ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.181G>A (p.Asp61Asn) (rs397507510)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000157678 SCV000057368 pathogenic not provided 2018-10-15 criteria provided, single submitter clinical testing The D61N missense variant has been observed in the de novo state in multiple individuals with Noonan syndrome undergoing genetic testing at GeneDx. In addition, the D61N variant has been reported previously in association with Noonan syndrome, in two infants diagnosed with Noonan syndrome and myeloproliferative disorders, and one infant diagnosed with Noonan syndrome and juvenile myelomonocytic leukemia (Tartaglia et al., 2002; Strullu et al., 2014). The D61N variant is not observed in large population cohorts (Lek et al., 2016). The D61N variant is located in the N-SH2 domain of the gene, which is the first of two sites involved in switching the protein between its inactive and active conformations. In vitro functional studies demonstrated that the D61N variant results in an increase in phosphatase activity compared to wild-type (Niihori et al., 2005). Furthermore, missense variants in the same residue (D61H, D61A, D61G) and in nearby residues (N58H, N58D, N58K, T59A, G60C, G60S, G60A, Y62N, Y62D, Y62C, Y63C) have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret D61N as a pathogenic variant.
Laboratory for Molecular Medicine, Partners HealthCare 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 2020-04-27 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 61 of the PTPN11 protein (p.Asp61Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in many individuals affected with Noonan syndrome (PMID: 15834506, 16358218, 24150203, 26242988, 27521173). ClinVar contains an entry for this variant (Variation ID: 40495). Experimental studies have shown that this missense change results in increased PTPN11 phosphatase activity in vitro (PMID: 15834506). A different missense substitution at this codon (p.Asp61Gly) has been determined to be pathogenic (PMID: 16358218, 15273746, 23321623, 26242988). This suggests that the aspartic acid residue is critical for PTPN11 protein function and that other missense substitutions at this position may also be pathogenic. 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.
Greenwood Genetic Center Diagnostic Laboratories,Greenwood Genetic Center RCV000157678 SCV000207649 pathogenic not provided 2015-01-15 no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc 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

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