ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.923A>C (p.Asn308Thr) (rs121918455)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000033517 SCV000057422 pathogenic not provided 2021-03-10 criteria provided, single submitter clinical testing Identified in patients with cystic hygroma and other abnormal ultrasound findings in published literature (Wilbe et al., 2017; Lee et al., 2009); Not observed in large population cohorts (Lek et al., 2016); 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 (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 18759865, 29057136, 15001945, 24803665, 28921562, 28991257, 19077116, 32978145)
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.
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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193110 SCV001361726 pathogenic Rasopathy 2019-10-22 criteria provided, single submitter clinical testing Variant summary: PTPN11 c.923A>C (p.Asn308Thr) results in a non-conservative amino acid change located in the PTP type protein phosphatase (IPR000242) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251440 control chromosomes (gnomAD). c.923A>C has been reported in the literature in multiple individuals affected with Noonan Syndrome and Related Conditions (e.g. Tartaglia_2006, Lee_2008, Pierpont_2009, Wilbe_2017). These data indicate that the variant is very likely to be associated with disease. In addition, other variants at the same codon have been reported to be associated with Noonan Syndrome, indicating it as a hotspot. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV001193110 SCV001587259 pathogenic Rasopathy 2020-01-05 criteria provided, single submitter clinical testing This sequence change replaces asparagine with threonine at codon 308 of the PTPN11 protein (p.Asn308Thr). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 28921562, 28991257). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40535). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Asn308 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMIDs: 16358218, 21340158, 11992261, 19077116). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000037668 SCV000206731 pathogenic Noonan syndrome 2012-11-20 no assertion criteria provided clinical testing

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