PCSK9 R237W - GET-Evidence



(PCSK9 Arg237Trp)

Short summary

Reported to cause hypocholesterolemia (a protective effect), but observations had no statistical significance and contradicting evidence exists.

Variant evidence
Computational 2

Polyphen 2 predicts damaging effect, other variants in this gene cause disease.

Functional -

Observations from Berge et al. lack statistical significance and are contradicted by Homer et al’s case.

See Berge KE et al. 2006 (16424354), Homer VM et al. 2008 (17765244).

Familial -
Clinical importance
Severity 2

Usually not symptomatic


No standard treatment

Penetrance 5

40% penetrance in the pedigree in Berge et al.

See Berge KE et al. 2006 (16424354).



Low clinical importance, Uncertain protective

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

Inheritance pattern


Summary of published research, and additional commentary

Using Berge et al’s data alone finds no significance (p=0.125 with two-tailed fisher’s exact test). Homer et al’s observation of the variant in a set of hypercholesterolemia cases further contradicts a hypothesis of hypocholestemic effect.

Allele frequency

  • T @ chr1:55518374: 0.1% (11/10756) in EVS
  • T @ chr1:55290961: 0.8% (1/128) in GET-Evidence
  • Frequency shown in summary reports: 0.1% (11/10756)


Benjannet S, Rhainds D, Essalmani R, Mayne J, Wickham L, Jin W, Asselin MC, Hamelin J, Varret M, Allard D, Trillard M, Abifadel M, Tebon A, Attie AD, Rader DJ, Boileau C, Brissette L, Chrétien M, Prat A, Seidah NG. NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol. J Biol Chem. 2004 Nov 19;279(47):48865-75. Epub 2004 Sep 9. PubMed PMID: 15358785.

The authors investigate the effect of a variety of variants in the gene on processing of the protein product. This variant, along with a couple others, did not result in very significant changes in the processing of pro-NARC-1 to NARC-1, and they classify it in group 3, called “silent mutations” (at least from the respect of processing/cleavage).

Berge KE, Ose L, Leren TP. Missense mutations in the PCSK9 gene are associated with hypocholesterolemia and possibly increased response to statin therapy. Arterioscler Thromb Vasc Biol. 2006 May;26(5):1094-100. Epub 2006 Jan 19. PubMed PMID: 16424354.

A screen of 38 unrelated hypocholesterolemic subjects as well as 25 unrelated familial hypocholesterolemia cases that responded well to statin therapy (63 total) found this variant in one of the first set of unrelated hypocholesterolemic subjects. A total of nine individuals were found to have missense variants in this gene. As controls they sequenced 441 hypercholesterolemic subjects that lacked mutations in LDLR and apolipoprotein B-100 and found none of them had these variants.

(Note, *hypo*cholesterolemia, not hyper.)
case+: 1, case-: 62
control+: 0, control-: 441
This gives p=0.12 using a two-tailed fisher’s exact test.
A pedigree is given for the family of this proband and shows no individuals with hypocholesterolemia that do not have the variant, but only 2/5 carriers have hypocholesterolemia (<2.5 percentile) — segregation is not inconsistent, but penetrance is implied to be low (40%) and not a significant LOD score.

Cameron J, Holla ØL, Ranheim T, Kulseth MA, Berge KE, Leren TP. Effect of mutations in the PCSK9 gene on the cell surface LDL receptors. Hum Mol Genet. 2006 May 1;15(9):1551-8. Epub 2006 Mar 28. PubMed PMID: 16571601.

Cites Berge et al. as reported this variant as a loss of function mutant. Functional testing seems to show a small increase in cell surface LDLR and internalization of LDL relative to wild type (while “gain of function” mutants causing hypercholesterolemia showed a decrease).

Homer VM, Marais AD, Charlton F, Laurie AD, Hurndell N, Scott R, Mangili F, Sullivan DR, Barter PJ, Rye KA, George PM, Lambert G. Identification and characterization of two non-secreted PCSK9 mutants associated with familial hypercholesterolemia in cohorts from New Zealand and South Africa. Atherosclerosis. 2008 Feb;196(2):659-66. Epub 2007 Aug 31. PubMed PMID: 17765244.

This variant was seen in one patient in a screen for PCSK9 mutations in 71 patients with familial hypercholesterolemia. The authors report “we did not further study this particular PCSK9 variant” because it had previously been reported associated with hypocholesterolemia.

Ding K, McDonough SJ, Kullo IJ. Evidence for positive selection in the C-terminal domain of the cholesterol metabolism gene PCSK9 based on phylogenetic analysis in 14 primate species. PLoS One. 2007 Oct 31;2(10):e1098. PubMed PMID: 17971861; PubMed Central PMCID: PMC2034530.

This paper refers to R237W as a gain of function rather than loss of function mutation. This may be a mistake, possibly arising from using variants reported by Homer et al. as a list of “gain of function” mutants?


hu034DB1 - CGI sample GS00253-DNA_A02_200_37
het T @ chr1:55518374


Other external references

  • Score: 0.994 (probably damaging)

Other in silico analyses

  • NBLOSUM100 score = 7
  • GET-Evidence autoscore = 4

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Gene search

"GENE" or "GENE A123C":

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