Familial hypercholesterolaemia

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 9 panels

4 reviews

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
  • Expert Review Green
  • UKGTN
  • Emory Genetics Laboratory
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • Eligibility statement prior genetic testing
Phenotypes
  • Gene part of the Global Lipid Genetic Consortium 12-SNP LDL-C gene score calculation (Talmud et al, 2013)
  • Hypercholesterolemia, familial, 3, 603776
  • {Low density lipoprotein cholesterol level QTL 1}, 603776
  • Familial Hypercholesterolemia
  • Hypercholesterolemia
  • Familial Hypercholesterolaemia
OMIM
607786
Clinvar variants
Variants in PCSK9
Penetrance
Complete
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

28 Jun 2016, Gel status: 4

Gene classified by Genomics England curator

Ellen Thomas (Genomics England Curator)

This gene has been classified as Green List (High Evidence).

28 Jun 2016, Gel status: 4

Set mode of pathogenicity

Ellen Thomas (Genomics England Curator)

Mode of pathogenicity for PCSK9 was changed to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

28 Jun 2016, Gel status: 4

Set Mode of Inheritance

Ellen Thomas (Genomics England Curator)

Mode of inheritance for PCSK9 was changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

7 Oct 2015, Gel status: 4

Added New Source

Ellen McDonagh (Genomics England Curator)

PCSK9 was added to Familial hypercholesterolaemiapanel. Source: UKGTN

7 Oct 2015, Gel status: 3

Added New Source

Ellen McDonagh (Genomics England Curator)

PCSK9 was added to Familial hypercholesterolaemiapanel. Source: Emory Genetics Laboratory

7 Oct 2015, Gel status: 2

Set Mode of Inheritance

Ellen McDonagh (Genomics England Curator)

Model of inheritance for gene PCSK9 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

7 Oct 2015, Gel status: 2

Added New Source

Ellen McDonagh (Genomics England Curator)

PCSK9 was added to Familial hypercholesterolaemiapanel. Source: Illumina TruGenome Clinical Sequencing Services

7 Oct 2015, Gel status: 1

Added New Source

Ellen McDonagh (Genomics England Curator)

PCSK9 was added to Familial hypercholesterolaemiapanel. Source: Radboud University Medical Center, Nijmegen

7 Oct 2015, Gel status: 0

Added New Source

Ellen McDonagh (Genomics England Curator)

PCSK9 was added to Familial hypercholesterolaemiapanel. Sources: Eligibility statement prior genetic testing