ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.922A>G (p.Asn308Asp) (rs28933386)

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Total submissions: 34
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000156977 SCV000616374 pathogenic Noonan syndrome 2017-04-03 reviewed by expert panel curation The c.922A>G (p.Asn308Asp) variant in PTPN11 has been reported in the literature as a confirmed and unconfirmed de novo occurrence in 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 20979190, and 11704759, 22465605). The variant has co-segregated with disease in more than 7 family members (PP1_Strong; PMID: 11992261). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Asn308Asp variant may impact the protein (PP3). Additionally, at least 2 functional studies have been concordant in showing that this variant may be deleterious to the protein (PS3; PMID 14974085, 15987685, 19509418, 20308328). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2, PP3, PM2, PP1_Strong, PS2_VeryStrong, PS3.
GeneDx RCV000077863 SCV000057421 pathogenic not provided 2018-08-17 criteria provided, single submitter clinical testing The N308D variant in the PTPN11 gene is the most common pathogenic variant associated with autosomal dominant Noonan syndrome (Tartaglia et al., 2001). In one report, 17 patients with this variant had a typical presentation of Noonan syndrome although none were in special education (Tartaglia et al., 2002). N308D has also been reported in a patient with an allelic disorder, Noonan like/Multiple Giant Cell Lesion syndrome (Beneteau et al., 2009). The variant is observed in 1/22300 alleles (0.001%) in individuals of Finnish ancestry in large population cohorts (Lek et al., 2016). N308D is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, functional studies show that N308D alters the local hydrogen bond network of the PTPN11 protein (Qiu et al., 2014) and increases basal phosphatase activity (Fragale et al., 2004). Furthermore, missense variants at the same residue (N308T, N308S) have been reported in association with Noonan Syndrome, supporting the functional importance of this residue and this region of the protein (Tartaglia et al., 2002; Stenson et al., 2014). We interpret N308D to be pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000156977 SCV000061329 pathogenic Noonan syndrome 2017-10-10 criteria provided, single submitter clinical testing The p.Asn308Asp variant in PTPN11 is an established pathogenic variant for Noona n syndrome and has been reported in approximately 11-20% of individuals with Noo nan syndrome across multiple studies (Tartaglia 2001, Jongmans 2005, Tartaglia 2 006, Jongmans 2011, Ezquieta 2012). In addition, de novo occurrences and germlin e mosaicism have been described (Tartaglia 2001, Elalaoui 2010, Ezquieta 2012). This variant has been identified in 3/246202 total chromosomes by the Genome Agg regation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs28933386). In summary, this variant meets criteria to be classified as pathogenic for Noon an syndrome in an autosomal dominant manner based on its frequency in affected i ndividuals and de novo occurrences. ACMG/AMP Criteria applied: PS4, PM6_Strong.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000999988 SCV000206699 pathogenic not specified 2019-01-24 criteria provided, single submitter clinical testing The PTPN11 p.Asn308Asp variant (rs28933386, ClinVar variant ID 13326) is frequently found in patients diagnosed with Noonan syndrome (Ezquita 2012, Jongmans 2005, Kosaki 2002, Papadopoulou 2012, Tafazoli 2018, Tartaglia 2001, Tartaglia 2002, Tartaglia 2006, Ueda 2017, van Nierop 2017, Zenker 2004), and co-segregates with affected individuals (Tartaglia 2002). The variant is located in the phospho-tyrosine phosphatase domain of PTPN11 (Qiu 2014, Tartaglia 2001), and additional missense variants at this residue have also been associated with Noonan syndrome (Tartaglia 2002, Tartaglia 2006). Functional characterization of the p.Asn308Asp protein indicates increased catalytic activity (Fragale 2004, Keilhack 2005, Qui 2014, Tartaglia 2006) due to stabilization of the active enzyme (Qiu 2014). This leads to over-activation of phospho-MEK and phospho-ERK signaling (Fragale 2004), consistent with the established disease mechanisms of Noonan syndrome. The p.Asn308Asp variant is therefore classified as pathogenic. References: Ezquieta B et al. Alterations in RAS-MAPK genes in 200 Spanish patients with Noonan and other neuro-cardio-facio-cutaneous syndromes. Genotype and cardiopathy. Rev Esp Cardiol (Engl Ed). 2012 65(5):447-55. Fragale A et al. Noonan syndrome-associated SHP2/PTPN11 mutants cause EGF-dependent prolonged GAB1 binding and sustained ERK2/MAPK1 activation. Hum Mutat 2004 23(3):267-77. Jongmans M et al. Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation. Eur J Hum Genet. 2011 19(8):870-4. Keilhack H et al. Diverse biochemical properties of Shp2 mutants. Implications for disease phenotypes. J Biol Chem. 2005 280(35):30984-93. Kosaki K et al. PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) mutations in seven Japanese patients with Noonan syndrome. J Clin Endocrinol Metab. 2002 87(8):3529-33. Papadopoulou A et al. Phenotypic spectrum of 80 Greek patients referred as Noonan syndrome and PTPN11 mutation analysis: the value of initial clinical assessment. Eur J Pediatr. 2012 171(1):51-8. Qiu W et al. Structural insights into Noonan/LEOPARD syndrome-related mutants of protein-tyrosine phosphatase SHP2 (PTPN11). BMC Struct Biol. 2014 14:10. Tafazoli A et al. Novel mutations and their genotype-phenotype correlations in patients with Noonan syndrome, using next-generation sequencing. Adv Med Sci. 2018 Mar;63(1):87-93. Tartaglia M et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001 29(4):465-8. Tartaglia M et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002 70(6): 1555-1563. Tartaglia M et al. Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet. 2006 78(2): 279-290. Ueda K et al. Craniosynostosis in patients with RASopathies: Accumulating clinical evidence for expanding the phenotype. Am J Med Genet A. 2017 Sep;173(9):2346-2352. van Nierop JWI et al. Cochlear implantation and clinical features in patients with Noonan syndrome and Noonan syndrome with multiple lentigines caused by a mutation in PTPN11. Int J Pediatr Otorhinolaryngol. 2017 Jun;97:228-234. Zenker M et al. Genotype-phenotype correlations in Noonan syndrome. J Pediatr. 2004 144(3):368-74.
Blueprint Genetics RCV000156977 SCV000207168 pathogenic Noonan syndrome 2015-11-10 criteria provided, single submitter clinical testing
Invitae RCV000033516 SCV000219003 pathogenic Rasopathy 2020-01-02 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 308 of the PTPN11 protein (p.Asn308Asp). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is present in population databases (rs28933386, ExAC 0.001%). This variant has been reported to segregate with disease in many families with Noonan syndrome and related conditions (PMID: 11704759, 16358218, 21340158, 21567923, Invitae). In at least one of these individuals the variant was found to be de novo. ClinVar contains an entry for this variant (Variation ID: 13326). Experimental studies have shown that this missense change is located in the conserved protein-tyrosine phosphatase domain of the PTPN11 protein and results in higher levels of activity (PMID: 16358218, 19509418, 20308328). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000077863 SCV000232628 pathogenic not provided 2017-01-11 criteria provided, single submitter clinical testing
UCLA Clinical Genomics Center, UCLA RCV000014254 SCV000255510 pathogenic Noonan syndrome 1 2014-06-03 criteria provided, single submitter clinical testing
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000077863 SCV000265839 pathogenic not provided 2015-08-18 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000077863 SCV000281404 pathogenic not provided 2014-08-26 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515324 SCV000611308 pathogenic Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 2017-05-18 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000077863 SCV000614840 pathogenic not provided 2017-07-11 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000576594 SCV000678233 pathogenic Noonan syndrome 1; LEOPARD syndrome 1 2017-08-01 criteria provided, single submitter clinical testing PTPN11 NM_002834 exon 8 p.Asn308Asp (c.922A>G): This variant is one of the most common and well established pathogenic variants for Noonan syndrome. This variant has been identified in >20 probands with Noonan syndrome and segregating with disease in at least 7 affected relatives (Tartaglia 2001 PMID:11704759, Tartaglia 2002 PMID:11992261, Brasil 2010 PMID:21340158, Jongmans 2011 PMID:21407260, Prada 2011 PMID:21567923, Ejarque 2015 PMID:25912702, van Trier 2016 PMID:27521173, van Nierop 2017 PMID:28483241). This variant is present in 3/246202 individuals of different ethnicities in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs28933386). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:13326). Evolutionary conservation and computational predictive tools for this variant are unclear. However, functional studies have shown a deleterious effect of this variant on the protein (Fragale 2004 PMID:14974085, Oishi 2006 PMID:16399795, Qiu 2014 PMID:24628801). Of note, at least one other variant at this position (p.Asn308Ser) has been associated with disease at this position, supporting that this region is functionally significant. In summary, this variant is classified as pathogenic (high presence of affected probands, segregation studies, absence from controls, functional studies).
Integrated Genetics/Laboratory Corporation of America RCV000033516 SCV000698085 pathogenic Rasopathy 2019-11-26 criteria provided, single submitter clinical testing Variant summary: PTPN11 c.922A>G (p.Asn308Asp) results in a conservative amino acid change located in the PTP type protein phosphatase of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251830 control chromosomes. c.922A>G has been reported in the literature in numerous individuals affected with Noonan Syndrome. These data indicate that the variant is very likely to be associated with disease. Residue 308 is located in the PTP domain and is reported as the most common residue affected in NS patients (N308D and N308S). Functional studies showed that this variant leads to a mild activation of the protein's catalytic activity (about 3-fold higher than WT; Keilhack_2005). 16 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. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics RCV000621227 SCV000736587 pathogenic Cardiovascular phenotype 2018-11-08 criteria provided, single submitter clinical testing Well-characterized mutation at same position;Other strong data supporting pathogenic classification;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Rarity in general population databases (dbsnp, esp, 1000 genomes)
Ambry Genetics RCV000622835 SCV000741974 pathogenic Inborn genetic diseases 2014-06-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000014254 SCV000778402 pathogenic Noonan syndrome 1 2017-02-09 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000014254 SCV000782251 pathogenic Noonan syndrome 1 2016-11-01 criteria provided, single submitter clinical testing
Gharavi Laboratory,Columbia University RCV000077863 SCV000809183 pathogenic not provided 2018-09-16 criteria provided, single submitter research
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000014254 SCV000897976 pathogenic Noonan syndrome 1 2018-10-26 criteria provided, single submitter clinical testing
Baylor Genetics RCV000850589 SCV000992812 pathogenic Noonan syndrome 1; Metachondromatosis; LEOPARD syndrome 1 2017-12-31 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000077863 SCV001246732 pathogenic not provided 2019-07-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001198282 SCV001369162 pathogenic Pulmonic stenosis (disease) 2019-08-12 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this varinat's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3. This variant was detected in hemizygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001199077 SCV001370072 pathogenic Rare genetic syndrome 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS3,PP3. This variant was detected in homozygous state.
Institute for Genomic Medicine (IGM) Clinical Laboratory,Nationwide Children's Hospital RCV000850589 SCV001423673 pathogenic Noonan syndrome 1; Metachondromatosis; LEOPARD syndrome 1 2018-11-21 criteria provided, single submitter clinical testing [ACMG/AMP/ClinGen RASopathy: PS2_VeryStrong, PS3, PS4, PP1_Strong, PM1, PP2, PP3] This alteration is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2_VeryStrong], is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], has a prevalence that is significantly increased compared with controls (RR/OR > 5; CI does not include 1.0) [PS4], has been shown to cosegregate with disease in multiple affected family members [PP1_Strong], is located in a mutational hotspot and/or critical and well-established functional domain [PM1], is a missense variant in a gene in which missense variants are a common mechanism of disease [PP2], is predicted to be damaging by multiple functional prediction tools [PP3].
Centogene AG - the Rare Disease Company RCV000014254 SCV001426644 pathogenic Noonan syndrome 1 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV001253546 SCV001429315 pathogenic LEOPARD syndrome 1 2019-02-26 criteria provided, single submitter clinical testing
Institute of Human Genetics,Klinikum rechts der Isar RCV000014254 SCV001430036 pathogenic Noonan syndrome 1 2020-06-10 criteria provided, single submitter clinical testing
OMIM RCV000014254 SCV000034502 pathogenic Noonan syndrome 1 2013-06-06 no assertion criteria provided literature only
GeneReviews RCV000014254 SCV000040937 pathologic Noonan syndrome 1 2011-08-04 no assertion criteria provided curation Converted during submission to Pathogenic.
Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) RCV000014254 SCV000143819 not provided Noonan syndrome 1 no assertion provided not provided
Baylor Genetics RCV000033516 SCV000196666 pathogenic Rasopathy no assertion criteria provided clinical testing Variant classified using ACMG guidelines
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV000077863 SCV000207660 pathogenic not provided 2015-01-15 no assertion criteria provided clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge RCV000014254 SCV001161845 pathogenic Noonan syndrome 1 no assertion criteria provided research

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