PCSK9 A443T - GET-Evidence

Note: This variant has not been sufficiently evaluated by a GET-Evidence editor.

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Curation:
Currentness:

PCSK9 A443T

(PCSK9 Ala443Thr)


Short summary

This variant was found in one female with hypercholesterolemia, but her daughter was symptomatic without the variant present. Later studies show that this variant correlates with lower LDL-C levels in African Americans.

Variant evidence
Computational

Catalytic domain, but conservative mutation and T is found in rat and murine.

See Allard D et al. 2005 (16211558).

Functional -
Case/Control

OR=2.6, p-value=0.28

See Allard D et al. 2005 (16211558).

Familial -1

Symptomatic daughter did not have variant

See Allard D et al. 2005 (16211558).

 
Clinical importance
Severity -
Treatability -
Penetrance -
 

Impact

Insufficiently evaluated not reviewed

(The "insufficiently evaluated" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

unknown

Summary of published research, and additional commentary

 

Total cases/controls case+ case– control+ control– p-value odds ratio
Familial Hypercholesterolemia, Autosomal Dominant, 3
1 129 0 340 0.2766

 

Allele frequency

  • A @ chr1:55523855: 2.8% (303/10758) in EVS
  • A @ chr1:55296442: 3.9% (5/128) in GET-Evidence
  • Frequency shown in summary reports: 2.8% (303/10758)

Publications
 

Allard D, Amsellem S, Abifadel M, Trillard M, Devillers M, Luc G, Krempf M, Reznik Y, Girardet JP, Fredenrich A, Junien C, Varret M, Boileau C, Benlian P, Rabès JP. Novel mutations of the PCSK9 gene cause variable phenotype of autosomal dominant hypercholesterolemia. Hum Mutat. 2005 Nov;26(5):497. Erratum in: Hum Mutat. 2005 Dec;26(6):592. PubMed PMID: 16211558.

This variant was found in one French female with hypercholesterolemia, but her daughter was symptomatic without this variant. The father died of MI at 43yo. It was not found in 340 controls. The authors conclude that it is likely a rare but benign variant.

Cases/controls case+ case– control+ control– p-value odds ratio
Familial Hypercholesterolemia, Autosomal Dominant, 3
1 129 0 340 0.2766

 

Huang CC, Fornage M, Lloyd-Jones DM, Wei GS, Boerwinkle E, Liu K. Longitudinal association of PCSK9 sequence variations with low-density lipoprotein cholesterol levels: the Coronary Artery Risk Development in Young Adults Study. Circ Cardiovasc Genet. 2009 Aug;2(4):354-61. Epub 2009 Jun 10. PubMed PMID: 20031607; PubMed Central PMCID: PMC2810147.

In a 20 year longitudinal study of 1,750 Black and 1,828 Caucasian individuals, this variant was found to correlate with significantly lower LDL-C levels in Black individuals (95.5 mg/dL vs 109.6 mg/dL for wildtype).

Genomes
 

 

GS18508 - var-GS18508-1100-36-ASM
hom A @ chr1:55296443

 

GS19703 - var-GS19703-1100-36-ASM
het A @ chr1:55296443

 

GS19834 - var-GS19834-1100-36-ASM
hom A @ chr1:55296443

 

Other external references
 

    dbSNP
  • rs28362263
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PolyPhen-2
  • Score: 0 (benign)
    Web search results (75 hits -- see all)
  • Longitudinal Association of PCSK9 Sequence Variations With ...
    The 3 genetic variants and the A443T variant in black men were associated with ... 2 genotypes within the PCSK9 A443T variant showed significantly lower ...
    circgenetics.ahajournals.org/cgi/content/full/2/4/354
  • PCSK9 variants linked to lower LDL cholesterol: Lipids Online
    Of note, African–Americans who were carriers of any of the three rare PCSK9 variants or A443T had lower carotid IMT and CAC at age 38–50 years. ...
    www.lipidsonline.org/news/article.cfm?aid=7924
  • doi:10.1086/507488
    type PCSK9, which was secreted from cells into the medium within ... (R46L and A443T) had no detectable. effect on the processing or secretion of PCSK9 (fig. 1B) ...
    sciencedirect.com/science?_ob=MImg&...&ie=/sdarticle.pdf
  • Novel mutations of the PCSK9 gene cause variable phenotype of ...
    Novel mutations of the PCSK9 gene cause variable phenotype of autosomal dominant hypercholesterolemia. ... Except for the A443T, all mutations are nonconservative and modify a ...
    www.ncbi.nlm.nih.gov/pubmed/16211558
  • A Spectrum of PCSK9 Alleles Contributes to Plasma Levels of ...
    A Spectrum of PCSK9 Alleles Contributes to Plasma Levels of Low-Density Lipoprotein Cholesterol ... Nevertheless, the L235F and A443T sequence variations were both ...
    www.ncbi.nlm.nih.gov/pmc/articles/PMC1380285/?tool=pubmed
  • Effect of mutations in the PCSK9 gene on the cell surface LDL ...
    PCSK9 is synthesized as a soluble zymogen which undergoes autocatalytic ... (13), L253F (14) and A443T (14) in the PCSK9 gene have been associated with low levels of ...
    hmg.oxfordjournals.org/cgi/content/full/15/9/1551
  • Effect of mutations in the PCSK9 gene on the cell surface LDL ...
    The proprotein convertase subtilisin/kexin type 9 (PCSK9) gene is involved in the post-transcriptional ... L253F (14) and A443T (14) in the PCSK9 gene have been. associated with ...
    hmg.oxfordjournals.org/cgi/reprint/15/9/1551.pdf
  • PCSK9, from gene to protein and plasma.
    The PCSK9 gene (Proprotein Convertase Subtilisin Kexin 9) encodes an ... A443T was found in a woman aged 50 who presented with mild hypercholesterolemia and no ...
    www.ashg.org/genetics/abstracts/abs06/f1364.htm
  • Longitudinal Association of PCSK9 Sequence Variations with ...
    Longitudinal Association of PCSK9 Sequence Variations with LDL-Cholesterol Levels: The ... The 3 genetic variants and the A443T variant in African American men were ...
    circgenetics.ahajournals.org/cgi/content/abstract/...
  • Boerwinkle, E (Eric)
    BACKGROUND: Mutations of PCSK9 are associated cross-sectionally with plasma low ... The 3 genetic variants and the A443T variant in black men were associated with ...
    lib.bioinfo.pl/auid:5792

Other in silico analyses
 

  • NBLOSUM100 score = 1
  • GET-Evidence autoscore = 3

Edit history
 

Gene search

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