Incidentalome

Gene: PCSK9

Green List (high evidence)

Well established gene evidence supporting both modes of pathogenicity and its gene-disease correlation.

Gain of function is the main mechanism of disease for familial hypercholesterolemia (FH) in PCSK9 however loss of function in PCSK9 is causative of Low-density lipoprotein cholesterol level quantitative trait locus-1 (LDLCQ1).

PMID: 18354137 - Functional study using HEK293 cell lines was conducted to assess correlation between gain of function mutations and disease phenotype of FH. It was shown that the variants in PCSK9 caused excessive degradation of LDLR thus lowering the amount of LDL-C being removed from the blood.

PMID: 16909389 – An in vitro functional study using HEK293 cells was conducted and showed that loss of function mutations in the PCSK9 gene inhibits autocatalytic cleavage which affects PCSK9 protein secretion.

PMID: 15772090 – 12 individuals from 3 unrelated families carried the heterozygous D374Y pathogenic mutation in PCSK9 causative of familial hypercholesterolemia.
PMID: 12730697- Identified 12 members from 1 family with an S127R mutation causative of familial hypercholesterolemia.

PMID: 15654334 – Loss of function mutations in PCSK9 (common in African ancestry) are causative of Low-density lipoprotein cholesterol level quantitative trait locus-1 (LDLCQ1). The authors identified 3 unrelated individuals with a nonsense mutation (Y142X) in PCSK9 causative of LDLCQ1.

Created: 30 Mar 2023, 11:54 p.m. | Last Modified: 30 Mar 2023, 11:54 p.m.

Panel Version: 0.226

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
Familial Hypercholesterolemia 3 (MONDO:0011369; MIM# 603776); Low-density lipoprotein cholesterol level quantitative trait locus-1 (LDLCQ1; MIM# 603776)

Publications

• 24404629
• 18354137
• 12730697
• 15654334
• 16909389

Mode of pathogenicity
Other

Green List (high evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Hypercholesterolemia, familial, 3, MIM# 603776