ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.172A>C (p.Asn58His) (rs397507505)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000157676 SCV000057359 pathogenic not provided 2017-11-22 criteria provided, single submitter clinical testing The N58H missense variants in the PTPN11 gene has been reported previously in association with autosomal dominant Noonan syndrome (Limal et al., 2006). The N58H variant lies in the N-SH2 domain of the gene, which is a hot spot for Noonan syndrome variants and is the first of two sites involved in switching the protein between its inactive and active conformations. The N58H 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037626 SCV000061288 pathogenic Noonan syndrome 2015-10-23 criteria provided, single submitter clinical testing The p.Asn58His variant in PTPN11 has been previously identified in at least 8 in dividuals with clinical features of Noonan syndrome or Cardio-facio-cutaneous sy ndrome, including two reportedly de novo occurrences (Tartaglia 2006, Limal 2006 , Ezquieta 2012, Bertelloni 2013, LMM unpublished data). It was absent from larg e population studies. In addition, two different amino acid changes at this posi tion (Asn58Asp, Asn58Lys) has also been reported in individuals with clinical fe atures of Noonan syndrome (Mustante 2003, Zenker 2004, Tartaglia 2006, Sherman 2 009, Digilio 2011, Coromilas 2015). Computational prediction tools and conservat ion analysis suggest that this variant may impact the protein, though this infor mation is not predictive enough to determine pathogenicity. In summary, this var iant meets our criteria to be classified as pathogenic for Noonan syndrome in an autosomal dominant manner ( MM) based upon segregation studies and absence from controls.
Eurofins NTD, LLC RCV000157676 SCV000340585 pathogenic not provided 2016-03-21 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000157676 SCV000511378 pathogenic not provided 2016-09-06 criteria provided, single submitter clinical testing
Invitae RCV000456871 SCV000549997 pathogenic Rasopathy 2017-12-04 criteria provided, single submitter clinical testing This sequence change replaces asparagine with histidine at codon 58 of the PTPN11 protein (p.Asn58His). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and histidine. This variant is not present in population databases (rs397507505, ExAC no frequency). This variant has been reported in several individuals affected with Noonan syndrome (PMID: 16263833, 23756559, 16358218, 21204800, 23624134). ClinVar contains an entry for this variant (Variation ID: 40486). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Asn58Asp) has been determined to be pathogenic (PMID: 15001945, 19125092, 15956085). This suggests that the asparagine residue is critical for PTPN11 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000456871 SCV001774647 pathogenic Rasopathy 2021-07-19 criteria provided, single submitter clinical testing Variant summary: PTPN11 c.172A>C (p.Asn58His) results in a conservative amino acid change located in the SH2 domain (IPR000980) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251000 control chromosomes (gnomAD). c.172A>C has been reported in the literature in multiple individuals affected with Noonan Syndrome (e.g. Tartaglia_2005, Limal_2006, Bertelloni_2013, Hakami_2016, Bessis_2019, Li_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Other missense variants at the same codon (N58D, N58K, N58I) have been classified as pathogenic by our laboratory indicating the asparagine residue is critical for the protein function. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Greenwood Genetic Center Diagnostic Laboratories,Greenwood Genetic Center RCV000157676 SCV000207647 pathogenic not provided 2015-01-15 no assertion criteria provided clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000037626 SCV000805099 pathogenic Noonan syndrome 2016-06-07 no assertion criteria provided clinical testing

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