ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.922A>G (p.Asn308Asp) (rs28933386)

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Total submissions: 25
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000077863 SCV000206699 pathogenic not provided 2017-06-01 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 (Tartaglia 2001, Kosaki 2002, Tartaglia 2002, Zenker 2004, Jongmans 2005, Tartaglia 2006, Ezquita 2012, Papadopoulou 2012, Ueda 2017, van Nierop 2017, Tafazoli 2018), and co-segregates with affected individuals (Tartaglia 2002). The variant is located in the phospho-tyrosine phosphatase domain of PTPN11 (Tartaglia 2001, Qiu 2014), 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, Tartaglia 2006, Qui 2014) 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.
Ambry Genetics RCV000621227 SCV000736587 pathogenic Cardiovascular phenotype 2017-05-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: 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
Athena Diagnostics Inc RCV000077863 SCV000614840 pathogenic not provided 2017-07-11 criteria provided, single submitter clinical testing
Baylor Genetics RCV000033516 SCV000196666 pathogenic Rasopathy no assertion criteria provided clinical testing Variant classified using ACMG guidelines
Blueprint Genetics, RCV000156977 SCV000207168 pathogenic Noonan syndrome 2015-11-10 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).
Center for Human Genetics, Inc RCV000014254 SCV000782251 pathogenic Noonan syndrome 1 2016-11-01 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
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000014254 SCV000897976 pathogenic Noonan syndrome 1 2018-10-26 criteria provided, single submitter clinical testing
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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000077863 SCV000232628 pathogenic not provided 2017-01-11 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement,Université de Bourgogne RCV000014254 SCV000778402 pathogenic Noonan syndrome 1 2017-02-09 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
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.
GeneReviews RCV000014254 SCV000040937 pathologic Noonan syndrome 1 2011-08-04 no assertion criteria provided curation Converted during submission to Pathogenic.
Gharavi Laboratory,Columbia University RCV000077863 SCV000809183 pathogenic not provided 2018-09-16 criteria provided, single submitter research
Greenwood Genetic Center Diagnostic Laboratories,Greenwood Genetic Center RCV000077863 SCV000207660 pathogenic not provided 2015-01-15 no assertion criteria provided clinical testing
Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) RCV000014254 SCV000143819 not provided Noonan syndrome 1 no assertion provided not provided
Integrated Genetics/Laboratory Corporation of America RCV000033516 SCV000698085 pathogenic Rasopathy 2017-08-22 criteria provided, single submitter clinical testing Variant summary: The c.922A>G variant affects a conserved nucleotide, resulting in amino acid change from Asn to Asp. 2/4 in-silico tools predict this variant to be deleterious (SNPs&GO not captured due to low reliability index). This variant is found in 1/121792 control chromosomes at a frequency of 0.0000082, which does not exceed maximal expected frequency of a pathogenic allele (0.0000625). This variant has been reported in many NS patients co-segregating 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 proteins catalytic activity (~3 fold higher than WT). In addition, multiple clinical laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant was classified as pathogenic.
Invitae RCV000033516 SCV000219003 pathogenic Rasopathy 2018-11-25 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). 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.
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.
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000077863 SCV000265839 pathogenic not provided 2015-08-18 criteria provided, single submitter clinical testing
OMIM RCV000014254 SCV000034502 pathogenic Noonan syndrome 1 2013-06-06 no assertion criteria provided literature only
UCLA Clinical Genomics Center, UCLA RCV000014254 SCV000255510 pathogenic Noonan syndrome 1 2014-06-03 criteria provided, single submitter clinical testing

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