ABCA1 p.Met1091Val
| Predicted by SNAP2: | A: D (71%), C: D (63%), D: D (91%), E: D (85%), F: D (66%), G: D (85%), H: D (85%), I: D (63%), K: D (91%), L: N (87%), N: D (85%), P: D (91%), Q: D (80%), R: D (91%), S: D (80%), T: D (80%), V: D (59%), W: D (66%), Y: D (71%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: N, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Accurate prediction of the functional significance... PLoS Genet. 2005 Dec;1(6):e83. Epub 2005 Dec 30. Brunham LR, Singaraja RR, Pape TD, Kejariwal A, Thomas PD, Hayden MR
Accurate prediction of the functional significance of single nucleotide polymorphisms and mutations in the ABCA1 gene.
PLoS Genet. 2005 Dec;1(6):e83. Epub 2005 Dec 30., [PMID:16429166]
Abstract [show]
The human genome contains an estimated 100,000 to 300,000 DNA variants that alter an amino acid in an encoded protein. However, our ability to predict which of these variants are functionally significant is limited. We used a bioinformatics approach to define the functional significance of genetic variation in the ABCA1 gene, a cholesterol transporter crucial for the metabolism of high density lipoprotein cholesterol. To predict the functional consequence of each coding single nucleotide polymorphism and mutation in this gene, we calculated a substitution position-specific evolutionary conservation score for each variant, which considers site-specific variation among evolutionarily related proteins. To test the bioinformatics predictions experimentally, we evaluated the biochemical consequence of these sequence variants by examining the ability of cell lines stably transfected with the ABCA1 alleles to elicit cholesterol efflux. Our bioinformatics approach correctly predicted the functional impact of greater than 94% of the naturally occurring variants we assessed. The bioinformatics predictions were significantly correlated with the degree of functional impairment of ABCA1 mutations (r2 = 0.62, p = 0.0008). These results have allowed us to define the impact of genetic variation on ABCA1 function and to suggest that the in silico evolutionary approach we used may be a useful tool in general for predicting the effects of DNA variation on gene function. In addition, our data suggest that considering patterns of positive selection, along with patterns of negative selection such as evolutionary conservation, may improve our ability to predict the functional effects of amino acid variation.
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No. Sentence Comment
63 To determine whether the severe phenotype conferred by the M1091T mutation is a result of the sensitivity of this site, or rather is specific to the insertion of the threonine residue, we generated and characterized cell lines transfected with plasmids bearing M1091L and M1091V alleles, both predicted to have no impact on ABCA1 function (subPSEC scores À2.65 and À2.71, respectively).
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ABCA1 p.Met1091Val 16429166:63:272
status: NEW87 (B) Cholesterol efflux was assessed in 293 cells stably transfected with wild-type, M1091T, M1091L, or M1091V ABCA1 alleles.
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ABCA1 p.Met1091Val 16429166:87:103
status: NEW139 In addition, both the M1091V and M1091L substitutions severely impaired the function of ABCA1, yet they were predicted to be functionally neutral.
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ABCA1 p.Met1091Val 16429166:139:22
status: NEW142 Therefore, when calculating amino acid probabilities for position 1091, the subPSEC method includes sequences from only ABCA1 and ABCA4, which represents enough sequence variability to predict that a relatively radical mutation such as M1091T will likely be deleterious but not enough to predict that relatively conservative mutations such as M1091L or M1091V will be deleterious.
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ABCA1 p.Met1091Val 16429166:142:353
status: NEW