ClinVar

Description

This missense variant is located in the propeptide domain of the PCSK9 protein. This variant has only been identified in 5/181812 chromosomes (4/13348 East Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). However, this variant is fairly common in the Japanese population (14/2340 chromosomes) (PMID: 26911352) and has been reported in over 60 heterozygous individuals affected with hypercholesterolemia in Japan (6% of the affected population; PMID: 17316651, 24859021, 25014035, 25962062, 26374825, 26632531, 28179607, 31491741, 33533259, 35929461; Pham et al., 2021, doi.org/10.3390/pr9020283). Individuals homozygous for this variant have shown markedly higher plasma LDL-C level than heterozygotes, but showed mild phenotype compared to individuals carrying biallelic LDLR mutations (PMID: 20006333, 21146822, 28179607). This variant has shown strong segregation with disease in multiple families (PMID: 20006333, 25014035). This variant has shown an association with an increased risk of myocardial infarction (PMID: 29802317, 33533259). Notably, this variant appears to exacerbate LDL-C levels and risk of myocardial infarction in individuals carrying LDLR mutations (PMID: 33533259). The impact of this variant on LDLR protein expression and function has not been reported in the literature, although an in vitro study has suggested that this variant may cause an increase in extracellular secretion of the mutant protein (PMID: 20006333). In summary, the available evidence indicates this variant to be a slight gain-of-function mutation that causes mild hypercholesterolemia. Based on the enrichment in affected individuals and co-segregation with disease in family studies, this variant is classified as Pathogenic.