ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.174C>G (p.Asn58Lys) (rs397507506)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000033457 SCV000057362 pathogenic not provided 2016-11-28 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; Croonen et al., 2013). The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. N58K is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. The N58K variant lies at a conserved position within the N-SH2 domain of the gene, which is a hot spot for Noonan syndrome pathogenic variants and is the first of two sites involved in switching the protein between its inactive and active conformations. Missense variants in the same codon (N58D/H) and in nearby residues (T59A, G60S/C/A, D61N/H/A/G, Y62N/D/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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000211846 SCV000061292 pathogenic Noonan syndrome 2020-02-19 criteria provided, single submitter clinical testing The c.174C>G, p.Asn58Lys variant in PTPN11 has been reported in at least 6 individuals with clinical features of Noonan syndrome and segregated with disease in at least 4 affected relatives from one family (Musant 2003, Tartaglia 2006, Digilio 2011, Derbent 2010, Croonen 2013, LMM data). It was absent from large population studies, and has been reported in ClinVar (Variation ID 40489). Another variant resulting in the same missense change has also been reported in ClinVar as a Pathogenic variant by several clinical laboratories (c.172A>C, p.Asn58His, Variation ID 40486) In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Noonan syndrome. ACMG/AMP criteria applied: PM2, PS4_Strong, PP1, PS1.
UCLA Clinical Genomics Center, UCLA RCV000037630 SCV000255445 likely pathogenic Noonan syndrome 1 2012-12-04 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515267 SCV000611302 pathogenic Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 2017-05-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588173 SCV000698063 pathogenic Rasopathy 2017-04-03 criteria provided, single submitter clinical testing Variant summary: The PTPN11 c.174C>G (p.Asn58Lys) variant located in the mutational hotspot, SH2 domain, involves the alteration of a non-conserved nucleotide and by 4/4 in-silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome, although these predictions have yet to be functionally assessed. This variant is absent in 122184 control chromosomes including broad and large populations from ExAC. Publications have cited this variant as a pathogenic variant and has been detected in several patients with Noonans syndrome, including multiple instances of a de novo origin (Musante_2003, Tartaglia_2006, Derbent_2010, Digilio_2011, Ezquieta_2012, Croonen_2012, Coromilas_2015, and Cizmarova_2015). Other missense variants at this residue (N58Y, N58D, N58H, and N58S) are reported in association with Noonan syndrome and are classified as pathogenic/likely pathogenic by submitters in ClinVar, strongly suggesting that the codon itself is a mutational hotspot. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as Pathogenic.
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000211846 SCV000746841 pathogenic Noonan syndrome 2017-12-18 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000033457 SCV001246726 pathogenic not provided 2017-09-01 criteria provided, single submitter clinical testing
Invitae RCV000588173 SCV001392879 pathogenic Rasopathy 2019-06-28 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). This variant has been observed in many individuals affected with Noonan syndrome (PMID: 12634870, 20954246, 22190897, 23321623). ClinVar contains an entry for this variant (Variation ID: 40489). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Asn58 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16263833, 15001945, 19125092). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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