ClinVar

Description

The p.Asn33Glyfs*66 variant in the SOX2 gene was identified de novo in this individual and has been previously reported as de novo in a 28 weeks gestation fetus with bilateral anophthalmia (Chassaing et al., 2014). This variant results in a 10bp duplication, which causes a shift in the protein reading frame leading to a premature termination codon 66 amino acids downstream. Although nonsense-mediated decay is not predicted to occur, the truncated protein is expected to result in loss-of-function. Heterozygous loss-of-function is an established mechanism of disease for the SOX2 gene. This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). However, the ability to detect large insertion/deletion variants is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Asn33Glyfs*66 variant as pathogenic for autosomal dominant SOX2-related eye disorders based on the information above. [ACMG evidence codes used: PVS1, PS2, PM2]