Table 1

References for Table 1. Proteins with substitutions that have been shown to be involved in disease. In bold are the substitutions for which there is evidence supporting the prediction. The first column is the substitution, the second column is the SIFT prediction, the third column are the references for the variant.

Protein: Fibrillin
S1077P | Tolerated | Marfan (Liu, et al. 1997/1998)
D1113G | # Damaging | Marfan (Liu, et al. 1997/1998)
P1148A | Tolerated | Polymorphism (Liu, et al. 1997/1998)
C1153Y | Damaging | In MFS (according to SWISS-PROT)
V1667I | Tolerated | Marfan (Liu, et al. 1997/1998)
N1341S | Tolerated | Marfan (Liu, et al. 1997/1998)
N1282S | Tolerated | Marfan (Liu, et al. 1997/1998)
V2018I | # Tolerated | Control (Pima Indian) (Peter Oefner, personal communication)
I2023T | Damaging | Marfan (Liu, et al. 1997/1998)
C2038Y | Damaging | Marfan (Peter Oefner, personal communication)
C2053F | Damaging | Marfan (Peter Oefner, personal communication)
C2500S | Damaging | Marfan (Peter Oefner, personal communication)
G2514R | Damaging | Marfan (Peter Oefner, personal communication)
C2110R | Damaging | Marfan (Peter Oefner, personal communication)
Y2113F | Tolerated | Control (Pygmy) (Peter Oefner, personal communication)
C2170F | Damaging | Marfan (Peter Oefner, personal communication)
D2329E | Tolerated | Control (Taiwan) (Peter Oefner, personal communication)
P2278S | Tolerated | Control (Sudan, Pakistan) (Peter Oefner, personal communication)

Protein: a-melanocyte stimulating hormone receptor
R151C | # Damaging | Increased risk of CMM (Palmer, et al. 1999) Also shown to be unable to produce cAMP upon stimulation (Frandberg, et al. 1998).
D84E | Damaging | Risk of melanoma (Valverde, et al. 1996) but then later found to not be associated with CMM.(Healy, et al. 1999, Palmer, et al. 1999)
R163Q | # Tolerated | Detected from comparison of mRNA sequences (Irizarry, et al. 2000) and sequencing projects (TSC-CSHL). No association with CMM (Box, et al. 2001)
L60V | Tolerated | No association with CMM (Palmer, et al. 1999 and Box, et al. 2001)
R160W | Damaging | Double risk of CMM (Palmer, et al. 1999)
D294H | Damaging | Double risk of CMM (Palmer, et al. 1999)

Protein: Peroxisome proliferator activated receptor a
R127Q | # Damaging | Found in diabetics (Au, et al. 1998)
L162V | Damaging | Found in diabetics and control (Au, et al), but increases cholesterol and apolipoprotein B levels in diabetics, and perhaps nondiabetics (Flavell, et al. 2000, Lacquemant, et al. 2000, Vohl, et al. 2000).
V227A | Tolerated | Detected in diabetics (Au, et al., 1998) but found in similar frequencies between diabetics and nondiabetics in another study (Hara, et al. 2001)
A268V | Tolerated | Detected in diabetics (Au et al., 1998) and comparison of mRNA sequences: L02932 and NM_005036(derived from L02932) (Irizarry, et al. 2000) No association with diabetes or coronary heart disease (Lacquemant, 2000)
D304N | Damaging | Detected in diabetics (Au, et al., 1998)
R409T | Damaging | Detected in diabetics (Au, et al., 1998)

Protein: 5,10-methylenetetrahydrofolate reductase, possible case of balancing selection
R68Q | Damaging | Submitted by University of Washington Genome Center ??? Role unknown.
# A222V | # Damaging | Diminished enzyme activity shown and increased risk of vascular disease and neural tube defects (Frosst, et al. 1995) BUT reduced risk of adult acute leukemia (Skibola,et al. 1999), childhood leukemia (Wiemels, et al. 2001), and colon cancer (Ma, et al. 1997)
E429A | Damaging | Diminished enyme activity (Weisberg, et al. 1998) Reduction in risk to acute leukemia (Skibola, et al. 1999)

Protein: Apolipoprotein A-I
D126H | Damaging | Detected in individuals from either the top or bottom 2.5th percentile of a normalized blood pressure distribution (Halushka, et al. 1999). ??? Role unknown.
K131N | Tolerated | From comparison of ESTs (Garg, et al. 1999) and in an electrophoretic screening of newborns. (Von Eckardstein, et al. 1990) ??? Role unknown.
R184P | Damaging | Detected in individuals from either the top or bottom 2.5th percentile of a normalized blood pressure distribution (Halushka, et al. 1999). ??? Role unknown.

Au, K.G., Zhang, J., Purdy, G.D., Fraser, D.J., Lee, D., Noren, N.K,. Cronin, M.T., Chen, J. (1998) Polymorphism screening of the human peroxisome proliferator activated receptor a gene in diabetic patients by ABI sequencing and high density oligonucleotide array technology. Am. J. Human Genet. 63:abs 997 (data on poster, noted by A.J. Brookes and entered into HGBASE).

Box N.F., Duff D.L., Irving R.E., Russell, A., Chen, W., Griffyths, L.R., Parsons, P.G., Green, A.C., Sturm, R.A. (2001) Melanocortin-1 receptor genotype is a risk factor for basal and squamous cell carcinoma. J Invest. Dermatol. 116:224-229.

Flavell, D.M., Pineda Torra, I., Jamshidi, Y., Evans, D. Diamon, J.R., Elkeles, R.S., Bujac, S.R., Miller, G. Talmud, P.J., Staels, B., Humphries, S.E. (2000) Variation in the PPARa gene is associated with altered function in vitro and plasma lipid concentrations in Type II diabetic subjects. Diabetologia 43:673-680.

Frandberg, P.A., Doufexis, M., Kapas, S., Chhajlani, V. (1998) Human pigmentation phenotype: a point mutation generates nonfunctional MSH receptor. Biochem. Biophys. Res. Commun. 245:490-492.

Frosst, P., Blom, H.J., Milos, R., Goyette, P. Sheppard, C.A., Matthews, R.G., Boers, G.J., den Heijer, M., Khuijtmans, L.A., van den Heuvel, L.P., et al. (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nature Genetics 10:111-113.

Garg, K., Green, P., Nickerson, D.A. (1999) Identification of candidate coding region single nucleotide polymorphisms in 165 human genes using assembled expressed sequence tags. Genome Research 9:1087-1092.

Halushka, M.K., Fan, J., Bentley, K., Hsie, L., Shen, N., Weder, A., Cooper, R., Lipshutz, R., Chakravarti, A. (1999) Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostatsis. Nature Genetics 22:239-247.

Hara, M., Wang, X., Paz, V.P., Iwasaki, N., Honda, M., Iwamoto, Y., Bell, G.I. (2001) Identification of three missense mutations in the peroxisome proliferator-activated receptor alpha gene in Japanese subjects with mature-onset diabetes of the young. J. Hum. Genet. 46:285-288.

Healy, E. Todd, C., Jackson, I.J., Birch-Machin, M., Rees, J.L. (1999) Skin type, melanoma, and melanocortin 1 receptor variants. J. Invest. Dermatol. 112:512-513.

Irizarry, K., Kustanovich, V., Li, C. Brown, N., Nelson, S. Wong, W., Lee, C.J. (2000) Genome-wide analysis of single-nucleotide polymorphisms in human expressed sequences. Nature Genetics 26:233-236.

Lacquemant, C., Lepretre, F., Pineda Torra, I., Manraj, M., Charpentier, G., Ruiz, J., Staels, B., Froguel, P.H. (2000) Mutation screening of the PPARa gene in type 2 diabetes associated with coronary heart disease. Diabetes & Metabolism 26:393-401.

Liu, W., Oefner, P.J., Qian, C., Odom, R.S., Francke, U. (1997/1998) Denaturing HPLC-Identified Novel FBN1 Mutations, Polymorphisms, and Sequence Variants in Marfan Syndrome and Related Connective Tissue Disorder. Genetic Testing 1:237-242.

Ma, J., Stampfer, M.J., Giovannucci, E., Artigas, C., Hunter, D.J., Fuchs, C., Willet, W.C., Selhub, J., Hennekens, C.H., Rozen, R. (1997) Methylenetetrahydrofolate reductase polymorphism, dietary interacations, and risk of colorectal cancer. Cancer Research 57:1098-1102.

Palmer, J.S., Duffy, D.L., Box, N.F., Aitken, J.F., O’Gorman, L.e., Green, A.C., Hayward, N.K., Martin N.G., Sturm, R.A. (1999) Melanocortin-1 receptor polymorphisms and risk of melanoma: is the association explained solely by pigmentation phenotype? Am. J. Hum. Genet. 66:176-186.

Skibola, C.F., Smith, M.T., Kane, E., Roman, E., Rollinson, S., Cartwright, R.A., Morgan, G. (1999) Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults. Proc. Nat. Acad. Sci. 96:12810-12815.

Valverde, P. Healy, E., Jackson, I., Rees, J.L., Thoday, A.J. (1995) Variants of the melanocyte-stimulating hormone receptor gene are associated with red hair and fair skin in humans. Nature Genetics 11:328-330.

Valverde, P. Healy, E. Sikkink, S., Haldane, F., Thody, A.J., Carothers, A., Jackson, I.J., Rees, J.L. (1996) The Asp84Glu variant of the melanocortin 1 receptor (MC1R) is associated with melanoma. Human Molecular Genetics 5:1663-1666.

Vohl, M., Lepage, P., Gaudet, D., Brewer, C.G., Betard, C., Perron, P., Houde, G., Cellier, c ., Faith, J.M., Despres, J., Morgan, K., Hudson, T.J. (2000) Molecular scanning of the human PPARa gene: association of the L162v mutation with hyperapobetalipoproteinemia. J. Lipid Res. 41:945-52.

von Eckardstein, A., Funke,H., Walter, M., Altland, K., Benninghoven, A., Assmann, G. (1990) Structural analysis of human apolipoprotein A-I variants. Journal of Biological Chemistry 265:8610-8617.

Weisberg, I., Tran, P., Christensen, B., Sibani, S., Rozen, R.(1998) A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Molecular genetics and metabolism 64: 169-172.

Wiemels, J.L, Smith, R.N., Taylor, G.M., Eden, O.B., Alexander, F.E., Greaves, M.F., and United Kingdom Childhood Cancer Study Investigators. (2001) Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia. Proc. Nat. Acad. Sci. 98:4004-4009.