Table 3.

nsSNPs from dbSNP Predicted to Be Damaging Were Shown to Be Involved in Disease

Melanocyte stimulating hormone receptor
 Predictions supported by evidence
  R151CDamagingIncreased risk of cutaneous malignant melanoma (CMM) (Palmer et al. 1999).
  R160WDamagingDoubles risk of CMM (Palmer et al. 1999).
  D294HDamagingDoubles risk of CMM (Palmer et al. 1999).
  L60VToleratedNo association with CMM (Palmer et al. 1999, Box et al. 2001).
  R163QToleratedDetected from EST (Irizarry et al. 2000) and contig comparisons (Sachidanandam et al. 2001). No association with CMM (Box et al. 2001).
 Prediction not supported by evidence
  D84EDamagingNot associated with CMM (Healy et al. 1999; Palmer et al. 1999).
Peroxisome proliferator activated receptor α
 Prediction supported by evidence
  R127QDamagingDetected in diabetic (Au et al. 1998; Brookes et al. 2000).
  L162VDamagingDetected in diabetics and controls (Au et al. 1998; Brookes et al. 2000), but increases cholesterol and apolipoprotein B levels in diabetics, and perhaps nondiabetics (Flavell et al. 2000; Lacquemant et al. 2000; Vohl et al. 2000).
  D304NDamagingDetected in diabetic (Au et al. 1998; Brookes et al. 2000).
  R409TDamagingDetected in diabetic (Au et al. 1998; Brookes et al. 2000)
  V227AToleratedFound in similar frequencies in diabetics and nondiabetics (Au et al. 1998; Brookes et al. 2000; Hara et al. 2001).
  A268VToleratedDetected in diabetic (Au et al. 1998; Brookes et al. 2000) and EST comparison (Irizarry et al. 2000). No association with diabetes or coronary heart disease (Lacquemant et al. 2000).
Methylenetetrahydrofolate reductase (under balancing selection)
 Prediction supported by evidence
  A222VDamagingCommon variant with diminished enzyme activity and increased risk of vascular disease and neural tube defects (Frosst et al. 1995) but also reduces risk of adult acute leukemia (Skibola et al. 1999), childhood leukemia (Wiemels et al. 2001), and colon cancer (Ma et al. 1997).
  E429ADamagingCommon variant with diminished enzyme activity (Weisberg et al. 1998) but reduces risk of adult acute leukemia (Skibola et al. 1999).
 Effect unknown
  R68QDamagingDetected by comparison of contig to reference gene.
Fibrillin
 Prediction supported by evidence
  D1113GDamagingIn Marfan patient (Liu et al. 1997/1998).
  C1153YDamagingIn Marfan patient (Bairoch and Apweiler 2000).
  I2023TDamagingIn Marfan patient (Liu et al. 1997/1998).
  C2038YDamagingIn Marfan patient (P. Oefner, pers. comm.)
  C2053FDamagingIn Marfan patient (P. Oefner, pers. comm.).
  C2500SDamagingIn Marfan patient (P. Oefner, pers. comm.).
  G2514RDamagingIn Marfan patient (P. Oefner, pers. comm.).
  C2110RDamagingIn Marfan patient (P. Oefner, pers. comm.).
  C2170FDamagingIn Marfan patient (P. Oefner, pers. comm.).
  P1148AToleratedIn control individual (Liu et al. 1997/1998).
  V2018IToleratedIn control individual (P. Oefner, pers. comm.).
  Y2113FToleratedIn control individual (P. Oefner, pers. comm.).
  D2329EToleratedIn control individual (P. Oefner, pers. comm.).
  P2278SToleratedIn control individual (P. Oefner, pers. comm.).
 Prediction not supported by evidence
  S1077PToleratedIn Marfan patient (Liu et al. 1997/1998).
  V1667IToleratedIn Marfan patient (Liu et al. 1997/1998).
  N1341SToleratedIn Marfan patient (Liu et al. 1997/1998).
  N1282SToleratedIn Marfan patient (Liu et al. 1997/1998).
Apolipoprotein A-I
 Effect unknown
  D126HDamagingDetected in individuals from either the top or bottom 2.5th percentile of a normalized blood pressure distribution (Halushka et al. 1999).
  R184PDamagingDetected in individuals from either the top or bottom 2.5th percentile of a normalized blood pressure distribution (Halushka et al. 1999).
  K131NToleratedDetected from comparison of ESTs (Garg et al. 1999) and in an electrophoretic screening of newborns (von Eckardstein et al. 1990).

[i] Five genes with a high fraction of nsSNPs from dbSNP predicted to be damaging; these nsSNPs have been shown to be involved in disease. The proteins that these genes code for are listed. Under each protein, the first column is the amino acid substitution caused by the nsSNP. For example, the first row under melanocyte stimulating hormone receptor gives the prediction for an nsSNP that corresponded to a change from the original amino acid R to amino acid C at position 151 in the melanocyte stimulating hormone receptor protein. The second column is the SIFT prediction for that particular amino acid substitution, and the third column is evidence supporting or conflicting with the prediction. Most predictions are supported by previously published evidence.