PCSK9 R46L - GET-Evidence



(PCSK9 Arg46Leu)

Short summary

This variant is reported to have a dominant protective effect against coronary heart disease. Carriers of this variant have about half the risk of coronary heart disease compared to non-carriers (6.3% risk in carriers vs. 11.8% risk in non-carriers).

Variant evidence
Computational 2

Other disruptive variants in this gene are associated with a similar protective, and BLOSUM score predicts a disruptive effect.

Functional -
Case/Control 4

p=0.003 for reduced risk of coronary heart disease

See 16554528.

Familial -
Clinical importance
Severity 4

Coronary heart disease is common cause of death.

Treatability 4
Penetrance 3

See 16554528.



Moderate clinical importance, Likely protective

(The "moderate clinical importance, likely" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern


Summary of published research, and additional commentary


Allele frequency

  • T @ chr1:55505647: 1.0% (108/10652) in EVS
  • T @ chr1:55278234: 0.8% (1/126) in GET-Evidence
  • Frequency shown in summary reports: 1.0% (108/10652)


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PubMed PMID: 16554528

While nonsense variants were found in black subjects and associated with decreased risk of coronary heart disease (CHD), these were very rare in white subjects. R46L was found in white subjects and was associated with a 15 percent reduction in LDL cholesterol and a 47 percent reduction (6.3 percent vs. 11.8 percent) in the risk of CHD (hazard ratio, 0.50; 95 percent confidence interval, 0.32 to 0.79; P=0.003).


hu0D879F - CGI sample GS00253-DNA_G01_200_37
het T @ chr1:55505647



Other external references

  • rs11591147
  • LDL cholesterol (rs11591147-T)
    Kathiresan 13-Jan-08 in Nat Genet
    OR or beta: 0.47 [0.41-0.53] % SD lower
    Risk allele frequency: 0.01
    p-value: 2.00E-44
    Initial sample: 2,758 individuals
    Replication sample: 18,544 individuals
  • Score: 0.099 (benign)

Other in silico analyses

  • NBLOSUM100 score = 6
  • GET-Evidence autoscore = 3

Edit history

Gene search

"GENE" or "GENE A123C":

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