U.S. flag

An official website of the United States government

NM_024006.4(VKORC1):c.-1639G>A AND Warfarin response

Clinical significance:Pathogenic; drug response (Last evaluated: Sep 1, 2010)

Review status:(0/4) 0 stars out of maximum of 4 stars

no assertion criteria provided

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000002295.8

Allele description [Variation Report for NM_024006.4(VKORC1):c.-1639G>A]

NM_024006.4(VKORC1):c.-1639G>A

Gene:
VKORC1:vitamin K epoxide reductase complex subunit 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
16p11.2
Genomic location:
Preferred name:
NM_024006.4(VKORC1):c.-1639G>A
Other names:
VKORC1, -1639G-A (rs9923231)
HGVS:
  • NC_000016.10:g.31096368C>T
  • NG_011564.1:g.3588G>A
  • LRG_582:g.3588G>A
  • NC_000016.9:g.31107689C>T
  • NM_024006.4:c.-1639G>A
  • c.-1639G>A
Nucleotide change:
-1639G>A
Links:
OMIM: 608547.0006; dbSNP: rs9923231
NCBI 1000 Genomes Browser:
rs9923231
Observations:
254

Condition(s)

Name:
Warfarin response
Synonyms:
COUMARIN SENSITIVITY; COUMARIN, POOR METABOLISM OF; WARFARIN RESISTANCE; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0007390; MedGen: C0750384; OMIM: 122700

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000022453OMIMno assertion criteria providedPathogenic
(Sep 1, 2010)
germlineliterature only

PubMed (3)
[See all records that cite these PMIDs]

SCV000202013Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicineno assertion criteria provideddrug response
(Dec 16, 2006)
Condition: Warfarin Metabolism
germlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided257254not providednot providednot providedliterature only, clinical testing

Citations

PubMed

A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity.

Yuan HY, Chen JJ, Lee MT, Wung JC, Chen YF, Charng MJ, Lu MJ, Hung CR, Wei CY, Chen CH, Wu JY, Chen YT.

Hum Mol Genet. 2005 Jul 1;14(13):1745-51. Epub 2005 May 11.

PubMed [citation]
PMID:
15888487

Warfarin pharmacogenetics: CYP2C9 and VKORC1 genotypes predict different sensitivity and resistance frequencies in the Ashkenazi and Sephardi Jewish populations.

Scott SA, Edelmann L, Kornreich R, Desnick RJ.

Am J Hum Genet. 2008 Feb;82(2):495-500. doi: 10.1016/j.ajhg.2007.10.002. Epub 2008 Jan 17.

PubMed [citation]
PMID:
18252229
PMCID:
PMC2427171
See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000022453.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (3)

Description

The derived -1639T or A allele (referred to differently depending on the publication) is associated with lower required warfarin dosing and higher risks of bleeding (Ross et al., 2010).

In a study to determine DNA sequence variants in 16 Chinese patients with warfarin sensitivity or resistance (122700), 104 randomly selected Chinese patients receiving warfarin, 95 normal Chinese controls, and 92 normal Caucasians, Yuan et al. (2005) identified homozygosity for a VKORC1 promoter polymorphism, -1639G-A (rs9923231), in genomic DNA of all 11 warfarin-sensitive patients. Among the 104 randomly selected Chinese patients receiving warfarin, those with the AA genotype required a lower dose than those with the AG or GG genotype (P less than 0.0001). Frequencies of AA, AG, and GG genotypes were comparable in Chinese patients receiving warfarin (79.7%, 17.6%, and 2.7%) and normal Chinese controls (82%, 18%, and 0%), but differed significantly from Caucasians (14%, 47%, and 39%) (P less than 0.0001). The promoter polymorphism abolished the E-box consensus sequences, and dual luciferase assay revealed that VKORC1 promoter with the G allele had a 44% increase of activity when compared with the A allele.

The VKORC1 promoter polymorphism -1639G-A occurs frequently in patients who are warfarin-sensitive and require lower doses, whereas patients with VKORC1 missense mutations are warfarin-resistant and require higher doses. Scott et al. (2008) studied this and other polymorphisms of CYP2C9 (601130) and VKORC1 in Ashkenazi and Sephardi Jewish individuals. Unlike African Americans and similar to other individuals of European descent, the -1639A allele was present at high frequencies in both Ashkenazi (0.467) and Sephardi (0.500) cohorts.

Ross et al. (2010), who referred to the VKORC1 rs9923231 polymorphism as a C-to-T change, genotyped 963 individuals from 7 geographic regions. Very low frequencies for the T allele were found in African populations (less than 10%), with the exception of the San (33%). The frequencies of the T allele were intermediate in Europe (30 to 65%), the Middle East (41 to 51%), Central/South Asia (17 to 61%), Oceania (23 to 39%), and the Americas (14 to 75%). The frequencies of the T allele were very high in East Asian populations, with frequencies ranging from 75% (She) to 100% (Han and Oroqen). Similar frequencies were found in a Canadian cohort of 316 individuals of European, East Asian, and South Asian ancestry. The findings indicated a high overall percentage (about 32%) of total variation of this allele due to genetic differences in various geographic regions.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000202013.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided257not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided257not provided254not provided

Last Updated: Jan 21, 2023