NM_000088.3(COL1A1):c.104-441G= AND Bone mineral density variation quantitative trait locus

Clinical significance:association (Last evaluated: Aug 1, 2009)

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

no assertion criteria provided

Based on:
1 submission [Details]
Record status:

Allele description [Variation Report for NM_000088.3(COL1A1):c.104-441G=]


COL1A1:collagen type I alpha 1 chain [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
  • NC_000017.11:g.50200388C=
  • NG_007400.1:g.6252G=
  • NM_000088.3:c.104-441G=
  • LRG_1t1:c.104-441G=
  • LRG_1:g.6252G=
  • NC_000017.10:g.48277749C=
OMIM: 120150.0051; dbSNP: rs1800012
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000088.3:c.104-441G= - intron variant - [Sequence Ontology: SO:0001627]


Bone mineral density variation quantitative trait locus
MedGen: C4015951

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000039157OMIMno assertion criteria providedassociation
(Aug 1, 2009)
germlineliterature only

PubMed (7)
[See all records that cite these PMIDs]

Gilsanz, V. Personal Communication. 2008. Los Angeles, Calif.

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only



Reduced bone density and osteoporosis associated with a polymorphic Sp1 binding site in the collagen type I alpha 1 gene.

Grant SF, Reid DM, Blake G, Herd R, Fogelman I, Ralston SH.

Nat Genet. 1996 Oct;14(2):203-5.

PubMed [citation]

Relation of alleles of the collagen type Ialpha1 gene to bone density and the risk of osteoporotic fractures in postmenopausal women.

Uitterlinden AG, Burger H, Huang Q, Yue F, McGuigan FE, Grant SF, Hofman A, van Leeuwen JP, Pols HA, Ralston SH.

N Engl J Med. 1998 Apr 9;338(15):1016-21.

PubMed [citation]
See all PubMed Citations (7)

Details of each submission

From OMIM, SCV000039157.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (7)


Screening the COL1A1 transcriptional control regions by PCR-SSCP in a sample of 50 subjects, Grant et al. (1996) found 3 polymorphisms in the first intron, 2 of which were rare (allele frequency approximately 4% and 3%) and 1 common (allele frequency approximately 22%). The common polymorphism was characterized as a G-to-T substitution at the first base of a consensus site for the transcription factor Sp1 (189906) in the first intron of COL1A1 (nucleotide 2046). Grant et al. (1996) devised a PCR-based screen and studied allele distribution in 2 populations of British women, 1 in Aberdeen and 1 in London. They found that the G/T polymorphism was significantly related to bone mass and osteoporotic fracture (166710). G/T heterozygotes had significantly lower bone mineral density (BMD) than G/G homozygotes (SS) in both populations, and BMD was lower still in G/T homozygotes (ss). The unfavorable Ss and ss genotypes were over-represented in patients with severe osteoporosis and vertebral fractures (54%), as compared with controls (27%) equivalent to a relative risk of 2.97 for vertebral fracture in individuals who carried the 's' allele. These results were confirmed and extended by Uitterlinden et al. (1998).

Uitterlinden et al. (1998) studied the Sp1-binding site polymorphism in 1,778 postmenopausal women in the Netherlands and found that compared with the 1,194 women with the SS genotype, the 526 women with the Ss genotype had 2% lower bone mineral density at the femoral neck (p = 0.003) and the lumbar spine (p = 0.02); the 58 women with the ss genotype had reductions of 4% at the femoral neck (p = 0.05) and 6% at the lumbar spine (p = 0.005). These differences increased with age. Women with the Ss and ss genotypes were overrepresented among the 111 women who had incident nonvertebral fractures.

Uitterlinden et al. (2001) studied the interaction between polymorphisms of the vitamin D receptor gene (VDR; 601769) and the Sp1-binding site polymorphism of COL1A1 and concluded that interlocus interaction is likely to be an important component of osteoporotic fracture risk.

Sainz et al. (1999) studied the Sp1-binding site polymorphism and measurements of the size and the density of vertebral bone in 109 healthy prepubertal girls. On average, 22 girls with the Ss genotype and 1 girl with the ss genotype had 6.7% and 33.2% lower cancellous bone density in the vertebrae, respectively, than girls with the SS genotype. In contrast, there was no association between the size of the vertebrae and the COL1A1 genotypes. (One of the authors (Gilsanz, 2008) noted that the correct ss genotype figure is 33.2% rather than the 49.4% cited in the 1999 article.)

In an association study involving 3,270 women enrolled in an osteoporosis screening program, Stewart et al. (2006) analyzed 3 SNPs in the promoter and intron 1 of the COL1A1 gene (the Sp1-binding site polymorphism rs1800012, which they designated +1245G/T; rs1107946, and rs2412298) and their haplotypes. The polymorphisms were in strong linkage disequilibrium and 3 haplotypes accounted for more than 95% of the alleles at the COL1A1 locus. Homozygote carriers of 'haplotype 2' had reduced BMD, whereas homozygote carriers of 'haplotype 3' had increased BMD. Stewart et al. (2006) concluded that there is bidirectional regulation of BMD by the 2 haplotypes in the 5-prime flank of COL1A1.

In a case-control study of 206 Caucasians with otosclerosis (see 166800) and 282 Caucasian controls, Chen et al. (2007) identified 2 haplotypes, composed of 5 SNPs in the COL1A1 gene (rs1800012, rs9898186, rs2269336, rs11327935, and rs1107946), that were significantly associated with otosclerosis. In osteoblast cell lines, the protective H2 haplotype decreased promoter activity, whereas the susceptibility H3 haplotype increased promoter activity by affecting binding of transcription factors to cis-acting elements, suggesting that increased amounts of collagen alpha-1 homotrimers are causally related to the development of otosclerosis. Consistent with this hypothesis, Chen et al. (2007) demonstrated hearing loss in mice from a naturally occurring mutant strain that only deposits homotrimeric type I collagen. The authors designated the Sp1-binding site polymorphism, rs1800012, as +1126G/T.

Jin et al. (2009) showed that the previously reported 5-prime untranslated region (UTR) SNPs in the COL1A1 gene (-1997G-T, rs1107946, 120150.0067; -1663indelT, rs2412298, 120150.0068; +1245G-T, rs1800012) affected COL1A1 transcription. Transcription was 2-fold higher with the osteoporosis-associated G-del-T haplotype compared with the common G-ins-G haplotype. The region surrounding rs2412298 recognized a complex of proteins essential for osteoblast differentiation and function including NMP4 (ZNF384; 609951) and Osterix (SP7; 606633), and the osteoporosis-associated -1663delT allele had increased binding affinity for this complex. Further studies showed that haplotype G-del-T had higher binding affinity for RNA polymerase II, consistent with increased transcription of the G-del-T allele, and there was a significant inverse association between carriage of G-del-T and bone mineral density (BMD) in a cohort of 3,270 Caucasian women. Jin et al. (2009) concluded that common polymorphic variants in the 5-prime UTR of COL1A1 regulate transcription by affecting DNA-protein interactions, and that increased levels of transcription correlated with reduced BMD values in vivo by altering the normal 2:1 ratio between alpha-1(I) and alpha-2(I) chains.

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

Last Updated: Mar 30, 2019

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