ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.1507G>A (p.Gly503Arg) (rs397507545)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000077852 SCV000057451 pathogenic not provided 2018-09-06 criteria provided, single submitter clinical testing The G503R (c.1507 G>A) missense pathogenic variant has been reported previously in association with Noonan spectrum disorders (Tartaglia et al., 2006). Another nucleotide change in the same codon, c.1507 G>C, which also leads to the G503R missense change, has been previously reported in association with Noonan syndrome (Sarkozy et al., 2003) and has been determined to be pathogenic. The G503R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. G503R is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. The G503R variant lies in the PTP domain of the encoded protein, which plays an essential role in catalytic activity. Missense variants in the same codon (G503A/E/V) and in nearby residues (R498W/L, R501K, S502A/T/L, M504V, Q506P, T507K) have been reported in the Human Gene Mutation Database in association with Noonan spectrum disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000077852 SCV000058284 pathogenic not provided 2017-11-16 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000824749 SCV000061282 pathogenic Juvenile myelomonocytic leukemia; Noonan syndrome 2018-03-23 criteria provided, single submitter clinical testing The p.Gly503Arg (c.1507G>A) variant in PTPN11 has been reported as a somatic cha nge in at least 1 individual with a hematologic malignancy and as a germline cha nge in >10 individuals with clinical features of Noonan syndrome, including at l east 1 apparently de novo occurrence (Tartaglia 2006, Ferrero 2008, Cammarata-Sc alisi 2012, LMM data). This variant has also been reported in ClinVar (Variation ID 40559) and was absent from large population studies. In addition, the p.Gly5 03Arg variant due to a different nucleotide substitution (c.1507G>C) has also be en reported in individuals with Noonan syndrome, Noonan syndrome with juvenile m yelomonocytic leukemia (JMML), JMML, and Noonan syndrome with Hodgkin?s lymphoma (Tartaglia 2003, Tartaglia 2006, Lo 2008). Three other variants involving this codon (p.Gly503Glu, p.Gly503Ala, p.Gly503Val) have been reported as pathogenic. Computational prediction tools and conservation analysis suggest that the p.Gly5 03Arg variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for Noonan syndrome in an autosomal dominant manner . ACMG/AMP Criteria applied: PS4; PM1; PM2; PM6; PP3.
Invitae RCV000033546 SCV000549991 pathogenic Rasopathy 2018-09-20 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 503 of the PTPN11 protein (p.Gly503Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant and another nucleotide change (c.1507G>C) with the same protein effect (p.Gly503Arg) have been reported in more than 10 unrelated individuals with Noonan syndrome or Noonan syndrome with multiple lentigines (PMID: 16358218, 23513489, 18678287, 18758896, 22465605, 15001945). ClinVar contains an entry for this variant (Variation ID: 40559). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"), although structural modeling and biochemical studies indicate that this missense variant may increase phosphatase activity of PTPN11 and facilitate the activation of Shp2 (PMID: 22681964). In summary, this variant is a rare missense change that is predicted to increase protein activity and has been reported in many affected individuals. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000618529 SCV000736863 pathogenic Cardiovascular phenotype 2017-07-07 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Well-characterized mutation at same position;Structural Evidence
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000660241 SCV000782255 pathogenic Noonan syndrome 1 2016-11-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000762886 SCV000893274 pathogenic Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 2018-10-31 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000077852 SCV001247471 pathogenic not provided 2018-09-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000157015 SCV000206742 pathogenic Noonan syndrome 2010-08-27 no assertion criteria provided clinical testing
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000660241 SCV001133024 pathogenic Noonan syndrome 1 2019-09-26 no assertion criteria provided clinical testing

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