ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.328G>A (p.Glu110Lys)

dbSNP: rs397507518
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000033484 SCV000057389 pathogenic not provided 2023-08-11 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 22465605, 29907801, 24451042, 30050098, 35769956, 24150203, 29493581, 35979676)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000037645 SCV000061307 pathogenic Noonan syndrome 2014-11-21 criteria provided, single submitter clinical testing The p.Glu110Lys variant in PTPN11 has been previously identified in three indivi duals with clinical features of Noonan syndrome (Ezquieta 2012, Rodriguez 2014, LMM unpublished data) and was reported to have occurred de novo in two of these individuals (Ezquieta 2012, LMM unpublished data). It was absent from large popu lation studies (http://evs.gs.washington.edu/EVS/; dbSNP rs397507518). In summar y, the p.Glu110Lys variant in PTPN11 meets our criteria to be classified as path ogenic (http://personalizedmedicine.partners.org/Laboratory-For-Molecular-Medici ne/).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589214 SCV000698075 likely pathogenic Noonan syndrome 3 2016-03-14 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000815390 SCV000955840 pathogenic RASopathy 2018-08-18 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 110 of the PTPN11 protein (p.Glu110Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. For these reasons, this variant has been classified as Pathogenic. 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 has been reported in individuals affected with Noonan syndrome in the literature, including at least one individual where the variant was reported de novo (PMID: 22465605, 24150203, 24451042). ClinVar contains an entry for this variant (Variation ID: 40507). This variant is not present in population databases (ExAC no frequency).
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV001813248 SCV002060952 pathogenic Noonan syndrome and Noonan-related syndrome 2020-08-07 criteria provided, single submitter clinical testing
Neuberg Centre For Genomic Medicine, NCGM RCV004771457 SCV005382496 pathogenic Noonan syndrome 1 2023-05-20 criteria provided, single submitter clinical testing The missense c.328G>A (p.Glu110Lys) variant in the PTPN11 gene which is located in a mutational hot spot has been reported previously in a heterozygous state in individuals affected with Noonan syndrome (Lepri et al., 2014; Rodríguez et al., 2014). Different amino acid change affecting codon 110 (p.Glu110Ala) is reported as a known pathogenic variant. The glutamic acid 110 localizes at the linker stretch, which connects the N-SH2 and C-SH2 domains of SHP-2. Mutations affecting this linker are predicted to alter the relative orientation or mobility of N-SH2, which may abrogate its autoinhibitory function (Tartaglia et al., 2006; Rodríguez et al., 2014). The amino acid Glutamic Acid at position 110 is changed to a Lysine changing protein sequence and it might alter its composition and physico-chemical properties. This variant has been reported to the ClinVar database as Pathogenic/ Likely Pathogenic. Multiple lines of computational evidence (Polyphen - Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Glu110Lys in PTPN11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV004984651 SCV005478344 pathogenic Cardiovascular phenotype 2024-11-04 criteria provided, single submitter clinical testing The p.E110K variant (also known as c.328G>A), located in coding exon 3 of the PTPN11 gene, results from a G to A substitution at nucleotide position 328. The glutamic acid at codon 110 is replaced by lysine, an amino acid with similar properties. This variant was detected in multiple individuals with features consistent with PTPN11-related RASopathy; in at least individual, it was reported to have occurred de novo (Ezquieta B et al. Rev Esp Cardiol (Engl Ed), 2012 May;65:447-55; Lepri FR et al. BMC Med Genet, 2014 Jan;15:14; Rodríguez FA et al. J. Pediatr. Endocrinol. Metab., 2014 Mar;27:305-9; Elmas M et al. J Pediatr Genet, 2022 Jun;11:110-116; Swarts JW et al. Am J Med Genet A, 2022 Nov;188:3242-3261). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Gain-of-function variants in PTPN11 are known to cause RASopathy; however, such associations with metachondromatosis have not been observed (Bowen ME et al. PLoS Genet, 2011 Apr;7:e1002050). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation for PTPN11-related RASopathy; however, it is unlikely to be causative of metachondromatosis.
Service de Génétique Moléculaire, Hôpital Robert Debré RCV000037645 SCV001438507 uncertain significance Noonan syndrome no assertion criteria provided clinical testing

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