ClinVar

Description

The p.Gln4494del variant in APOB gene has been previously reported in at least 4 unrelated individuals affected with familial hypercholesterolemia (Alves et al., 2014; Rieck et al., 2020; Miroshnikova et al., 2021). This variant did not completely segregate with disease in one family (Alves et al., 2014). This variant has been identified in 90/128,394 European non-Finnish chromosomes (104/281,716 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant has been observed in the population at a frequency higher than expected for a potentially disease-causing variant. The p.Gln4494del variant results in an in-frame deletion of 1 amino acid in exon 29 of the APOB gene. Computational tools predict that this variant is deleterious; however, the accuracy of in silico algorithms is limited. Functional studies of this variant demonstrated a reduction in the binding and uptake of LDL and a change to the secondary structure of the ApoB100 protein (Alves et al., 2014; Fernández-Higuero et al., 2015). These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, despite some supporting functional evidence the significance of the p.Gln4494del variant is uncertain due to limited case data and population frequency data. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: BS1; PS3_Moderate; PP3]