Submissions for variant NM_002834.5(PTPN11):c.215C>T (p.Ala72Val)

dbSNP: rs121918454

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	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).
Invitae	RCV003654183	SCV004537106	likely pathogenic	RASopathy	2023-06-25	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ala72 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12161469, 18759865, 26918529). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 15834506, 16358218, 17177198, 28074573). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTPN11 function. ClinVar contains an entry for this variant (Variation ID: 41443). This missense change has been observed in individual(s) with hematological malignancies and/or Noonan syndrome with juvenile myelomonocytic leukemia (PMID: 12717436, 14644997, 14982869, 15385933, 30896080). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 72 of the PTPN11 protein (p.Ala72Val).
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	B-cell chronic lymphocytic leukemia	2016-05-31	no assertion criteria provided	literature only