ClinVar

Description

The p.P174S variant (also known as c.520C>T), located in coding exon 3 of the PCSK9 gene, results from a C to T substitution at nucleotide position 520. The proline at codon 174 is replaced by serine, an amino acid with some similar properties. This variant was previously observed in conjunction with a mutation in the LDLR gene in a family with familial hypercholesterolemia (FH). The proband, who was homozygous for both the LDLR mutation and p.P174S, presented with what was considered an attenuated homozygous FH phenotype. In addition, five relatives with both alterations had lower than expected LDL levels for heterozygous FH. However, one relative with both alterations had LDL levels consistent with heterozygous FH (Slimani A et al. Atherosclerosis. 2012;222(1):158-66). This variant also co-occurred with an APOB mutation in an individual from a FH cohort and co-occurred with two mutations in ABCG8 in a proband with hypercholesterolemia and sitosterolemia without xanthomas whose mother had this variant and one ABCG8 mutation and normal cholesterol levels (Buonuomo PS et al. Atherosclerosis. 2017 07;262:71-77; Meshkov A et al. Genes (Basel). 2021 01;12(1)). This variant has also been detected in a cohort free of coronary heart disease where the mean LDL level of carriers was slightly higher than that of non-carriers (Lacaze P et al. Open Heart. 2021 07;8(2)). One in vitro functional study has indicated that this variant may result in loss of function and weaker binding to LDLR protein (Mikaeeli S et al. FEBS J. 2020 02;287(3):515-528). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.