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Familial hypercholesterolaemia (GMS)

Gene: PCSK9

Green List (high evidence)

PCSK9 (proprotein convertase subtilisin/kexin type 9)
EnsemblGeneIds (GRCh38): ENSG00000169174
EnsemblGeneIds (GRCh37): ENSG00000169174
OMIM: 607786, Gene2Phenotype
PCSK9 is in 8 panels

6 reviews

Ivone Leong (Genomics England Curator)

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

Rebecca Foulger (Genomics England curator)

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

Ellen Thomas (Genomics England Curator)

Comment on mode of pathogenicity: Needs a small curated list of missense gain-of-function variants.
Created: 28 Jun 2016, 12:28 p.m.

Ellen McDonagh (Genomics England Curator)

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.

Ellen Thomas (Genomics England)

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

steve Humphries (UCL)

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

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Emory Genetics Laboratory
  • Illumina TruGenome Clinical Sequencing Services
  • Expert Review Green
  • UKGTN
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Hypercholesterolemia, familial, 3, OMIM:603776
OMIM
607786
Clinvar variants
Variants in PCSK9
Penetrance
None
Publications
Mode of Pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Panels with this gene

History Filter Activity

2 Mar 2021, Gel status: 3

Set Phenotypes

Ivone Leong (Genomics England Curator)

Phenotypes for gene: PCSK9 were changed from Hypercholesterolemia, familial, 3, 603776; Familial Hypercholesterolaemia; Hypercholesterolemia; {Low density lipoprotein cholesterol level QTL 1}, 603776; Familial Hypercholesterolemia to Hypercholesterolemia, familial, 3, OMIM:603776

7 Oct 2019, Gel status: 3

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set mode of pathogenicity

Rebecca Foulger (Genomics England curator)

gene: PCSK9 was added gene: PCSK9 was added to Familial hypercholesterolaemia - targeted panel. Sources: Radboud University Medical Center, Nijmegen,UKGTN,Expert Review Green,Illumina TruGenome Clinical Sequencing Services,Emory Genetics Laboratory Mode of inheritance for gene: PCSK9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PCSK9 were set to 16224054; 23433573 Phenotypes for gene: PCSK9 were set to Hypercholesterolemia, familial, 3, 603776; Familial Hypercholesterolaemia; Hypercholesterolemia; {Low density lipoprotein cholesterol level QTL 1}, 603776; Familial Hypercholesterolemia Mode of pathogenicity for gene: PCSK9 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments