ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.236A>G (p.Gln79Arg) (rs121918466)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000157680 SCV000057385 pathogenic not provided 2021-04-13 criteria provided, single submitter clinical testing In vitro expression of PTPN11-Q79R in cardiac cell cushions from chick embryos resulted in increased phosphatase activity and significantly increased outgrowth of cushion cells compared to wild-type protein expression (Krenz et al., 2005); Located in the N-SH2 domain of the gene, which is a hot spot for Noonan syndrome variants and is the first of two sites involved in switching the protein between its inactive and active conformations (Tartaglia et al., 2001); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 32164556, 31560489, 31219622, 29907801, 30050098, 30417923, 29766225, 29396779, 26855057, 29084544, 11992261, 12634870, 26817465, 27348588, 27521173, 22681964, 16987887, 19251646, 17020470, 26607044, 24803665, 11704759, 16166557, 17641779, 19017799, 22848035, 12529711)
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037641 SCV000061303 pathogenic Noonan syndrome 2015-07-16 criteria provided, single submitter clinical testing The p.Gln79Arg variant in PTPN11 has been reported in >30 individuals with clini cal features of Noonan syndrome and segregated with disease in >10 affected rela tives (Tartaglia 2001, Tartaglia 2002, Schollen 2003, Musante 2003, Yoshida 2004 , Zenker 2004, Chan 2006, Bertola 2006, LMM unpublished data). This variant has also occurred de novo in multiple affected individuals (LMM unpublished data). I t has not been identified in large population studies. In-vivo animal models and in-vitro studies provide evidence that the p.Gln79Arg variant impacts protein f unction (Krenz 2005, Nakamura 2007). In summary, this variant meets our criteria to be classified as pathogenic for Noonan syndrome in an autosomal dominant man ner based upon segregation studies, de novo occurrences in affected individuals, extremely low frequency in the general population, and functional evidence.
Invitae RCV000033480 SCV000253880 pathogenic Rasopathy 2020-10-19 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 79 of the PTPN11 protein (p.Gln79Arg). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with disease in many families with Noonan syndrome (PMID: 11704759, 11992261, 12529711, 12634870, 17020470, 22848035). ClinVar contains an entry for this variant (Variation ID: 13340). Experimental studies have shown that this missense change results in increased phosphatase activity (PMID: 16166557). Furthermore, transgenic mice expressing this variant were found to have congenital heart defects (PMID: 17641779, 19017799). For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000157680 SCV000265842 pathogenic not provided 2015-09-29 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515381 SCV000611306 pathogenic Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 2017-05-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590740 SCV000698073 pathogenic Noonan syndrome 3 2016-08-15 criteria provided, single submitter clinical testing Variant summary: The PTPN11 c.236A>G (p.Gln79Arg) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant. It is located at N-SH2 domain of the protein (InterPro) which is a known functionally important domain in PTPN11 protein. This variant is absent in 121794 control chromosomes. This variant has been widely reported as a pathogenic variant in literature found in many Noonan Syndrome (NS) and/or Noonan Syndrome and Related Conditions (NSRD), including reports of de novo occurrences and co-segregation with disease (Tartaglia_2001, Schollen_2003, Niihori_2005, Ezquieta_2012, Karback_2012). In vitro studies show that this mutant results in significantly elevated phosphatase activity and endocardial cushion growth (Krenz_2005). Furthermore, in vivo mice expression model showed that this mutant leads to embryonic lethality and the embryonic hearts showed altered cardiomyocyte cell cycling ventricular noncompaction, and ventricular septal defects. Fetal expression of Q79R led to the specific activation of the ERK1/2 pathway, and breeding Q79R transgenics into Erk1/2-null backgrounds confirmed that the pathway was necessary and sufficient for mediating the effects of mutant Shp2 (Nakamura_2007). Another variant at the same residue, p.Q79K, has also been reported in NSRD patients (PMIDs: 12960218, 22848035, 16358218) and is classified as likely pathogenic by a clinical lab in ClinVar. Several clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000014268 SCV000782249 pathogenic Noonan syndrome 1 2016-11-01 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000157680 SCV000928050 pathogenic not provided 2018-11-13 criteria provided, single submitter clinical testing
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn RCV000014268 SCV000999314 pathogenic Noonan syndrome 1 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000014268 SCV001451638 pathogenic Noonan syndrome 1 2019-02-26 criteria provided, single submitter clinical testing Across a selection of the available literature, the PTPN11 c.236A>G (p.Gln79Arg) missense variant has been identified in a heterozygous state in at least 13 individuals from four unrelated families affected with Noonan syndrome (Schollen et al. 2003; Niihori et al. 2005; Atik et al. 2016). Schollen et al. (2003) reported a large four generation Belgian family with ten affected members, in whom the p.Gln79Arg variant segregated with Noonan syndrome. The p.Gln79Arg variant was absent from 100 healthy controls and is not reported in the Genome Aggregation Database in a region of good sequence coverage, suggesting that it is rare. The Gln79 residue in present in the N-SH2 domain, which functions as an intra-molecular switch to control the protein's catalytic activity (Schollen et al. 2003; Nakamura et al. 2007). Functional studies in HEK293 cells, rat cardiomyocytes and chick valve explants found that the p.Gln79Arg is a gain-of-function variant resulting in increased MAPK 1/2 signaling and thereby increased growth, which can be reversed by use of MAPK 1/2 inhibitors (Niihori et al. 2005; Krenz et al. 2005). In addition, transgenic mice expressing the p.Gln79Arg variant protein in cardiomyocytes during gestation, showed altered cardiomyocyte cell cycling, ventricular noncompaction, and ventricular septal defects (Nakamura et al. 2007). Based on the collective evidence and application of the ACMG criteria, the p.Gln79Arg variant is classified as pathogenic for Noonan syndrome.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens RCV000014268 SCV001976968 pathogenic Noonan syndrome 1 2021-10-01 criteria provided, single submitter clinical testing PM1, PM2, PM5, PP3, PP4, PP5
OMIM RCV000014268 SCV000034517 pathogenic Noonan syndrome 1 2003-01-01 no assertion criteria provided literature only
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000037641 SCV000206693 pathogenic Noonan syndrome 2014-05-02 no assertion criteria provided clinical testing
Greenwood Genetic Center Diagnostic Laboratories,Greenwood Genetic Center RCV000157680 SCV000207654 pathogenic not provided 2015-01-15 no assertion criteria provided clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000037641 SCV000805100 pathogenic Noonan syndrome 2016-07-06 no assertion criteria provided clinical testing
Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital RCV000014268 SCV001482317 pathogenic Noonan syndrome 1 2019-05-31 no assertion criteria provided research

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