Assessing the pathogenicity of in-frame CACNA1F indel variants using structural modeling

Small in-frame insertion-deletion (indel) variants are a common form of genomic variation whose impact on rare disease phenotypes has been understudied. The prediction of the pathogenicity of such variants remains challenging. X-linked incomplete congenital stationary night blindness type 2 (CSNB2) is a nonprogressive, inherited retinal disorder caused by variants in CACNA1F, encoding the Cav1.4α1 channel protein. Here, structural analysis was used through homology modeling to interpret 10 disease-correlated and 10 putatively benign CACNA1F in-frame indel variants. CSNB2-correlated changes were found to be more highly conserved compared with putative benign variants. Notably, all 10 disease-correlated variants but none of the benign changes were within modeled regions of the protein. Structural analysis revealed that disease-correlated variants are predicted to destabilize the structure and function of the Cav1.4α1 channel protein. Overall, the use of structural information to interpret the consequences of in-frame indel variants provides an important adjunct that can improve the diagnosis for individuals with CSNB2.