ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.178G>C (p.Gly60Arg) (rs397507507)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413720 SCV000490934 pathogenic not provided 2015-03-06 criteria provided, single submitter clinical testing The G60R variant has been reported previously is association with juvenile myelomonocytic leukemia (Loh et al., 2004). The G60R 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. The G60R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other 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 this residue and in nearby residues (N58K, G60S, G60C, G60V, G60A, D61N, Y62N, Y63C) 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. Therefore, G60R is interpreted to be a disease-causing variant
Integrated Genetics/Laboratory Corporation of America RCV001201204 SCV001372285 likely pathogenic Rasopathy 2020-06-01 criteria provided, single submitter clinical testing Variant summary: PTPN11 c.178G>C (p.Gly60Arg) results in a non-conservative amino acid change located in the SH2 domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250992 control chromosomes (gnomAD). c.178G>C has been reported in the literature in individuals affected with Juvenile Myelomonocytic Leukemia (JMML) (e.g. Kratz_2005, Loh_2004, Strullu_2014). These data indicate that the variant is likely to be associated with disease. Other variants affecting the same amino acid residue or nearby residues (e.g. p.N58K, p.G60A, p.G60C, p.G60S, p.D61A, p.D61N) are reported via internal testing and/or in HGMD and ClinVar databases as disease-associated/pathogenic variants for Noonan syndrome, suggesting that this protein region is functionally important. A ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic for JMML in the setting of Noonan Syndrome And Related Conditions.

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