ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.846C>G (p.Ile282Met) (rs397507530)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000033506 SCV000057411 pathogenic not provided 2018-11-06 criteria provided, single submitter clinical testing The I282M pathogenic variant in the PTPN11 gene has been reported previously in association with Noonan syndrome (Atik et al., 2016; Kratz et al., 2015). This variant has also been observed de novo in patients referred for Noonan syndrome testing at GeneDx. It is not observed in large population cohorts (Lek et al., 2016). The I282M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, other pathogenic variants in this residue (I282V, I282T) and in nearby residues (Y279C, F285L, F285S, F285C) 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, we consider the I282M variant to be pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037661 SCV000061323 likely pathogenic Noonan syndrome 2018-12-21 criteria provided, single submitter clinical testing The p.Ile282Met variant in PTPN11 has been reported in 3 individuals with clinic al features of Noonan syndrome and was inherited from an affected parent in one of these cases (Atik 2016, Klapecki 2005, LMM unpublished data). This variant wa s absent from large population studies. It has been reported in ClinVar (Variat ion ID 40526) and has been reported as a somatic variant in a glioblastoma (Frat tini 2013). Computational prediction tools and conservation analysis suggest th at this variant may impact the protein, though this information is not predictiv e enough to determine pathogenicity. Furthermore, another variant at this positi on (p.Ile282Val) has been reported in multiple individuals with clinical feature s of Noonan syndrome and is classified as pathogenic by our laboratory and in Cl inVar (Variation ID 40525). In summary, although additional studies are required to fully establish its clinical significance, the p.Ile282Met variant is likely pathogenic for autosomal dominant Noonan syndrome. ACMG/AMP criteria applied: P M2, PM5, PP3, PS4_Supporting.

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