ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.236A>G (p.Gln79Arg) (rs121918466)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000037641 SCV000206693 pathogenic Noonan syndrome 2014-05-02 no assertion criteria provided clinical testing
Blueprint Genetics RCV000157680 SCV000928050 pathogenic not provided 2018-11-13 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc RCV000014268 SCV000782249 pathogenic Noonan syndrome 1 2016-11-01 criteria provided, single submitter 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
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
GeneDx RCV000157680 SCV000057385 pathogenic not provided 2018-12-06 criteria provided, single submitter clinical testing The Q79R missense variant has been observed de novo and reported in association with Noonan syndrome (Tartaglia M. et al., 2001; Karbach et al., 2012; Atik et al., 2016; Xu et al., 2017; internal data). It lies 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). The Q79R variant is not observed in large population cohorts (Lek et al., 2016). Missense variants in the same (Q79P) and nearby (E76A, E76V, E76G, E76D) residues have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Sarkozy et al., 2003; Stenson et al. 2014), supporting the functional importance of this region of the protein. Based on currently available evidence, we consider Q79R to be pathogenic.
Greenwood Genetic Center Diagnostic Laboratories,Greenwood Genetic Center RCV000157680 SCV000207654 pathogenic not provided 2015-01-15 no assertion criteria provided clinical testing
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000033480 SCV000253880 pathogenic Rasopathy 2018-10-17 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.
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.
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000157680 SCV000265842 pathogenic not provided 2015-09-29 criteria provided, single submitter clinical testing
OMIM RCV000014268 SCV000034517 pathogenic Noonan syndrome 1 2003-01-01 no assertion criteria provided literature only

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