ClinVar

Description

The c.330+1G>A variant in the UBE2A gene has not been previously reported in association with disease and was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant alters the canonical donor splice site in intron 5, which is predicted to result in abnormal gene splicing. Heterozygous loss of function is an established mechanism of disease for the UBE2A gene; however, this variant occurs in the last intron of UBE2A and the impact to protein function is uncertain. A previously reported variant (c.330G>A) altering the same 5' splice donor site was shown to result in skipping of exon 5, which was predicted to result in a truncated protein (Giugliano et al., 2018). These data suggest the c.330+1G>A may result in a premature truncation similar to the c.330G>A variant. Other variants predicted to result in premature truncation (c.331-2A>G, p.Gln128*, p.Tyr130Valfs*9) located downstream of the c.330+1G>A variant have been reported in association with UBE2A-associated neurodevelopmental disorder (Nascimento et al., 2006; Czeschik et al., 2013; Ma et al., 2019). These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the c.330+1G>A variant as likely pathogenic for UBE2A-associated neurodevelopmental disorder in an X-linked manner based on the information above. [ACMG evidence codes used: PVS1_Strong; PM2]