Familial hypercholesterolaemia (GMS)

Gene: PCSK9

Comment on phenotypes: This gene is also associated with {Low density lipoprotein cholesterol level QTL 1}, 603776

Created: 2 Mar 2021, 1:27 p.m. | Last Modified: 2 Mar 2021, 1:27 p.m.

Panel Version: 1.8

Gene part of the Global Lipid Genetic Consortium 12-SNP LDL-C gene score calculation (Talmud et al, 2013, PMID:23433573).

Created: 8 Oct 2019, 8:18 p.m. | Last Modified: 8 Oct 2019, 8:18 p.m.

Panel Version: 0.3

Comment on mode of pathogenicity: Needs a small curated list of missense gain-of-function variants.

Created: 28 Jun 2016, 12:28 p.m.

On the Inherited Cardiac Condition Genes panel for Familial Hypercholesterolaemia reported in: Development of a Comprehensive Sequencing Assay for Inherited Cardiac Condition Genes, Pua et al, Journal of Cardiovascular Translational Research, online Feb 2016 (doi:10.​1007/​s12265-016-9673-5). The panel contains disease-causing, putatively pathogenic, research and phenocopy genes, and it is unclear from the publication whether this gene falls into the disease-causing category. No. of mutations indicated in supplemental table = 29.

Created: 19 Feb 2016, 2:48 p.m.

Green List (high evidence)

Loss of function variants cause low cholesterol. A small list of specific missense mutations cause FH by gain-of-function mechanism (usually a severe phenotype).

Created: 2 Dec 2015, 10:10 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Green List (high evidence)

loss of function mutations cause low levels of LDL-c. FH is caused by Gain-of-function mutations
Mutations in PCSK9 are found in <2% of monogenic FH patients but are the most severely affected (LDL-~c highest)

Created: 24 Nov 2015, 4:43 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
hypercholesterolaemia; elevated LDL-Cholesterol

Publications

• Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response. Naoumova RP, Tosi I, Patel D, Neuwirth C, Horswell SD, Marais AD, van Heyningen C, Soutar AK. Arterioscler Thromb Vasc Biol. 2005 Dec
• 25(12):2654-60. Epub 2005 Oct 13. PMID: 16224054

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Variants in this GENE are reported as part of current diagnostic practice