Description
The L550P variant has been previously published in association with Noonan syndrome (Tartaglia et al. 2007). The L550P variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). L550P is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. 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, in vitro studies have shown that L550P increases ERK activation and RAS exchange rates compared to wild type (Smith et al., 2013). Missense variants in nearby residues (S548R, T549K, R552W/G/T/K/M/S) 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, we interpret L550P as a pathogenic variant.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | yes | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
