ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.215C>G (p.Ala72Gly) (rs121918454)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000157679 SCV000057378 pathogenic not provided 2018-11-19 criteria provided, single submitter clinical testing The A72G variant in the PTPN11 gene has been reported previously in indiviudals with Noonan syndrome (Tartaglia et al., 2001; Tartaglia et al., 2002; Sarkozy et al., 2003; Ko et al., 2008). This variant has also been reported in an individual with Noonan syndrome and myeloproliferative disease (Kratz et al., 2005). The A72G variant is not observed in large population cohorts (Lek et al., 2016). The A72G variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, 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. Additionally, other missense variants at this same codon (A72P, A72S, A72V) as well as missense variants in neighboring codons (E69Q, F71I, F71L, T73I, E76A, E76D, E76G, E76V) have been reported in association with Noonan syndrome, supporting the functional importance of this region of the protein (Tartaglia et al., 2001; Tartaglia et al., 2002; Bocchinfuso et al., 2007; Lee et al., 2009; Stenson et al., 2014). We interpret A72G as a pathogenic variant.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000157006 SCV000199999 pathogenic Noonan syndrome 2018-03-20 criteria provided, single submitter clinical testing The p.Ala72Gly variant in PTPN11 has been previously identified in >10 individua ls with clinical features of Noonan syndrome (Tartaglia 2001, Sarkozy 2003, Ferr eira 2005, Kratz 2005, Ko 2008, LMM data) and 1 individual with Noonan syndrome and myeloproliferative disorder (Kratz 2005). This variant was reported to have occurred de novo in at least four of these individuals (Ferreira 2005, LMM data) . It was absent from large population studies. This variant has also been report ed in ClinVar (Variation ID 13325). Several other variants involving this codon (p.Ala72Pro, p.Ala72Thr, p.Ala72Ser, p.Ala72Val) have been reported as pathogen ic. In summary, this variant meets criteria to be classified as pathogenic for N oonan in an autosomal dominant manner based upon case observations, de novo occu rrences, presence of other pathogenic variants at this codon, and absence from c ontrols. ACMG/AMP Criteria applied: PS4; PM5_Strong; PM6_Strong; PM2.
Fulgent Genetics,Fulgent Genetics RCV000515213 SCV000611304 pathogenic Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 2017-05-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587329 SCV000698071 pathogenic Noonan syndrome 3 2017-03-11 criteria provided, single submitter clinical testing Variant summary: The PTPN11 c.215C>G (p.Ala72Gly) variant involves the alteration of a highly conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. The Ala72 codon is located within the N-SH domain and interacts directly with PTP domain residue Glu506. Although p.Ala72Gly has not been tested in functional studies, other alterations of this codon, p.Ala72Val and p.Ala72Ser, were shown to promote SHP-2 gain-of-function by destabilizing the catalytically inactive conformation of the protein, and prolong signal flux through the RAS/MAPK pathway (Tartaglia, 2006). The variant is absent from control datasets of ExAC and gnomAD (121394 chrs and 245816 chrs tested, respectively), however was reported in multiple affected individuals with clinically confirmed dx of NS and NSRD (Tartaglia, 2001; Tartaglia, 2006, Sarkozy, 2003 and Ezquieta, 2012) including several de novo events. The codon Ala72 appears to be a mutational hot-spot, as other alteration, such as p.A72P, p.A72V, p.A72S have been reported in patients with NS and NSRD. In addition, multiple reputable databases/clinical laboratories cite the variant as Pathogenic. Taking together, the variant of interest was classified as Pathogenic.
Invitae RCV000707460 SCV000836559 pathogenic Rasopathy 2018-11-13 criteria provided, single submitter clinical testing This sequence change replaces alanine with glycine at codon 72 of the PTPN11 protein (p.Ala72Gly). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with Noonan syndrome, and shown to occur de novo in some of them (PMID: 15956085, 11704759, 15001945, 19020799). It has also been reported in an individual with hypertrophic cardiomyopathy and mitral valve anomaly (PMID: 12960218). ClinVar contains an entry for this variant (Variation ID: 13325). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Ala72Ser) has been determined to be pathogenic (PMID: 12161469, 17339163, 18678287, 26918529, 11704759, 14974085, 16399795). This suggests that the alanine 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.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000157006 SCV000897638 pathogenic Noonan syndrome 2019-03-29 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000157679 SCV000927961 pathogenic not provided 2018-09-28 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000014253 SCV001190490 likely pathogenic Noonan syndrome 1 2020-01-21 criteria provided, single submitter research ACMG codes: PS4M, PM2, PP3, PP5
CeGaT Praxis fuer Humangenetik Tuebingen RCV000157679 SCV001246729 pathogenic not provided 2019-09-01 criteria provided, single submitter clinical testing
OMIM RCV000014253 SCV000034501 pathogenic Noonan syndrome 1 2001-12-01 no assertion criteria provided literature only
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000157006 SCV000206732 pathogenic Noonan syndrome 2012-10-22 no assertion criteria provided clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV000157679 SCV000207653 pathogenic not provided 2015-01-15 no assertion criteria provided clinical testing

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