rs397507510
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The ENST00000351677.7(PTPN11):c.181G>A(p.Asp61Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D61Y) has been classified as Likely pathogenic.
Frequency
Consequence
ENST00000351677.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PTPN11 | NM_002834.5 | c.181G>A | p.Asp61Asn | missense_variant | 3/16 | ENST00000351677.7 | NP_002825.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PTPN11 | ENST00000351677.7 | c.181G>A | p.Asp61Asn | missense_variant | 3/16 | 1 | NM_002834.5 | ENSP00000340944 | A1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1460946Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726814
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:9
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 29, 2022 | 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) - |
Pathogenic, criteria provided, single submitter | clinical testing | Centro Nacional de Genética Medica "Dr. Eduardo E. Castilla", Administración Nacional de Laboratorios e Institutos de Salud | Feb 02, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 18, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 28, 2023 | PP2, PM1, PM2_supporting, PM5_strong, PS3, PS4 - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 15, 2019 | 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. - |
Pathogenic, no assertion criteria provided | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Jan 15, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Feb 28, 2018 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Noonan syndrome 1 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 09, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Oct 02, 2021 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Oct 17, 2022 | ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM5 moderated, PP2 supporting - |
LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Aug 01, 2017 | 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). - |
Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Dec 13, 2022 | The c.181G>A variant in PTPN11 has previously been reported in individuals with Noonan syndrome [PMID: 11992261, 15834506, 16358218, 22847776, 24150203, 26242988, 27521173, 29907801, 26918529, 32164556] and has been deposited in ClinVar [ClinVar ID: 40495] as Pathogenic by multiple submitters. The c.181G>A variant is observed in 1 allele (~0.00065% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), suggesting it is not a common benign variant in the populations represented in those databases. The c.181G>A variant in PTPN11 is located in exon 3 of this 16-exon gene and predicted to replace an evolutionarily conserved aspartate amino acid with asparagine at position 61 in the N-SH2 domain of the encoded protein [PMID: 24628801]. In vitro functional studies demonstrated increased phosphatase activity in fibroblast cells carrying c.181G>A variant [PMID: 15834506]. Other missense variants affecting the same p.(Asp61) residue have been reported in the literature (p.Asp61Gly) [PMID: 26918529] and ClinVar [ClinVar IDs: 13330] in individuals with Noonan syndrome. Based on available evidence this de novo c.181G>A p.(Asp61Asn) variant identified in PTPN11 is classified here as Pathogenic for Noonan syndrome 1. - |
RASopathy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 06, 2019 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 26, 2024 | 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. - |
Metachondromatosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 09, 2022 | - - |
LEOPARD syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 09, 2022 | - - |
PTPN11-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 10, 2023 | 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. - |
Noonan syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 27, 2016 | 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. - |
Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Dec 22, 2021 | 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). - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 16, 2019 | 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. - |
Noonan syndrome and Noonan-related syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Aug 01, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at