ClinVar Miner

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

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Total submissions: 6
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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 2016-02-11 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
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

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