520399, 16358218, 20578946, 15690106). Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.1528C>G (p.Gln510Glu) variant is classified as Pathogenic.
GeneReviews	RCV000055888	SCV000086894	not provided	LEOPARD syndrome 1		no assertion provided	literature only
Baylor Genetics	RCV000033553	SCV000196655	pathogenic	RASopathy		no assertion criteria provided	clinical testing	Variant classified using ACMG guidelines