ClinVar

Noonan Syndrome 12

In an Indian boy (patient 4) who died at age 2 weeks with Noonan syndrome (NS12; 618624), Capri et al. (2019) identified heterozygosity for a de novo germline c.215A-T transversion (c.215A-T, NM_012250.5) in the RRAS2 gene, resulting in a gln72-to-leu (Q72L) substitution within the switch II region. The mutation was not present in general population genetic databases. Functional analysis in HEK293T cells showed constitutively enhanced ERK (see 601795) phosphorylation with the Q72L mutant compared to wildtype protein.

In a boy (patient HU1) with severe failure to thrive and features of Noonan syndrome, who died at age 3 years, Niihori et al. (2019) identified heterozygosity for the Q72L mutation (c.215A-T, NM_012250.6) in the RRAS2 gene. The mutation was shown to have arisen de novo. Functional analysis in HEK293T cells showed elevated association of RAF1 (164760) and activation of ERK1/2 (see 176948) and ELK1 (311040). Low-dose overexpression of the Q72L variant in zebrafish larvae resulted in a significantly increased ceratohyal angle compared to wildtype larvae; overexpression at higher dose caused lethal developmental impairments. Noting the severe phenotype present in patient HU1 compared to other RRAS2-mutated patients, as well as the more potent effects with the Q72L variant compared to other Noonan-associated RRAS2 variants in their in vitro and in vivo assays, the authors suggested a possible genotype/phenotype correlation.

Somatic Mutation in Ovarian Cancer

Chan et al. (1994) identified a somatic gln72-to-leu (Q72L) mutation in the TC21 gene in epithelial ovarian tumor tissue (167000) and demonstrated that the mutation was associated with high transforming activity.