In all sibs with Leber congenital amaurosis in two consanguineous Arab-Algerian families, Perrault et al. (1996) found homozygosity for a T>C transition in exon 8 at nucleotide 1767 of the GUC2D gene. The nucleotide change converted phenylalanine to serine in the protein. The substitution of an aromatic nonpolar amino acid by an uncharged polar amino acid within the kinase-like domain markedly altered the hydrophobicity of the protein and was expected to affect its stability severely. Perrault et al. (1996) reported the predicted change at amino acid 589 (F589S), but a later study stated that the correct position is 565.

Safieh et al., (2016) described a 6- month old Saudi girl with Leber congenital amaurosis (LCA) born to consanguineous parents.  Direct sequencing for the GUCY2D gene identified a novel (c.743C>T; p.S248L) missense mutation, which was predicted to be pathogenic based on in silico analysis.  The mutation was absent among 300 matched controls.  The authors concluded that this mutation expanded the genotypic spectrum of congenital retinal dystrophies in the Saudi population.

Perrault et al. (1996) conducted a genetic analysis for three families from Tunisia with Leber congenital amaurosis. The first family was a Jewish Sephardi family in which affected members were homozygous for a 1-bp deletion (c.460delC) in exon 2 at nucleotide 460 of GUC2D that modified the downstream amino acid sequence, abolished an SmaI restriction site, and resulted in a premature translation termination at codon 165. The second family was of Arab Tunisian origin. Affected members were homozygous for a 1-bp deletion in exon 2 at nucleotide 693 (693delC) of GUC2D that modified the downstream amino acid sequence, created a BspMI restriction site, and resulted in a premature translation termination at codon 215. In the third family, a consanguineous Arab Tunisian family, all sibs had homozygosity for a G>T transversion at nucleotide 227 of GUC2D converting an alanine into a serine (p.A52S). Heterozygosity for the same mutation was detected in affected members of a family of Basque ancestry. As the same base change was detected in 2 of 100 controls, it was difficult to decide whether this was a disease-causing mutation or a rare polymorphism.