Abstract
After completion of Human Genome Project (HGP) in 2003, as well as the new technology development in genomic research, the most accurate genetics blueprint of human is available. Researchers started to dissect and understand the genetic map of the human species. As a consequence, analyses of novel or unclassified genetic variations become increasingly important in translational medicine. One of the medical specialties in modern medicine is clinical genetics, which is overseen by the American Board of Medical Genetics (ABMG). In 2008, ABMG published a guideline for interpretation of new variants using ACMG Standards and Guidelines (Richards et al. Genet Med 10:294–300, 2008). In this chapter, we provide updated procedures of evaluating different databases, computational tools, and structural analysis methods that we currently utilize to assist in clinical interpretation.
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References
Richards, C. S., Bale, S., Bellissimo, D. B., Das, S., Grody, W. W., Hegde, M. R., Lyon, E., Ward, B. E., and the Molecular Subcommittee of the ACMG; Laboratory Quality Assurance Committee. (2008) ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007, Genetics in Medicine 10, 294–300.
Stenson, P., Mort, M., Ball, E., Howells, K., Phillips, A., Thomas, N., and Cooper, D. (2009) The Human Gene Mutation Database: 2008 update, Genome Med 1, 13.
Copeland, W. C. (2008) Inherited Mitochondrial Diseases of DNA Replication, Annual Review of Medicine 59, 131–146.
Ferré, M., Amati-Bonneau, P., Tourmen, Y., Malthièry, Y., and Reynier, P. (2005) eOPA1: An online database for OPA1 mutations, Human Mutation 25, 423–428.
Kumar, P., Henikoff, S., and Ng, P. C. (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm, Nat. Protocols 4, 1073–1081.
Adzhubei, I. A., Schmidt, S., Peshkin, L., Ramensky, V. E., Gerasimova, A., Bork, P., Kondrashov, A. S., and Sunyaev, S. R. (2010) A method and server for predicting damaging missense mutations, Nat Meth 7, 248–249.
Cartegni, L., Wang, J., Zhu, Z., Zhang, M. Q., and Krainer, A. R. (2003) ESEfinder: a web resource to identify exonic splicing enhancers, Nucleic Acids Research 31, 3568–3571.
Cartegni, L., Chew, S. L., and Krainer, A. R. (2002) Listening to silence and understanding nonsense: exonic mutations that affect splicing, Nat Rev Genet 3, 285–298.
Brunak, S., Engelbrecht, J., and Knudsen, S. (1991) Prediction of human mRNA donor and acceptor sites from the DNA sequence, Journal of Molecular Biology 220, 49–65.
Reese, M. G., Eeckman, F. H., Kulp, D., and Haussler, D. (1997) Improved splice site detection in Genie, J Comput Biol 4, 311–323.
Ingman, M., and Gyllensten, U. (2005) mtDB: Human Mitochondrial Genome Database, a resource for population genetics and medical sciences, Nucleic Acids Research 34, D749-D751.
Helm, M., Brule, H., Friede, D., Giege, R., Putz, D., and Florentz, C. (2000) Search for characteristic structural features of mammalian mitochondrial tRNAs, RNA 6, 1356–1379.
Cohn, A. C., Toomes, C., Potter, C., Towns, K. V., Hewitt, A. W., Inglehearn, C. F., Craig, J. E., and Mackey, D. A. (2007) Autosomal Dominant Optic Atrophy: Penetrance and Expressivity in Patients With OPA1 Mutations, American Journal of Ophthalmology 143, 656–662.e651.
Delettre, C., Lenaers, G., Griffoin, J.-M., Gigarel, N., Lorenzo, C., Belenguer, P., Pelloquin, L., Grosgeorge, J., Turc-Carel, C., Perret, E., Astarie-Dequeker, C., Lasquellec, L., Arnaud, B., Ducommun, B., Kaplan, J., and Hamel, C. P. (2000) Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy, Nat Genet 26, 207–210.
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Zhang, V.W., Wang, J. (2012). Determination of the Clinical Significance of an Unclassified Variant. In: Wong, Ph.D., LJ. (eds) Mitochondrial Disorders. Methods in Molecular Biology, vol 837. Humana Press. https://doi.org/10.1007/978-1-61779-504-6_23
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DOI: https://doi.org/10.1007/978-1-61779-504-6_23
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