ClinVar

Description

The p.E70G variant (also known as c.209A>G), located in coding exon 1 of the VHL gene, results from an A to G substitution at nucleotide position 209. The glutamic acid at codon 70 is replaced by glycine, an amino acid with similar properties. This alteration has not been reported in the literature to date, however an alteration at the same codon, p.E70K, has been observed in multiple individuals with a history of hemangioblastoma and has been shown to cause a modest reduction (20%) in the ability of the VHL protein to bind with the alpha subunit of the hypoxia-inducible transcription factor (Olschwang S et. al, Hum. Mut. 1998;12:424-30; Hes FJ et. al. Clin. Genet. 2007 Aug;72:122-9; Cho HJ et al. J Korean Med Sci. 2009 Feb;24:77-83; Miller F et al. J Biol Chem. 2005 Mar;280:7986-96). One study using a multiparametric in silico prediction based on overall structure and stability of pVHL classified this missense alteration as "high risk" (Fields FR et al. PLoS One, 2020 Nov;15:e0234100). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.