ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.923A>G (p.Asn308Ser) (rs121918455)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000157682 SCV000206717 pathogenic not provided 2018-01-05 criteria provided, single submitter clinical testing The PTPN11 c.923A>G; p.Asn308Ser variant (rs121918455) is frequently found in patients diagnosed with Noonan syndrome (Demir 2010, Digilio 2011, Ko 2008, Pierpont 2009, Sarkozy 2003, Tartaglia 2002), and co-segregated with affected individuals (Tartaglia 2002). The variant is located in the phospho-tyrosine phosphatase domain of PTPN11 (Tartaglia 2001, Qiu 2014), and additional missense variants at this residue have also been associated with Noonan syndrome (Tartaglia 2002, Tartaglia 2005, Tartaglia 2006). Functional characterization of the p.Asn308Ser protein indicates increased catalytic activity and altered substrate specificity (Keilhack 2005), consistent with the established disease mechanisms of Noonan syndrome. Based on the above information, this variant is considered pathogenic. REFERENCES Demir K et al. A mother and son with Noonan syndrome resulting from a PTPN11 mutation: first report of molecularly proven cases from Turkey. Turk J Pediatr. 2010 May-Jun;52(3):321-4. Digilio MC et al. RASopathies: Clinical Diagnosis in the First Year of Life. Mol Syndromol. 2011 Sep;1(6):282-289. Keilhack H et al. Diverse biochemical properties of Shp2 mutants. Implications for disease phenotypes. J Biol Chem. 2005 Sep 2;280(35):30984-93. Ko JM et al. PTPN11, SOS1, KRAS, and RAF1 gene analysis, and genotype-phenotype correlation in Korean patients with Noonan syndrome. J Hum Genet. 2008;53(11-12):999-1006. Pierpont EI et al. Genotype differences in cognitive functioning in Noonan syndrome. Genes Brain Behav. 2009 Apr;8(3):275-82. Qiu W et al. Structural insights into Noonan/LEOPARD syndrome-related mutants of protein-tyrosine phosphatase SHP2 (PTPN11). BMC Struct Biol. 2014 Mar 14;14:10. Sarkozy A et al. Correlation between PTPN11 gene mutations and congenital heart defects in Noonan and LEOPARD syndromes. J Med Genet. 2003 Sep;40(9):704-8. Tartaglia M et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001 Dec;29(4):465-8. Tartaglia M et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002 Jun;70(6):1555-63. Tartaglia M et al. Noonan syndrome and related disorders: genetics and pathogenesis. Annu Rev Genomics Hum Genet. 2005;6:45-68. Tartaglia M et al. Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet. 2006 Feb;78(2):279-90.
Athena Diagnostics Inc RCV000157682 SCV000614841 pathogenic not provided 2013-07-29 criteria provided, single submitter clinical testing
Baylor Genetics RCV000033518 SCV000196667 pathogenic Rasopathy no assertion criteria provided clinical testing Variant classified using ACMG guidelines
Blueprint Genetics RCV000037669 SCV000264159 pathogenic Noonan syndrome 2015-12-03 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc RCV000014255 SCV000782252 pathogenic Noonan syndrome 1 2016-11-01 criteria provided, single submitter clinical testing
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000014255 SCV000292239 pathogenic Noonan syndrome 1 2015-09-04 criteria provided, single submitter clinical testing This variant identified in a very young patient diagnosed with the Noonan syndrome has already been reported to cause this syndrome.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000037669 SCV000805103 pathogenic Noonan syndrome 2017-03-08 no assertion criteria provided clinical testing
Donald Williams Parsons Laboratory,Baylor College of Medicine RCV000037669 SCV000292262 pathogenic Noonan syndrome criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000157682 SCV000332342 pathogenic not provided 2015-06-25 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515421 SCV000611309 pathogenic Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000157682 SCV000057423 pathogenic not provided 2017-11-22 criteria provided, single submitter clinical testing The N308S variant in the PTPN11 gene has been reported previously in association with Noonan syndrome and in patients with an allelic disorder, Noonan-like/Multiple Giant Cell Lesion syndrome (Tartaglia et al., 2002; Neumann et al., 2009). The N308S variant has been observed de novo in multiple cases referred for testing at GeneDx. This variant is not observed in large population cohorts (Lek et al., 2016). This substitution occurs at a position that is conserved across species and in-silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Codon Asn308 lies in the PTP domain of the PTPN11 gene and is considered to be a mutation hot spot" (Tartaglia et al, 2001; Tartaglia et al, 2002). Missense variants at the same codon (N308D, N308T) have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014). In addition, functional studies of N308S have shown that it alters substrate specificity at the catalytic site (Keilhack et al., 2005). Therefore, the presence of the N308S variant is consistent with the diagnosis of a Noonan spectrum disorder; however, based on the available data, predictions about the presence or extent of bony involvement associated with this variant cannot be made."
Greenwood Genetic Center Diagnostic Laboratories,Greenwood Genetic Center RCV000157682 SCV000207659 pathogenic not provided 2015-01-15 no assertion criteria provided clinical testing
Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) RCV000014255 SCV000143820 not provided Noonan syndrome 1 no assertion provided not provided
Integrated Genetics/Laboratory Corporation of America RCV000588570 SCV000698086 pathogenic Noonan syndrome 3 2016-05-23 criteria provided, single submitter clinical testing Variant summary: The PTPN11 c.923A>G (p.Asn308Ser) variant involves the alteration of a conserved nucleotide. Residue Asn308 is buried within the PTP domain, and is reported as the most common residue affected in NS patients(N308D and N308S). 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). However, functional assays suggest that this variant alters substrate specificity (Keilhack_JBC_2005), and N308S SHP-2-expressing fetal liver cells also displayed a hypersensitive pattern of CFU-GM colony growth in response to GM-CSF (Schubbert_Blood_2005). This variant has been reported in numerous patients with NS and related conditions and was absent in 122002 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000033518 SCV000260037 pathogenic Rasopathy 2018-11-25 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 308 of the PTPN11 protein (p.Asn308Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (rs121918455, ExAC no frequency). This variant has been observed in many individuals with Noonan Syndrome and shown to segregate with disease in several families (PMID: 11992261, 20718194, 19077116, 24451042, 25595571, 22781091). ClinVar contains an entry for this variant (Variation ID: 13327). A different missense substitution at this codon (p.Asn308Asp) has also been determined to be pathogenic (PMID: 11992261). This suggests that the asparagine residue is critical for PTPN11 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037669 SCV000061331 pathogenic Noonan syndrome 2013-09-13 criteria provided, single submitter clinical testing The p.Asn308Ser variant has previously been associated with the clinical feature s of Noonan syndrome and Noonan syndrome associated with multiple giant-cell les ions in bone (Ko 2008, Tartaglia 2002, Pierpont 2009, Sarkozy 2003, Tartaglia 20 05). This variant has been observed to have occurred de novo in sporadic cases a nd to segregate with clinical features in familial cases. Variants affecting pos ition 308 (p.Asn308Ser and p.Asn308Asp) are the most frequently identified patho genic PTPN11 mutations in individuals with clinical features of Noonan syndrome in our laboratory. In summary, this variant meets our criteria to be classified as pathogenic ( based upon seg regation studies, de novo occurrence, and absence from controls.
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000157682 SCV000265838 pathogenic not provided 2015-08-05 criteria provided, single submitter clinical testing
Molecular Genetics Laboratory,BC Children's and BC Women's Hospitals RCV000014255 SCV000599278 pathogenic Noonan syndrome 1 2016-05-25 criteria provided, single submitter clinical testing
OMIM RCV000014255 SCV000034503 pathogenic Noonan syndrome 1 2007-06-01 no assertion criteria provided literature only

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