ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.215C>T (p.Ala72Val) (rs121918454)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Database of Curated Mutations (DoCM) RCV000425022 SCV000507236 likely pathogenic Neuroblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434875 SCV000507237 likely pathogenic Acute myeloid leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420663 SCV000507238 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431335 SCV000507239 likely pathogenic Chronic lymphocytic leukemia 2016-05-31 no assertion criteria provided literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000413699 SCV000058291 uncertain significance not provided 2013-03-01 criteria provided, single submitter clinical testing
GeneDx RCV000413699 SCV000491000 pathogenic not provided 2015-05-22 criteria provided, single submitter clinical testing The A72V missense variant in the PTPN11 gene has been reported previously in association with leukemogenesis in Noonan syndrome (Tartaglia et al., 2006; Bocchinfuso et al., 2007). It 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. A72V is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants at the same codon (A72S, A72P, A72G) and in nearby residues (Y62N/C, Y63C, E69Q/V, F71I, T73I, E76I/G/A/D/, Q79P/R) have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. In addition, functional studies of the A72V variant have shown that it results in a conformational shift impairing interactions between the N-SH2 domain and catalytic site while displacing the N-SH2 loop of the protein (Bocchoinfuso et al., 2007).

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