ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.172A>G (p.Asn58Asp)

dbSNP: rs397507505
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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000033455 SCV000057360 pathogenic not provided 2022-02-25 criteria provided, single submitter clinical testing The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19077116, 16804314, 32164556, 32059087, 19125092, 24803665, 15956085, 26918529, 15001945, 20030748, 18678287, 30693642, 30556322, 33144682, 33726816, 11992261, 16053901, 29493581, 9491886)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000037627 SCV000061289 pathogenic Noonan syndrome 2014-03-20 criteria provided, single submitter clinical testing The Asn58Asp variant in PTPN11 has previously been identified in >10 individuals with clinical features of Noonan syndrome, including at least 3 individuals whe re the variant was reported to have occurred de novo (Zenker 2004, Ferrero 2008, Ferreira 2005, Kitsiou-Tzeli 2006, Pierpont 2009, Tumurkhuu 2010, LMM unpublish ed data). This variant was not identified in large population studies. In summar y, this variant meets our criteria to be classified as pathogenic (http://pcpgm. partners.org/LMM).
Invitae RCV000234028 SCV000287694 pathogenic RASopathy 2023-08-14 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PTPN11 protein function. ClinVar contains an entry for this variant (Variation ID: 40487). This missense change has been observed in individual(s) with clinical features or diagnoses of Noonan syndrome (PMID: 15001945, 15956085, 16804314, 19077116, 19125092, 21590266). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 58 of the PTPN11 protein (p.Asn58Asp).
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768061 SCV000898915 pathogenic Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 2021-03-30 criteria provided, single submitter clinical testing PTPN11 NM_002834.4 exon 3 p.Asn58Asp (c.172A>G): This variant has been reported in the literature in at least 6 individuals with Noonan syndrome, occuring de novo in at least 3 of these individuals (Zenker 2004 PMID:15001945, Ferreira 2005 PMID:15956085, Ferrero 2008 PMID:18678287, Pierpont 2009 PMID:19077116, Tumurkhuu 2010 PMID:20030748, Papadopolou 2012 PMID:21590266). This variant is not present in large control databases. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:40487). Evolutionary conservation and computational predictive tools for this variant are unclear. Of note, this variant occurs within the N-SH2 domain, a critical region for the function of this gene, and increases the likelihood that this variant is damaging (Tartaglia 2002 PMID: 11992261, Strullu 2014 PMID:25097206). Furthermore, two other variants at this position (p.Asn58His and p.Asn58Lys) have also been reported in association with disease, supporting that this region has significance. In summary, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000234028 SCV000918104 pathogenic RASopathy 2017-10-16 criteria provided, single submitter clinical testing Variant summary: The PTPN11 c.172A>G (p.Asn58Asp) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant has been reported in multiple patients with Noonan syndrome and is absent in 277532 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV001283812 SCV001736886 pathogenic Noonan syndrome 1 2021-04-26 criteria provided, single submitter research ACMG codes:PS2; PS4M; PM1; PP2; PP3; PP5
Revvity Omics, Revvity Omics RCV000033455 SCV002019554 pathogenic not provided 2019-05-20 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV001813242 SCV002060728 pathogenic Noonan syndrome and Noonan-related syndrome 2021-02-03 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000033455 SCV002067360 pathogenic not provided 2019-08-12 criteria provided, single submitter clinical testing DNA sequence analysis of the PTPN11 gene demonstrated a sequence change, c.172A>G, in exon 3 that results in an amino acid change, p.Asn58Asp. This sequence change is not present in large population databases such as ExAC and gnomAD. The p.Asn58Asp change affects a moderately conserved amino acid residue located in a domain of the PTPN11 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Asn58Asp substitution. This variant has been reported in several individuals with a clinical diagnosis of Noonan syndrome, occurring de novo in at least 3 of these individuals (PMID:15001945, PMID:15956085, PMID:18678287, PMID:19077116, PMID:20030748, PMID:21590266). Furthermore, missense variants affecting the same amino acid residue (p.Asn58Lys and p.Asn58His) and nearby residues have also been reported in association with Noonan syndrome supporting the functional importance of protein domain (PMID: 12634870, PMID: 16263833). This sequence change is the likely cause of this phenotype, however functional studies have not been performed to prove this conclusively.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille RCV001283812 SCV002559208 pathogenic Noonan syndrome 1 criteria provided, single submitter clinical testing
Ambry Genetics RCV002408493 SCV002715650 pathogenic Cardiovascular phenotype 2017-08-09 criteria provided, single submitter clinical testing The p.N58D pathogenic mutation (also known as c.172A>G), located in coding exon 3 of the PTPN11 gene, results from an A to G substitution at nucleotide position 172. The asparagine at codon 58 is replaced by aspartic acid, an amino acid with highly similar properties. This alteration has been identified in numerous individuals with clinical features or a clinical diagnosis of Noonan Syndrome, including multiple de novo occurrences (Ezquieta B et al. Rev Esp Cardiol (Engl Ed), 2012 May;65:447-55; Choudhry KS et al. Mol. Genet. Metab., 2012 Jun;106:237-40; Stevenson DA et al. Clin. Genet., 2011 Dec;80:566-73; Pierpont EI et al. Genes Brain Behav., 2009 Apr;8:275-82; Ferrero GB et al. Eur J Med Genet 2008 Jul;51:566-72; Kitsiou-Tzeli S et al. Horm. Res., 2006 Jun;66:124-31; Ferreira LV et al. J. Clin. Endocrinol. Metab., 2005 Sep;90:5156-60; Zenker M et al. J. Pediatr., 2004 Mar;144:368-74). Two other alterations at the same amino acid position (p.N58K and p.N58H) have also been reported in patients with Noonan Syndrome. This variant is located in a mutation hotspot in the N-terminal Src homology 2 domain and is indicated to be structurally deleterious (Ambry internal data; Russo AA et al. Nature, 1998 Sep;395:237-43; Kannengiesser C et al. Hum. Mutat., 2009 Apr;30:564-74). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation
Genetics and Molecular Pathology, SA Pathology RCV001283812 SCV002761828 pathogenic Noonan syndrome 1 2022-05-24 criteria provided, single submitter clinical testing The PTPN11 c.172A>G variant is a single nucleotide change in exon 3/16 of the PTPN11 gene, which is predicted to change the amino acid asparagine at position 58 in the protein to aspartic acid. This variant has been identified as a de novo variant in this fetus (PS2). The variant has been reported in 8 probands with a clinical presentation of Noonan Syndrome (e.g. PMID: 15001945; PMID: 16804314) (PS4). This variant is absent from population databases (PM2). This variant is a missense change at an amino acid residue where multiple different missense changes have been seen before in association with disease (e.g. PMID: 12634870) (PM5). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs397507505) and in the HGMD database: CM044250. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 40487).
3billion RCV001283812 SCV003842014 pathogenic Noonan syndrome 1 2023-02-23 criteria provided, single submitter clinical testing The variant is not observed in the gnomAD v2.1.1 dataset. he variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.76; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040487). Different missense changes at the same codon (p.Asn58His, p.Asn58Lys, p.Asn58Tyr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040486, VCV000040488, VCV000040489, VCV000181494). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics RCV003333001 SCV004041175 pathogenic Metachondromatosis 2023-07-24 criteria provided, single submitter clinical testing
Baylor Genetics RCV001283812 SCV004041274 pathogenic Noonan syndrome 1 2023-07-24 criteria provided, single submitter clinical testing
Baylor Genetics RCV003333002 SCV004041375 pathogenic LEOPARD syndrome 1 2023-07-24 criteria provided, single submitter clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV003335059 SCV004046308 pathogenic PTPN11 Related Disorders criteria provided, single submitter clinical testing This variant has been previously reported as a heterozygous change in patients with Noonan syndrome, including several individuals in whom the variant was reported as a de novo change (PMID: 19125092, 21590266, 15001945, 16804314, 15956085, 18678287, 19077116, 20030748, 32164556). This variant is in the N-SH2 domain, which is a hotspot domain for pathogenic variants associated with Noonan syndrome (PMID: 11992261). It is absent from the gnomAD population database and thus is presumed to be rare. In silico tools used to predict the effect of this variant on protein function yield discordant results. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.172A>G (p.Asn58Asp) variant is classified as Pathogenic.
Preventiongenetics, part of Exact Sciences RCV003407390 SCV004115769 pathogenic PTPN11-related condition 2023-05-24 criteria provided, single submitter clinical testing The PTPN11 c.172A>G variant is predicted to result in the amino acid substitution p.Asn58Asp. This variant has been reported in multiple individuals with Noonan syndrome including at least one report of it occurring de novo (see for example - Zenker et al. 2004. PubMed ID: 15001945; Kitsiou-Tzeli et al. 2006. PubMed ID: 16804314; Hakami et al. 2016. PubMed ID: 26918529). Additionally, different missense variants affecting this amino acid (p.Asn58His, p.Asn58Tyr, p.Asn58Ser, p.Asn58Lys) have been reported as pathogenic (Human Gene Mutation Database). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City RCV001283812 SCV001469214 pathogenic Noonan syndrome 1 2020-05-06 no assertion criteria provided clinical testing

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