ABCG5 R50C - GET-Evidence

Curation:
Currentness:

ABCG5 R50C

(ABCG5 Arg50Cys)


Short summary

This variant has a mild protective effect on blood cholesterol. It is associated with slightly lower total and LDL cholesterol levels.

Variant evidence
Computational 1

Disruptive amino acid change

Functional -
Case/Control 4

High statistical significance from a genome-wide association study

See Aulchenko YS et al. 2009 (19060911).

Familial

No familial data

 
Clinical importance
Severity 2

High cholesterol may lead to heart disease

Treatability 4

Diet, weight loss, and drug treatment can address high cholesterol.

Penetrance 1

See Aulchenko YS et al. 2009 (19060911).

 

Impact

Low clinical importance, Likely protective

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

Inheritance pattern

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Summary of published research, and additional commentary

 

Allele frequency

  • A @ chr2:44065090: 6.8% (736/10758) in EVS
  • A @ chr2:43918593: 12.5% (16/128) in GET-Evidence
  • Frequency shown in summary reports: 6.8% (736/10758)

Publications
 

Aulchenko YS, Ripatti S, Lindqvist I, Boomsma D, Heid IM, Pramstaller PP, Penninx BW, Janssens AC, Wilson JF, Spector T, Martin NG, Pedersen NL, Kyvik KO, Kaprio J, Hofman A, Freimer NB, Jarvelin MR, Gyllensten U, Campbell H, Rudan I, Johansson A, Marroni F, Hayward C, Vitart V, Jonasson I, Pattaro C, Wright A, Hastie N, Pichler I, Hicks AA, Falchi M, Willemsen G, Hottenga JJ, de Geus EJ, Montgomery GW, Whitfield J, Magnusson P, Saharinen J, Perola M, Silander K, Isaacs A, Sijbrands EJ, Uitterlinden AG, Witteman JC, Oostra BA, Elliott P, Ruokonen A, Sabatti C, Gieger C, Meitinger T, Kronenberg F, Döring A, Wichmann HE, Smit JH, McCarthy MI, van Duijn CM, Peltonen L; ENGAGE Consortium. Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nat Genet. 2009 Jan;41(1):47-55. Epub 2008 Dec 7. PubMed PMID: 19060911; PubMed Central PMCID: PMC2687074.

In a GWAS study of Europeans, this variant was associated with total cholesterol and low density lipids, with significances of 1.5E-11 and 2.6E-10 respectively. Because this is a genome-wide association, a p-value of 5 * 10^-8 was set as the cut-off, this exceeds that threshold 100- to 1000-fold.

Positive betas of 0.145 and 0.157 (effect of variant in standard deviations) are reported associating the reference allele at this position (G, with a “causal allele frequency” of 0.92, see Table 2) with higher cholesterol and LDL levels. This means that this variant (A, which we find has an allele frequency of ~0.07). The amount of total LDL variance explained by all genes in the study was 1-5%; we treat this variant, which was the strongest effect found, as having “penetrance” of 1-2%.

Genomes
 

 

 

 

hu604D39 - CGI sample GS00253-DNA_B02_200_37
het A @ chr2:44065090

 

GS12004 - var-GS12004-1100-36-ASM
het A @ chr2:43918594

 

GS18502 - var-GS18502-1100-36-ASM
het A @ chr2:43918594

 

GS19025 - var-GS19025-1100-36-ASM
het A @ chr2:43918594

 

GS19648 - var-GS19648-1100-36-ASM
het A @ chr2:43918594

 

GS19649 - var-GS19649-1100-36-ASM
het A @ chr2:43918594

 

GS19669 - var-GS19669-1100-36-ASM
het A @ chr2:43918594

 

GS19701 - var-GS19701-1100-36-ASM
het A @ chr2:43918594

 

GS19703 - var-GS19703-1100-36-ASM
het A @ chr2:43918594

 

GS19834 - var-GS19834-1100-36-ASM
hom A @ chr2:43918594

 

GS21767 - var-GS21767-1100-36-ASM
het A @ chr2:43918594

 

Other external references
 

    dbSNP
  • rs6756629
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    GWAS
  • Cholesterol, total (rs6756629-G)
    Aulchenko 7-Dec-08 in Nat Genet
    OR or beta: 0.15 [NR] SD increase
    Risk allele frequency: 0.92
    p-value: 2.00E-11
    Initial sample: 22,562 individuals
    Replication sample: NR
    www.ncbi.nlm.nih.gov/pubmed/19060911
  • LDL cholesterol (rs6756629-G)
    Aulchenko 7-Dec-08 in Nat Genet
    OR or beta: 0.16 [NR] SD increase
    Risk allele frequency: 0.92
    p-value: 3.00E-10
    Initial sample: 17,797 individuals
    Replication sample: NR
    www.ncbi.nlm.nih.gov/pubmed/19060911
    PolyPhen-2
  • Score: 0.985 (probably damaging)
    Web search results (9 hits -- see all)
  • BioMed Central | Full text | A detailed Hapmap of the ...
    Two genes, ABCG5 and ABCG8, comprise the STSL and mutations in either cause sitosterolemia. ... is provided in Table 1. Only two loci in ABCG5, R50C and Q604E showed variations ...
    www.biomedcentral.com/1471-2350/7/13
  • A detailed Hapmap of the Sitosterolemia locus spanning 69 kb ...
    Two genes, ABCG5 and ABCG8, comprise the STSL and mutations in either cause sitosterolemia. ... is provided in Table 1. Only two loci in ABCG5, R50C and Q604E showed variations ...
    www.biomedcentral.com/content/xml/1471-2350-7-13.xml
  • Potential etiologic and functional implications of genome ...
    Genome Technology Branch, National Human Genome Research Institute, and ... R50C. rs6756629. ABCG5. ABCG5. LDL. PP & CDP. rs1800562. C282Y. rs1800562. HFE ...
    genome.gov/Pages/.../News&Features/PNASGWASOnlineCatalog.pdf
  • Type II- 98%
    ... PROT ID Variant site Phosphorylation site SWISS-PROT variant ID Removed kinase ... rs3177338) 12482879 ABCG5 Q9H222 Q604E 603 VAR_012249 PIKK (0.979) Polymorphism ...
    nih.go.kr/phosphovariant/html/family_whole/TypeII-_98.txt
  • Type II- 95%
    ... SWISS-PROT ID Variant site Phosphorylation site SWISS-PROT variant ID Removed ... Polymorphism (dbSNP:rs35597368) CHST6 Q9GZX3 R50C 48 VAR_021421 PKC (0.893) ...
    nih.go.kr/phosphovariant/html/family_whole/TypeII-_95.txt

Other in silico analyses
 

  • NBLOSUM100 score = 8
  • GET-Evidence autoscore = 4

Edit history
 

Gene search

"GENE" or "GENE A123C":

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