ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.1492C>T (p.Arg498Trp) (rs397507541)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000254686 SCV000886027 pathogenic not provided 2017-05-05 criteria provided, single submitter clinical testing
Ambry Genetics RCV000623675 SCV000742100 pathogenic Inborn genetic diseases 2017-01-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Baylor Genetics RCV000722171 SCV000854620 pathogenic Noonan syndrome 1 2018-11-18 no assertion criteria provided clinical testing
Baylor Miraca Genetics Laboratories, RCV000033539 SCV000196653 pathogenic Rasopathy no assertion criteria provided clinical testing Variant classified using ACMG guidelines
GeneDx RCV000254686 SCV000057444 pathogenic not provided 2018-12-10 criteria provided, single submitter clinical testing The R498W missense change has been reported in several individuals with PTPN11-related disorders (Sarkozy et al., 2004; Kratz et al., 2006; Kratz et al., 2005). In vitro functional studies of the R498W pathogenic variant have shown that the resulting protein is catalytically impaired, has significantly reduced basal activity, and has a reduced response to stimulation with phosphotyrosol (Edwards et al., 2014). The R498W variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The variant lies within a region of the gene coding for the highly conserved PTP domain of the protein-tyrosine phosphatase 11. Pathogenic missense variants in nearby residues (R501K, S502A/T/L, G503R) have been reported in the Human Gene Mutation Database in association with PTPN11-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, R498W is a pathogenic variant.
GeneReviews RCV000055885 SCV000086891 pathologic LEOPARD syndrome 1 2010-11-16 no assertion criteria provided curation Converted during submission to Pathogenic.
Invitae RCV000033539 SCV000824558 pathogenic Rasopathy 2018-03-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 498 of the PTPN11 protein (p.Arg498Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with Noonan syndrome with multiple lentigines in a family (PMID: 15121796) and has been reported in additional individuals affected with PTPN11-related conditions (PMID: 27562378, 22190897, 24891296). ClinVar contains an entry for this variant (Variation ID: 40553). Experimental studies have shown that this missense change results in a PTPN11 protein with signficantly reduced phosphatase activity (PMID: 24891296). A different missense substitution at this codon (p.Arg498Leu) has been determined to be pathogenic (PMID: 15121796, 17875892, 18241070, 17339163, 24935154). This suggests that the arginine 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000824747 SCV000204034 pathogenic Noonan syndrome with multiple lentigines; Noonan syndrome 2016-10-06 criteria provided, single submitter clinical testing The p.Arg498Trp variant in PTPN11 has been identified in at least 10 individuals with clinical features of LEOPARD syndrome (LS) or Noonan syndrome with or with out myeloproliferative disorder, and segregated with clinical features in famili es (NS/MPD; Kratz 2005, Kratz 2006, Sarkozy 2004, LMM data). It has not been ide ntified in large population studies. Missense variants in PTPN11 are strongly as sociated with Noonan spectrum disorders, and another variant (p.Arg498Leu) affec ting the same amino acid residue is known pathogenic. In summary, this variant m eets criteria to be classified as pathogenic for autosomal dominant Noonan spect rum disorders.

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