ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.172A>G (p.Asn58Asp) (rs397507505)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768061 SCV000898915 pathogenic Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 2018-04-13 criteria provided, single submitter clinical testing PTPN11 NM_002834.4 exon 3 p.Asn58Asp (c.172A>G): This variant has been reported in the literature in at least 6 individuals with Noonan syndrome, occuring de novo in at least 3 of these individuals (Zenker 2004 PMID:15001945, Ferreira 2005 PMID:15956085, Ferrero 2008 PMID:18678287, Pierpont 2009 PMID:19077116, Tumurkhuu 2010 PMID:20030748, Papadopolou 2012 PMID:21590266). This variant is not present in large control databases. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:40487). Evolutionary conservation and computational predictive tools for this variant are unclear. Of note, this variant occurs within the N-SH2 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). Furthermore, two other variants at this position (p.Asn58His and p.Asn58Lys) have also been reported in association with disease, supporting that this region has significance. In summary, this variant is classified as pathogenic.
GeneDx RCV000033455 SCV000057360 pathogenic not provided 2018-06-26 criteria provided, single submitter clinical testing The N58D missense variant in the PTPN11 gene has been reported previously in individuals with Noonan syndrome, including several individuals in which the variant occurred de novo without confirmed parentage (Ferreira et al., 2005; Kitsiou-Tzeli et al., 2006; Zenker et al., 2004; Hakami et al., 2016). The N58D variant is not observed in large population cohorts (Lek et al., 2016). The N58D variant lies in the N-SH2 domain of the gene, which is a hot spot for Noonan syndrome variants and is the first of two sites involved in switching the protein between its inactive and active conformations (Martinelli et al., 2012). Missense variants in the same reside (N58H/K) and in nearby residues (I56V, T59A, G60S/C/A/V, D61H/N/G/A, Y62D/N/C) 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. Therefore, we interpret N58D as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000234028 SCV000918104 pathogenic Rasopathy 2017-10-16 criteria provided, single submitter clinical testing Variant summary: The PTPN11 c.172A>G (p.Asn58Asp) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant has been reported in multiple patients with Noonan syndrome and is absent in 277532 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000234028 SCV000287694 pathogenic Rasopathy 2018-07-03 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 58 of the PTPN11 protein (p.Asn58Asp). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is not present in population databases (rs397507505, ExAC no frequency). This variant has been reported in several individuals with clinical features or diagnoses of Noonan syndrome (PMID: 19125092, 21590266, 19077116, 15001945), including two cases where the variant was reported to have occurred de novo (PMID: 15956085, 16804314). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037627 SCV000061289 pathogenic Noonan syndrome 2014-03-20 criteria provided, single submitter clinical testing The Asn58Asp variant in PTPN11 has previously been identified in >10 individuals with clinical features of Noonan syndrome, including at least 3 individuals whe re the variant was reported to have occurred de novo (Zenker 2004, Ferrero 2008, Ferreira 2005, Kitsiou-Tzeli 2006, Pierpont 2009, Tumurkhuu 2010, LMM unpublish ed data). This variant was not identified in large population studies. In summar y, this variant meets our criteria to be classified as pathogenic (http://pcpgm. partners.org/LMM).

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