Submissions for variant NM_002834.5(PTPN11):c.181G>A (p.Asp61Asn)

dbSNP: rs397507510

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000157678	SCV000057368	pathogenic	not provided	2022-04-29	criteria provided, single submitter	clinical testing	Published functional studies demonstrate the variant results in significantly increased activation of the PTPN11 protein compared to wild type (Niihori et al., 2005); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 32164556, 11992261, 25097206, 26242988, 24803665, 27521173, 26817465, 12634870, 24150203, 28607217, 30417923, 26918529, 30050098, 29907801, 31560489, 30755392, 33300679, 33502061, 32719394, 27535533, 15834506, 9491886, 16053901, 29493581)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000599619	SCV000199993	pathogenic	Noonan syndrome	2016-05-27	criteria provided, single submitter	clinical testing	The p.Asp61Asn variant in PTPN11 has been previously reported in >20 individuals with clinical features of Noonan syndrome (Tartaglia 2002, Tartaglia 2006, Stru llu 2014, LMM data), and at least 4 of whom also had a myoproliferative disorder including juvenile myelomonocytic leukemia (JMML; Loh 2004, Strullu 2014). It i s also absent from large population studies. Computational prediction tools and conservation analysis suggest that the p.Asp61Asn variant may impact the protein , though this information is not predictive enough to determine pathogenicity. I n summary, this variant meets our criteria to be classified as pathogenic for No onan syndrome in an autosomal dominant manner based upon prevalence in affected probands and absence from controls.
Invitae	RCV000033463	SCV000659041	pathogenic	RASopathy	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 61 of the PTPN11 protein (p.Asp61Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome (PMID: 15834506, 16358218, 24150203, 26242988, 27521173). ClinVar contains an entry for this variant (Variation ID: 40495). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTPN11 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 15834506). This variant disrupts the p.Asp61 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15273746, 16358218, 23321623, 26242988). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000576434	SCV000678232	pathogenic	Noonan syndrome 1; LEOPARD syndrome 1	2017-08-01	criteria provided, single submitter	clinical testing	PTPN11 NM_002834.3 exon3 p.Asp61Asn (c.181G>A): This variant has been reported in the literature in at least 7 individuals with Noonan syndrome, including some individuals with juvenile myelomonocytic leukemia (JMML) (Tartaglia 2002 PMID:11992261, Strullu 2014 PMID:25097206, Joyce 2016 PMID:26242988, Van Trier 2016 PMID:27521173). This variant is not present in large control databases. This variant is present in ClinVar (Variation ID:40495). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Of note, this variant occurs within the N-SH2/PTP interaction 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). Several variants at this codon (p.Asp61Gly, p.Asp61Ala, p.Asp61His) have been reported in association with Noonan syndrome and as a de novo, suggesting that this codon may be particularly important. In summary, this variant is classified as pathogenic based on the data above (number of probands, absence from controls, presence in functionally critical region).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586404	SCV000698039	pathogenic	Noonan syndrome 3	2019-08-06	criteria provided, single submitter	clinical testing	Variant summary: PTPN11 c.181G>A (p.Asp61Asn) results in a conservative amino acid change located in the SH2 domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 252048 control chromosomes. c.181G>A has been reported in the literature in multiple individuals affected with Noonan Syndrome and Related Conditions. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000157678	SCV000886026	pathogenic	not provided	2017-08-18	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000157678	SCV000927554	pathogenic	not provided	2018-02-28	criteria provided, single submitter	clinical testing
3billion	RCV001775072	SCV002012105	pathogenic	Noonan syndrome 1	2021-10-02	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with supporting evidence (ClinVar ID: VCV000372703.2, PS1). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Asp61His, p.Asp61Tyr, p.Asp61Val, p.Asp61Gly, Asp61Ala) has been reported as pathogenic (PM5). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.648, 3Cnet: 0.972, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813245	SCV002060806	pathogenic	Noonan syndrome and Noonan-related syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000157678	SCV002067410	pathogenic	not provided	2019-11-15	criteria provided, single submitter	clinical testing	DNA sequence analysis of the PTPN11 gene demonstrated a sequence change, c.181G>A, in exon 3 that results in an amino acid change, p.Asp61Asn. This sequence change has not been reported in population databases (gnomAD, ExAC). The p.Asp61Asn change has been identified in several individuals with Noonan syndrome (PMIDs: 11992261, 26242988, 27521173). Other variants at the same amino acid residue (p.Asp61Ala, p.Asp61His, p.Asp61Gly) have also been reported as pathogenic for Noonan syndrome (PMIDs: 19927903, 11704759, 20112233). Functional studies showed that PTPN11 phosphatase activity increased in the presence of this variant (PMID: 15834506). The p.Asp61Asn change affects a highly conserved amino acid residue located in the N-SH2 domain of the PTPN11 protein, which is known to be functional. In-silico pathogenicity prediction tools (PolyPhen2, Align GVGD, REVEL) predict this variant to be deleterious.
Centro Nacional de Genética Medica "Dr. Eduardo E. Castilla", Administración Nacional de Laboratorios e Institutos de Salud	RCV000157678	SCV002098088	pathogenic	not provided	2022-02-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002408496	SCV002711072	pathogenic	Cardiovascular phenotype	2019-05-16	criteria provided, single submitter	clinical testing	The p.D61N pathogenic mutation (also known as c.181G>A), located in coding exon 3 of the PTPN11 gene, results from a G to A substitution at nucleotide position 181. The aspartic acid at codon 61 is replaced by asparagine, an amino acid with highly similar properties. This pathogenic variant has been reported in multiple individuals with confirmed or suspected Noonan syndrome, including multiple de novo cases (Tartaglia M et al. Am. J. Hum. Genet., 2002 Jun;70:1555-63; Ferreira LV et al. J. Clin. Endocrinol. Metab., 2005 Sep;90:5156-60; Ferrero GB et al. Eur J Med Genet Jul;51:566-72; Derbent M et al. Am. J. Med. Genet. A, 2010 Nov;152A:2768-74; Lee BH et al. J. Pediatr., 2011 Dec;159:1029-35; Pasmant E et al. Am. J. Med. Genet. A, 2012 Sep;158A:2290-1; Strullu M et al. J. Med. Genet., 2014 Oct;51:689-97; van Trier DC et al. Int. J. Pediatr. Otorhinolaryngol., 2015 Jun;79:874-8; Atik T et al. Indian J Pediatr, 2016 Jun;83:517-21; Joyce S et al. Eur. J. Hum. Genet., 2016 May;24:690-6). This variant is located in the NSH2 domain, which interacts with the PTP domain to regulate switching of the resulting protein between its inactive and active conformations (Tartaglia M et al. Nat. Genet., 2001 Dec;29:465-8; Tartaglia M et al. Am. J. Hum. Genet., 2006 Feb;78:279-90) and other disease-causing variants at the same codon (p.D61G, p.D61H, p.D61A) have been described (Strullu M et al. J. Med. Genet., 2014 Oct;51:689-97; Tartaglia M et al. Am. J. Hum. Genet., 2002 Jun;70:1555-63). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV001775072	SCV003807279	pathogenic	Noonan syndrome 1	2022-10-17	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM5 moderated, PP2 supporting
Baylor Genetics	RCV003147305	SCV003835377	pathogenic	LEOPARD syndrome 1	2022-08-09	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147304	SCV003835409	pathogenic	Metachondromatosis	2022-08-09	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001775072	SCV003835494	pathogenic	Noonan syndrome 1	2022-08-09	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224113	SCV003920364	pathogenic	Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1	2021-12-22	criteria provided, single submitter	clinical testing	PTPN11 NM_002834.3 exon3 p.Asp61Asn (c.181G>A): This variant has been reported in the literature in at least 7 individuals with Noonan syndrome, including some individuals with juvenile myelomonocytic leukemia (JMML) (Tartaglia 2002 PMID:11992261, Strullu 2014 PMID:25097206, Joyce 2016 PMID:26242988, Van Trier 2016 PMID:27521173). This variant is not present in large control databases. This variant is present in ClinVar (Variation ID:40495). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Of note, this variant occurs within the N-SH2/PTP interaction 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). Several variants at this codon (p.Asp61Gly, p.Asp61Ala, p.Asp61His) have been reported in association with Noonan syndrome and as a de novo, suggesting that this codon may be particularly important. In summary, this variant is classified as pathogenic based on the data above (number of probands, absence from controls, presence in functionally critical region).
PreventionGenetics, part of Exact Sciences	RCV003415760	SCV004116537	pathogenic	PTPN11-related condition	2023-08-10	criteria provided, single submitter	clinical testing	The PTPN11 c.181G>A variant is predicted to result in the amino acid substitution p.Asp61Asn. This variant has been reported in multiple individuals with Noonan syndrome (Tartaglia et al. 2002. PubMed ID: 11992261; Niihori et al. 2005. PubMed ID: 15834506; Tartaglia et al. 2006. PubMed ID: 16358218; Joyce et al. 2016. PubMed ID: 26242988). Additionally, different amino acid substitutions affecting the same amino acid (p.Asp61His, p.Asp61Ala, p.Asp61Gly) and nearby amino acids (p.Gly60Ser, p.Gly60Cys, p.Gly60Ala, p.Gly60Val, p.Tyr62Asn, p.Tyr62Asp, p.Tyr62Cys) have been reported as pathogenic (Human Gene Mutation Database). This variant has been interpreted as pathogenic by multiple labs in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/40495/). This variant is interpreted as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000157678	SCV004226874	pathogenic	not provided	2023-03-28	criteria provided, single submitter	clinical testing	PP2, PM1, PM2_supporting, PM5_strong, PS3, PS4
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000157678	SCV000207649	pathogenic	not provided	2015-01-15	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000157678	SCV001954618	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000157678	SCV001973230	pathogenic	not provided		no assertion criteria provided	clinical testing