ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.923A>C (p.Asn308Thr) (rs121918455)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000037668 SCV000206731 pathogenic Noonan syndrome 2012-11-20 no assertion criteria provided clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000033517 SCV000884433 pathogenic not provided 2017-08-14 criteria provided, single submitter clinical testing The PTPN11 c.923A>C;p.Asn308Thr variant has been described in several individuals with a clinical diagnosis of Noonan syndrome (Ndiaye 2014, Pierpont 2009, Tartaglia 2006). The variant is listed in the ClinVar database (Variation ID: 40535) and the dbSNP variant database (rs121918455) but not described in the general population-based databases (Exome Variant Server, Genome Aggregation Database). The amino acid at this position is well conserved across species and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. Considering available information, this variant is classified as pathogenic. References: Ndiaye R et al. Mutation N308T of protein tyrosine phosphatase SHP-2in two Senegalese patients with Noonan syndrome. J Med Genet Gen. 2014 6(1): 6-10. Pierpont EI et al. Genotype differences in cognitive functioning in Noonan syndrome. Genes Brain Behav. 2009 Apr;8(3):275-82. Tartaglia M et al. Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet. 2006 Feb;78(2):279-90.
GeneDx RCV000033517 SCV000057422 pathogenic not provided 2017-11-30 criteria provided, single submitter clinical testing The N308T pathogenic variant in the PTPN11 gene has been reported in association with autosomal dominant Noonan syndrome (Lee et al., 2009; Pierpont et al., 2009; Ndiaye et al., 2014; Newman et al., 2017; Wilbe et al., 2017) and has been observed as apparently de novo at GeneDx. Additionally, Wilbe et al. (2017) identified this variant in two affected singleton pregnancies and subsequently identified gondal mosaicism in the unaffected father. The N308T variant is not observed in large population cohorts (Lek et al., 2016). N308T is a conservative amino acid substitution, which occurs at a conserved position in the PTP domain that is considered to be a mutation hot spot (Tartaglia et al, 2001; Tartaglia et al, 2002). Other missense variants in this codon (N308D/S) have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014). In summary, N308T in the PTPN11 gene is interpreted as a pathogenic variant.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037668 SCV000061330 pathogenic Noonan syndrome 2016-09-12 criteria provided, single submitter clinical testing The p.Asn308Thr variant has been reported in 7 individuals with clinical feature s of Noonan syndrome (Tartaglia 2006, Pierpont 2009, LMM data) and was absent fr om large population studies. Computational prediction tools and conservation ana lysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In addition, two amino aci d changes at this position (p.Asn308Ser, p.Asn308Asp) are well established patho genic variants for Noonan syndrome further suggesting that a change at this posi tion may not be tolerated. In summary, this variant meets our criteria to be cla ssified as pathogenic for Noonan syndrome in an autosomal dominant manner based upon frequency in probands and absence from controls.

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