In conclusion, NS mutations in patients, such as those in KRAS, NRAS, SHOC2, MRAS, PP1, CBL, RIT1, LZTR1, PTPN11, SOS1, NF1, SPRED1, RAF1, BRAF, MEK1, and MEK2, deserve further investigation of the specific mechanism of action in primary lymphedema. This evidence concerns the gene CBL and lymphedema.