ABCC6 R1268Q - GET-Evidence

Curation:
Currentness:

ABCC6 R1268Q

(ABCC6 Arg1268Gln)


Short summary

This common polymorphism appears to not have a significant phenotypic impact. A few studies report weak but significant associations with plasma lipids (in Inuits) and thalidomide toxicity.

Variant evidence
Computational -1

Not a disruptive amino acid change according to BLOSUM100, Polyphen predicts this is benign.

Functional -
Case/Control 3

Some report weak but statistically significant associations to lipids or drug interactions.

See Germain DP et al. 2000 (10913334), Wang J et al. 2001 (11776382), Deeken JF et al. 2009 (20038957).

Familial

No familial data

 
Clinical importance
Severity 1
Treatability
Penetrance 1
 

Impact

Low clinical importance, Uncertain pharmacogenetic

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

Inheritance pattern

unknown

Summary of published research, and additional commentary

 

Allele frequency

  • T @ chr16:16251599: 21.9% (2355/10758) in EVS
  • T @ chr16:16159099: 13.3% (17/128) in GET-Evidence
  • Frequency shown in summary reports: 21.9% (2355/10758)

Publications
 

Ringpfeil F, Lebwohl MG, Christiano AM, Uitto J. Pseudoxanthoma elasticum: mutations in the MRP6 gene encoding a transmembrane ATP-binding cassette (ABC) transporter. Proc Natl Acad Sci U S A. 2000 May 23;97(11):6001-6. PubMed PMID: 10811882; PubMed Central PMCID: PMC18548.

This variant is described as being compound heterozygous in three of eight families with PXE.

Germain DP, Perdu J, Remones V, Jeunemaitre X. Homozygosity for the R1268Q mutation in MRP6, the pseudoxanthoma elasticum gene, is not disease-causing. Biochem Biophys Res Commun. 2000 Aug 2;274(2):297-301. PubMed PMID: 10913334.

The authors report noticing this variant in a large Pseudoxanthoma elasticum (PXE) pedigree and, upon following up, finding in an unrelated partner and at a relatively high frequency in their Caucasian controls (62 subjects). Three healthy volunteers were homozygous for this variant. They conclude that the variant does not cause PXE although it could have a modifier role.

Wang J, Near S, Young K, Connelly PW, Hegele RA. ABCC6 gene polymorphism associated with variation in plasma lipoproteins. J Hum Genet. 2001;46(12):699-705. PubMed PMID: 11776382.

In a study of 216 Inuit, the authors report that this variant is associated with lower plasma triglycerides and higher plasma HDL cholesterol (p = 0.012 and p = 0.045, respectively). They magnitude of the effect is not reported, and the authors do not report on how much of overall variance this variant would explain.

Deeken JF, Cormier T, Price DK, Sissung TM, Steinberg SM, Tran K, Liewehr DJ, Dahut WL, Miao X, Figg WD. A pharmacogenetic study of docetaxel and thalidomide in patients with castration-resistant prostate cancer using the DMET genotyping platform. Pharmacogenomics J. 2009 Dec 29. [Epub ahead of print] PubMed PMID: 20038957.

This variant has a weak but statistically significant association with toxicity of thalidomide, but it’s unclear from the publication whether carriers of the variant are more or less susceptible.

Genomes
 

hu025CEA - CGI sample GS01669-DNA_D02 from PGP sample 27316983
het T @ chr16:16251599

 

 

hu2D6140 - CGI sample GS01173-DNA_F06 from PGP sample 64191565
het T @ chr16:16251599

 

hu2DBF2D - CGI sample GS01173-DNA_G02 from PGP sample 67180598
het T @ chr16:16251599

 

 

hu342A08 - CGI sample GS01175-DNA_B05 from PGP sample 83494370
het T @ chr16:16251599

 

hu3CAB43 - CGI sample GS01175-DNA_D03 from PGP sample 27486199
het T @ chr16:16251599

 

hu4040B8 - CGI sample GS01175-DNA_D01 from PGP sample 31286272
het T @ chr16:16251599

 

hu4339C0 - CGI sample GS01175-DNA_H01 from PGP sample 94797469
het T @ chr16:16251599

 

hu44DCFF - CGI sample GS01669-DNA_C07 from PGP sample 74521372
het T @ chr16:16251599

 

hu4CA5B9 - CGI sample GS01669-DNA_B03 from PGP sample 14427241
het T @ chr16:16251599

 

 

 

huAE4A11 - CGI sample GS01669-DNA_F02 from PGP sample 40767107
het T @ chr16:16251599

 

huB1FD55 - CGI sample GS01173-DNA_B07 from PGP sample 61499538
het T @ chr16:16251599

 

huBAAC98 - CGI sample GS01173-DNA_F02 from PGP sample 70008981
het T @ chr16:16251599

 

huBEDA0B - CGI sample GS00253-DNA_C01_200_37
het T @ chr16:16251599

 

huFAF983 - CGI sample GS01175-DNA_F02 from PGP sample 95788191
het T @ chr16:16251599

 

GS07357 - var-GS07357-1100-36-ASM
hom T @ chr16:16159100

 

GS10851 - var-GS10851-1100-36-ASM
het T @ chr16:16159100

 

GS12004 - var-GS12004-1100-36-ASM
hom T @ chr16:16159100

 

GS18502 - var-GS18502-1100-36-ASM
het T @ chr16:16159100

 

GS19239 - var-GS19239-1100-36-ASM
het T @ chr16:16159100

 

GS19669 - var-GS19669-1100-36-ASM
hom T @ chr16:16159100

 

GS19701 - var-GS19701-1100-36-ASM
het T @ chr16:16159100

 

GS20509 - var-GS20509-1100-36-ASM
het T @ chr16:16159100

 

Other external references
 

    dbSNP
  • rs2238472
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PharmGKB
  • [Prostatic Neoplasms]
    [docetaxel; thalidomide]
    Risk or phenotype-associated allele: G Phenotype: The ABCC6 rs2238472 G variant was associated with toxicity in response to docetaxel and thalidomide. Study size: 47 Study population/ethnicity: Patients diagnosed with castration-resistant prostate cancer enrolled in a randomized phase II clinical trial comparing docetaxel to docetaxel with thalidomide. Significance metric(s): p = 0.006 Type of association: CO; TOX
    www.ncbi.nlm.nih.gov/pubmed/20038957
    Web search results (93 hits -- see all)
  • Template Paper
    In this study we investigated the association of the ABCC6 gene and AS. ... In conclusion, the missense mutation R1268Q in the ABCC6 gene is not a specific marker of PXE, but is ...
    ijbs.org/User/ContentFullText.aspx?VolumeNO=2&StartPage=9
  • Four most Frequent PXE Mutations in the ABCC6 Gene are not ...
    Background: Mutations in ABCC6 cause Pseudoxanthoma elasticum (PXE), a mendelian disorder ... Q378X) and two SNP (V614A, R1268Q) in a total of 3316 participants ...
    www.ashg.org/genetics/ashg07s/f20670.htm
  • Directory of open access journals
    In this study we investigated the association of the ABCC6 gene and AS. ... In conclusion, the missense mutation R1268Q in the ABCC6 gene is not a specific marker of PXE, but is ...
    www.doaj.org/doaj?func=abstract&id=252501&recNo=2&toc=1
  • Retina International's Scientific Newsletter - ABCC6 Mutations
    R1268Q, single heterozygote (1) PXE. Arg 1141 ter. C-T. 3421. 24. BsiYI ... Base-Pair Substitutions in the ABCC6 Gene Results in Pseudoxanthoma Elasticum. ...
    www.retina-international.org/sci-news/abcc6mut.htm
  • Pharma DMET - SNPedia
    Gene Symbol Marker Name Translation Table Name Category Marker Type ... snp rs6416668 ABCC6 ABCC6_53629C>T(P945P) noncore snp rs2856585 ABCC6 ABCC6_65693G>A(R1268Q) noncore snp ...
    www.snpedia.com/index.php/Pharma_DMET
  • ABCC6 Gene - GeneCards | MRP6 Protein | MRP6 Antibody
    Complete information for ABCC6 gene (protein-coding), ATP-binding cassette, sub-family C (CFTR/MRP), member 6
    www.genecards.org/cgi-bin/carddisp.pl?gc_id=GC16M016151
  • A Spectrum of ABCC6 Mutations Is Responsible for ...
    A Spectrum of ABCC6 Mutations Is Responsible for Pseudoxanthoma Elasticum ... X (2000) Homozygosity for the R1268Q mutation in MRP6, the pseudoxanthoma elasticum ...
    www.ncbi.nlm.nih.gov/pmc/articles/PMC1226061/?tool=pubmed
  • Mendelian Inheritance in Man Document Reader
    The ABCC6 protein consists of 1,503 amino acids with a molecular weight of 165 ... high expression of ABCC6 in liver and kidney, ABCC6 substrates may be ...
    www.angis.org.au/bin/Databases/BIRX/birx_doc?phtomim+603234

Other in silico analyses
 

  • NBLOSUM100 score = 0
  • GET-Evidence autoscore = 4

Edit history
 

Gene search

"GENE" or "GENE A123C":

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