ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.174C>A (p.Asn58Lys) (rs397507506)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000157677 SCV000057361 pathogenic not provided 2017-04-06 criteria provided, single submitter clinical testing The N58K missense variant in the PTPN11 gene has been reported previously in association with autosomal dominant Noonan syndrome (Musante et al., 2003); however, the nucleotide substitution causing this variant at the cDNA level was c.174 C>G rather than C>A. The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). N58K is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. The N58K variant lies in the N-SH2 domain of the gene, which is a hot spot for Noonan syndrome alterations and is the first of two sites involved in switching the protein between its inactive and active conformations. Other missense variants involving this codon (N58D/H) have been published (Tartaglia et al., 2006). Additionally, missense variants in nearby residues (T59A, G60C/S/A, D61H/N/A/G, Y62N/D/C, 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037629 SCV000061291 pathogenic Noonan syndrome 2013-05-23 criteria provided, single submitter clinical testing The Asn58Lys variant in PTPN11 has previously been identified in at least 4 indi viduals with clinical features of Noonan syndrome with at least 2 reported to ha ve occurred de novo (Musante 2003, Tartaglia 2006, Ezquieta 2012, Croonen 2013). In addition, this variant has been observed in our lab in two individuals with clinical features of Noonan and found to segregate with clinical features of Noo nan syndrome in one family. Two other variants at this position, Asn58His and As n58Asp, have been reported in several individuals with clinical features of Noon an syndrome in the literature and by our laboratory. In summary, this variant me ets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM).
Invitae RCV000556984 SCV000659040 pathogenic Rasopathy 2017-03-27 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 58 of the PTPN11 protein (p.Asn58Lys). The asparagine residue is moderately conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a PTPN11-related disease. ClinVar contains an entry for this variant (Variation ID: 40488). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). A different variant (c.174C>G) giving rise to the same protein effect observed here (p.Asn58Lys) has been reported in several individuals affected with Noonan syndrome (PMID: 20954246, 22190897, 12634870, 16358218). In two of these individuals, this variant was reported to arise de novo (PMID: 25914815, 23321623). In addition, different missense substitutions at this codon (p.Asn58Asp, p.Asn58His) have been determined to be pathogenic (PMID: 15001945, 19125092, 15956085, 16263833, 23756559, 16358218, 21204800, 23624134). This suggests that the asparagine 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.
Integrated Genetics/Laboratory Corporation of America RCV000587067 SCV000698062 pathogenic Noonan syndrome 3 2016-01-25 criteria provided, single submitter clinical testing Variant summary: Variant affects a non-conserved nucleotide and results in a replacement of a medium size and polar Asparagine (N) with a large size and basic Lysine (K). 4/4 in silico tools predict the variant to be disease causing. It is absent from the large and broad cohorts of the ExAC project while it was found in several NS patients either as a de novo or as a familiar mutation suggesting pathogenicity. Variants affecting the same amino acid, Asn58His and Asn58Asp, Asn58Tyr have been reported by our laboratory in the pathogenic spectrum suggesting the Asn58 residue to be a mutational hotspot and further supporting a casual outcome for the variant. Furthermore, clinical diagnostic centers classify variant as Pathogenic via ClinVar (without evidence to independently evaluate). Considering all evidence, the variant was classified as Pathogenic.
Greenwood Genetic Center Diagnostic Laboratories,Greenwood Genetic Center RCV000157677 SCV000207648 pathogenic not provided 2015-01-15 no assertion criteria provided clinical testing

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