Description
The R135L (c.404 G>T) variant has been published previously in association with adRP (Andréasson et al., 1992; Fernandez-San et al., 2015). The 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. R135L 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 involved in rhodopsin kinase, transducin, and arrestin binding (Rakoczy et al., 2011) that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In addition, functional studies have shown R135L leads to misfolding and impaired activity of the RHO protein (Chuang et al., 2004; Iannaccone et al., 2006). Missense variants in the same residue (R135G/W/P) and in nearby residues (L131PK, V137M, C140S) have been reported in the Human Gene Mutation Database in association with RP (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we consider this variant to be pathogenic.
| # | 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 |
