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DMD#26047; "A bioinformatics approach for the phenotype prediction of non-synonymous single nucleotide polymorphisms in human cytochrome P450s", by Wang LL, Li Y, and Zhou SF. Supplementary Table 2. nsSNPs of human CYP genes and corresponding phenotypical effect based on in vitro and in vivo experiments. Gene Symbol CYP1A2 Residue Residue Position 1 2 SNP ID Phenotypical effect Pro 41 Arg swiss:var_025182 Decreased enzyme activity Phe 185 Leu Dramastic reduction in swiss:var_020850 O-deethylation of phenacetin and 7-ethoxyresorufin Asp 347 Asn swiss:var_020793 Decreased expression Arg 376 Gln swiss:var_025188 Dcreased enzyme activity Ile 385 Phe swiss:var_020794 Arg 430 Trp swiss:var_020796 Arg 455 His swiss:var_025189 Decreased activity Met 1 Thr Trp 57 Cys Gly 61 Glu rs28936700 GLC3A Tyr 81 Asn rs9282671 Glaucoma, primary open angle, adult-onset Gly 232 Arg OMIM0013 Gly 365 Trp Arg 368 His rs28936414 GLC3A Asp 374 Asn rs28936413 GLC3A OMIM0009 Site-Directed Mutagenesis in vitro yes in vitro yes in vivo yes in vitro yes in vivo yes in vivo yes in vitro yes in vivo no in vivo no in vivo no in vivo no in vivo no in vivo no in vivo no in vivo no Decreased expression Peters anomaly GLC3A swiss:var_001245 GLC3A 1 Reference (Saito et al., 2005) (Murayama et al., 2004) Decreased expression swiss:var_008350 Peters anomaly CYP1B1 Experiment (Zhou et al., 2004) (Saito et al., 2005) (Zhou et al., 2004) (Chevalier et al., 2001; Zhou et al., 2004) (Saito et al., 2005) (Vincent et al., 2001) (Vincent et al., 2001) (Bejjani et al., 1998) (Melki et al., 2004) (Melki et al., 2004) (Stoilov et al., 1998) (Vincent et al., 2002) (Bejjani et al., 1998) CYP2A6 CYP2B6 Glu 387 Lys swiss:var_008352 GLC3A Asn 423 Tyr OMIM0016 Glaucoma, primary open angle, juvenile-onset Arg 469 Trp rs28936701 GLC3A Val 110 Leu Phe 118 Leu Arg 128 Leu Arg 128 Gln Ser 131 Ala Leu 160 His Arg 203 Ser Ser 224 Pro rs28399447 Poor tegafur metabolism Val 365 Met rs28399454 Decreased activity Phe 392 Tyr rs1809810 Decreased activity Ile 471 Thr rs5031016 Decreased activity Lys 476 Arg rs6413474 Decreased activity. Gly 479 Val rs5031017 Loss of activity Arg 485 Leu rs28399468 Decreased activity Met 46 Val swiss:var_023564 Decreased expression. Gly 99 Glu swiss:var_023565 Decreased expression. Lys 139 Glu Arg 140 Gln swiss:var_023566 Decreased activity Pro 166 Ala dbsnp:rs3826711 Decreased activity Decrease of enzyme function rs28399440 Decrease of enzyme function Decrease of enzyme function rs4986891 Loss of activity Decrease of enzyme function rs1801272 Poor nicotine metabolism swiss:var_018333 Decreased activity rs12721655 Decreased expression. 2 in vivo no in vivo no in vivo no in vivo In vivo/in vitro In vivo/in vitro no in vitro In vivo/in vitro yes in vivo in vivo/in vitro in vivo/in vitro in vivo/in vitro in vivo/in vitro in vivo/in vitro no no no no no yes yes yes yes in vivo in vivo/in vitro no yes in vivo no in vitro yes in vitro yes in vitro yes in vitro yes in vivo no (Stoilov et al., 1998) (Melki et al., 2004) (Bejjani et al., 1998) (Mwenifumbo et al., 2008) (Mwenifumbo et al., 2008) (Mwenifumbo et al., 2008) (Kitagawa et al., 2001) (Mwenifumbo et al., 2008) (Hadidi et al., 1997) (Ho et al., 2008) (Daigo et al., 2002) (Fukami et al., 2004) (Fukami et al., 2005) (Ariyoshi et al., 2001) (Yoshida et al., 2002) (Haberl et al., 2005) (Oscarson et al., 1999) (Yoshida et al., 2002) (Lang et al., 2004) (Lang et al., 2004) (Lang et al., 2004) (Lang et al., 2004) (Gatanaga et al., 2007) Thr 168 Ile Decreased expression. Gln 172 His Met 198 Thr Lys 262 Arg Arg 336 Cys Ile 328 Thr Ile 391 Asn swiss:var_023567 Decreased expression. Pro 428 Thr Decreased expression. Arg 139 Lys Arg 186 Gly Ile 269 Phe rs11572103 Increased Km for paclitaxel 6-hydroxylation Lys 399 Arg rs10509681 Decreased paclitaxel turnover Leu 90 Pro Decreased activity Arg 125 His Decreased activity Thr 130 Arg Decreased activity Arg 144 Cys rs1799853 Altered warfarin sensitivity Arg 150 His rs7900194 Decreased activity Leu 208 Val OMIM0003 warfarin sensitivity Gln 214 Leu Decreased activity Thr 299 Ala Decreased activity Arg 335 Trp rs3745274 Decreased activity rs2279343 Decreased /increased activity Decreased expression. rs28399499 rs11572080 Decreased expression. Decreased paclitaxel turnover Decreased activity CYP2C8 CYP2C9 Decreased activity rs28371685 Decreased activity 3 in vitro in vivo/in vitro yes in vitro in vivo/in vitro no yes yes in vitro In vivo/in vitro yes in vitro yes in vitro in vivo/in vitro in vivo/in vitro in vivo/in vitro in vivo/in vitro in vivo/in vitro yes in vitro in vivo/in vitro yes in vitro in vivo/in vitro no in vivo in vivo/in vitro in vitro in vivo/in vitro yes yes yes yes yes yes yes yes no yes yes yes (Klein et al., 2005) (Tsuchiya et al., 2004; Hofmann et al., 2008) (Rotger et al., 2007) (Kirchheiner et al., 2003; Klein et al., 2005) (Klein et al., 2005) (Wang et al., 2006) (Lang et al., 2004) (Klein et al., 2005) (Dai et al., 2001b) (Hichiya et al., 2005) (Dai et al., 2001b) (Dai et al., 2001b) (Guo et al., 2005) (DeLozier et al., 2005) (Maekawa et al., 2006) (King et al., 2004) (Blaisdell et al., 2004) (Leung et al., 2001) (Maekawa et al., 2006) (DeLozier et al., 2005) (Higashi et al., 2002; Blaisdell et al., 2004) Ile 359 Leu rs1057910 Tolbutamide poor metabolizer Asp 360 Glu rs28371686 Decreased activity Asp 397 Ala Decreased activity Ala 477 Thr Decreased activity Pro 489 Ser rs9332239 Decreased activity Met 1 Val rs28399504 Poor mephenytoin metabolism Trp 120 Arg swiss:var_008357 2C19*8; loss of activity Arg 132 Gln swiss:var_008358 2C19*6; loss of activity Trp 212 Ter OMIM0003 Pro 227 Leu rs6413438 Ile 331 Val Arg 433 Trp Arg 442 Cys Pro 34 Ser Gly 42 Arg Thr 107 Ile Poor mephenytoin metabolism CYP2C19 CYP2D6 Val 136 Decreased activity Decreased activity 2C19*5A & 2C19*5B; loss of activity 2C19*16; lowered catalytic swiss:var_021275 activity 2D6*10 & 2D6*14; poor rs1065852 debrisquone metabolism 2D6*12; impaired metabolism rs5030862 of sparteine swiss:var_008359 rs28371706 2D6*17; poor debrisquone metabolism Met Decreased activity 2D6*14; poor debrisquone metabolism Gly 169 Arg rs5030865 Gly 169 Ter OMIM0004 Arg 296 Cys rs16947 Val 338 Met poor debrisquine metabolism Decreased activity Decreased activity 4 in vivo/in vitro in vivo/in vitro yes yes in vitro in vivo/in vitro in vivo/in vitro in vivo/in vitro in vivo/in vitro in vivo/in vitro yes In vivo in vivo/in vitro in vivo/in vitro no yes in vivo no in vivo in vivo/in vitro no yes in vivo no in vivo/in vitro in vivo in vivo/in vitro yes yes yes yes yes yes yes no yes In vivo in vivo/in vitro no yes in vivo no (Shintani et al., 2001) (Dickmann et al., 2001; Allabi et al., 2004) (DeLozier et al., 2005) (Maekawa et al., 2006) (Blaisdell et al., 2004) (Ferguson et al., 1998) (Ibeanu et al., 1999) (Ibeanu et al., 1998b) (De Morais et al., 1994) (Blaisdell et al., 2002) (Blaisdell et al., 2002) (Ibeanu et al., 1998a) (Morita et al., 2004) (Yokota et al., 1993; Johansson et al., 1994) (Marez et al., 1996) (Masimirembwa et al., 1996; Oscarson et al., 1997) (Wennerholm et al., 2002) (Wang et al., 1999) (Broly et al., 1995) (Johansson et al., 1993; Oscarson et al., 1997) (Wennerholm et al., 2002) CYP2E1 Ser 486 Thr swiss:var_008341 Decreased activity Arg 76 His swiss:var_008360 2E1*2; reduced activity Thr Arg 143 158 Ala Cys swiss:var_014317 swiss:var_014318 CYP2J2 Ile Asn CYP2R1 Leu 192 404 99 Asn Tyr Pro Arg 129 Gln Thr 185 Ser Phe 189 Ser Ser 221 Pro Leu 293 Pro CYP3A4 CYP3A5 swiss:var_014319 swiss:var_014321 swiss:var_021534 2J2*2; significantly reduced metabolism of both arachidonic acid and linoleic acid 2J2*3; significantly reduced metabolism of both arachidonic acid and linoleic acid 2J2*4; significantly reduced metabolism of arachidonic acid only 2J2*6; significantly reduced metabolism of both arachidonic acid and linoleic acid 25-hydroxyvitamin D3 deficiency; complete loss of activity swiss:var_011600 Decreased activity rs12721627 Decreased activity 3A4*17; lowered turnover for testosterone and chlorpyrifos 3A4*2; lowered intrinsic swiss:var_008363 clearance towards nifedipine 3A4*18; increased turnover for testosterone, chlorpyrifos and rs28371759 estrone (in vitro); low metabolic turnover for midazolam (in vivo) rs4987161 Thr 362 Met swiss:var_011606 Decreased activity Leu 373 Phe rs12721629 3A4*12; altered testosterone hydroxylase activity Pro 416 Leu rs4986909 Decreased activity Arg 28 Cys swiss:var_024731 Decreased activity. 5 in vivo/in vitro in vivo/in vitro in vivo/in vitro yes yes (Johansson et al., 1993; Johansson et al., 1994) (Hu et al., 1997) (King et al., 2002) yes (King et al., 2002) in vivo/in vitro yes in vivo/in vitro yes (King et al., 2002) (King et al., 2002) in vivo/in vitro yes in vivo/in vitro yes in vitro yes in vitro in vivo/in vitro in vivo/in vitro yes (Cheng et al., 2004) yes yes (Eiselt et al., 2001) (Murayama et al., 2002) (Dai et al., 2001a) (Sata et al., 2000) (Dai et al., 2001a; Kang et al., 2008) in vivo/in vitro yes in vitro yes in vitro yes in vitro in vivo/in vitro yes yes (Murayama et al., 2002) (Eiselt et al., 2001) (Eiselt et al., 2001) (Lee et al., 2003) CYP3A7 CYP4A11 CYP4F2 His 30 Tyr Tyr 53 Cys Decreased activity. Leu 82 Arg Decreased activity. Ala 337 Thr Phe 446 Ser Ile 456 Val Ile 488 Thr Thr 409 Arg Phe 434 Ser rs28383468 rs28383479 Severely decreased activity. Decreased activity. swiss:var_024733 Decreased activity. Severely decreased activity. rs28365085 Severely decreased activity. Increased activity. rs4233507 rs2108622 essential, susceptibility to hypertension, reduced by more than half the 20-HETE synthase activity of CYP4A11 Association with increased warfarin dosage Val 433 Met Trp 44 Arg swiss:var_023084 BCD Gly 61 Ser swiss:var_023085 BCD Glu 79 Asp swiss:var_023086 BCD Ile 111 Thr swiss:var_023087 BCD Met 123 Val swiss:var_023088 BCD His 331 Pro swiss:var_023089 BCD Ser 341 Pro swiss:var_023090 BCD Arg 508 His swiss:var_023091 BCD Ala 189 Val CYP4V2 OMIM0003 CYP11A1 Ala 359 Val OMIM0005 Congenital adrenal insufficiency, decreased activity Congenital adrenal insufficiency, with 46,XY sex reversal, decreased activity 6 in vivo no in vitro in vivo/in vitro in vivo/in vitro in vivo/in vitro yes in vivo no in vivo no in vitro yes yes yes yes (Hustert et al., 2001) (Lee et al., 2007b) (Lee et al., 2003) (Lee et al., 2003) (Lee et al., 2003) (Saeki et al., 2003) (Saeki et al., 2003) (Rodriguez-Antona et al., 2005) (Gainer et al., 2005) in vivo in vivo/in vitro no yes in vivo no in vivo no in vivo no in vivo no in vivo no in vivo no in vivo no in vivo no in vivo/in vitro yes in vivo/in vitro yes (Stec et al., 2007; Caldwell et al., 2008) (Li et al., 2004) (Li et al., 2004) (Li et al., 2004) (Li et al., 2004) (Li et al., 2004) (Li et al., 2004) (Li et al., 2004) (Li et al., 2004) (Katsumata et al., 2002) (al Kandari et al., 2006) Arg 353 Trp swiss:var_016951 Pro 42 Ser swiss:var_001260 Pro 94 Leu OMIM0016 Trp 116 Ter OMIM0006 Asn 133 His swiss:var_001261 Thr 318 Met swiss:var_001262 Thr 319 Met swiss:var_001263 Ala 368 Asp OMIM0017 Arg 374 Gln swiss:var_001264 Tyr 423 Ter OMIM0015 Arg 448 His swiss:var_001265 Arg 181 Trp rs28931609 CYP11B1 Congenital adrenal insufficiency, loss of activity Steroid 11--hydroxylase deficiency Steroid 11--hydroxylase deficiency, reduced activity Steroid 11--hydroxylase deficiency, decreased activity Steroid 11--hydroxylase deficiency Steroid 11--hydroxylase deficiency Steroid 11--hydroxylase deficiency Steroid 11--hydroxylase deficiency, reduced activity Steroid 11--hydroxylase deficiency Steroid 11--hydroxylase deficiency Steroid 11--hydroxylase deficiency CMO-II; reduces 18hydroxylase and abolishes 18-oxidase activities; leaves 11 -hydroxylase activity intact Thr 185 Ile swiss:var_018471 CMO-II Glu 198 Asp swiss:var_001268 CMO-I, reduced activity Glu 225 Ter OMIM0006 CMO-I Glu 272 Ter OMIM0013 CMO-II Val 385 Ala rs28930074 CMO-I;CMO-II; reduced activity CYP11B2 Leu 461 Pro CMO-I; abolishes the 18-hydroxylase activity swiss:var_018472 required for conversion of 11-deoxycorticosterone to aldosterone 7 in vivo/in vitro yes in vivo in vivo/in vitro in vivo/in vitro yes in vivo no in vivo no in vivo in vivo/in vitro no yes in vivo no in vivo no in vivo no in vivo/in vitro no yes (Joehrer et al., 1997) (Krone et al., 2006) (Naiki et al., 1993) (Joehrer et al., 1997) (Pascoe et al., 1992a) (Joehrer et al., 1997) (Krone et al., 2006) (Pascoe et al., 1992a) (Joehrer et al., 1997) (White et al., 1991) (Pascoe et al., 1992b) yes in vivo in vivo/in vitro yes in vivo no in vivo no in vivo/in vitro (Katsumata et al., 2002) no yes (Peter et al., 1998) (Portrat-Doyen et al., 1998) (Peter et al., 1997) (Williams et al., 2004) (Pascoe et al., 1992b) (Portrat-Doyen et al., 1998) (Nomoto et al., 1997) in vivo/in vitro yes Thr 498 Ala swiss:var_018473 CMO-II Trp 17 Ter OMIM0016 AH5 Tyr 27 Ter OMIM0028 AH5 Pro 35 Leu AH5; 38% 17-hydroxylase swiss:var_022745 activity and 33% 17,20-lyase activity Tyr 64 Ser swiss:var_001271 AH5 Phe 93 Cys swiss:var_013147 AH5 Arg 96 Trp AH5; 25% of both 17swiss:var_022746 hydroxylase and 17,20-lyase activities Arg 96 Gln OMIM0029 AH5 Ser 106 Pro swiss:var_001272 AH5 Phe 114 Val swiss:var_022747 AH5 Asp 116 Val swiss:var_022748 AH5 Arg 125 Gln AH5 AH5; 10% 17-hydroxylase swiss:var_022749 and 17,20-lyase activities Asn 177 Asp Tyr 201 Asn OMIM0027 AH5 Arg 239 Ter OMIM0006 AH5 Tyr 329 Asp swiss:var_022750 AH5 Pro 342 Thr swiss:var_001274 AH5; reduced activity Arg 347 Cys swiss:var_022752 AH5 His AH5; selectively ablates 17,20-lyase activity, while swiss:var_001275 preserving most 17-hydroxylase activity Arg 347 yes In vivo no In vivo no in vivo/in vitro in vivo/in vitro in vivo/in vitro in vivo/in vitro In vivo in vivo/in vitro in vivo/in vitro in vivo/in vitro CYP17A1 OMIM0030 in vivo/in vitro 8 yes yes yes (Suzuki et al., 1998) (Mussig et al., 2005) (Biason-Lauber et al., 2000) (Imai et al., 1993) (Di Cerbo et al., 2002) (Laflamme et al., 1996) yes no yes yes yes in vivo in vivo/in vitro in vivo/in vitro yes in vivo no in vivo in vivo/in vitro in vivo/in vitro no in vivo/in vitro (Dunlop et al., 2003) no yes yes yes (Brooke et al., 2006) (Lin et al., 1991) (Van Den Akker et al., 2002) (Van Den Akker et al., 2002) (Ergun-Longmire et al., 2006) (Biason-Lauber et al., 2000) (Taniyama et al., 2005) (Ahlgren et al., 1992) (Martin et al., 2003) (Ahlgren et al., 1992) (Van Den Akker et al., 2002) (Gupta et al., 2001; Van Den Akker et al., 2002) yes Arg Gln Arg 362 Cys swiss:var_022753 AH5 His 373 Leu swiss:var_001277 AH5 Trp 406 Arg swiss:var_022754 AH5 Arg 416 His Phe CYP19A1 358 AH5; selectively ablates 17,20-lyase activity, while swiss:var_001276 preserving most 17-hydroxylase activity 417 Cys OMIM0031 AH5 AH5; ablates both 17,20-lyase activity and 17-hydroxylase swiss:var_022755 activity; loss of heme-binding and loss of phosphorylation Pro 428 Leu swiss:var_022756 AH5 Arg 440 His swiss:var_001278 AH5 Phe 453 Ser Arg 496 Cys swiss:var_001280 AH5 Arg 496 His AH5; 30% 17-hydroxylase swiss:var_022757 activity and 29% 17,20-lyase activity OMIM0033 in vivo/in vitro yes in vivo no in vivo no in vivo/in vitro In vivo in vivo/in vitro Glu 210 Lys OMIM0012 Aromatase deficiency Arg 264 Cys rs700519 Met 364 Thr Arg 365 Gln swiss:var_016962 Arg 375 Cys swiss:var_016963 Aromatase deficiency Arg 435 Cys swiss:var_016964 Cys 437 Tyr Decreased activity Decreased activity Aromatase deficiency (0.4% of wild-type activity) Aromatase deficiency (1.1% of wild-type activity) Aromatase deficiency swiss:var_016965 (complete loss of activity) 9 yes in vivo in vivo/in vitro in vivo in vivo/in vitro AH5 (Geller et al., 1997; Gupta et al., 2001) in vivo/in vitro In vivo in vivo/in vitro in vivo/in vitro in vivo/in vitro in vivo/in vitro in vivo/in vitro in vivo/in vitro no (Martin et al., 2003) (Monno et al., 1993) (Martin et al., 2003) (Ergun-Longmire et al., 2006) (Biason-Lauber et al., 2000; Gupta et al., 2001) yes no yes no yes yes no yes yes yes yes yes yes (Martin et al., 2003) (Fardella et al., 1994) (Yang et al., 2006) (Yanase et al., 1992) (Biason-Lauber et al., 2000) (Maffei et al., 2004) (Ma et al., 2005) (Ma et al., 2005) (Carani et al., 1997) (Morishima et al., 1995) (Ito et al., 1993) (Ito et al., 1993) Pro Pro CYP21A2 30 30 Gln Leu CAH; does not affect swiss:var_026060 membrane binding; enzyme function abolished CAH; non-classic form; 50% swiss:var_001281 activity; 10% of non-classic CAH Texan patients His 62 Leu swiss:var_018364 CAH Gly 64 Glu swiss:var_007923 CAH; no activity Ile 77 Thr CAH Gly 90 Val swiss:var_026061 CAH Tyr 102 Arg Pro 105 Leu swiss:var_001284 CAH Arg 124 His swiss:var_026062 CAH Leu 166 Pro CAH Cys 169 Tyr swiss:var_001285 CAH Cys 169 Arg CAH Ile 171 Asn CAH Ile 173 Asn Gly 178 Ala swiss:var_026063 CAH Gly 178 Arg CAH Val 211 Leu swiss:var_026064 Ile 236 Asn swiss:var_001288 CAH; salt wasting form Val 238 Glu Met 239 Lys OMIM0014 rs6475 rs12530380 CAH; hydroxylase polymorphism CAH; simple virilizing form; 1-2% activity CAH; non-classic form; pathogenicity uncertain CAH; salt wasting form swiss:var_001290 CAH; salt wasting form 10 in vivo/in vitro yes in vivo/in vitro yes in vivo in vivo/in vitro in vivo/in vitro in vivo/in vitro in vivo in vivo/in vitro in vivo in vivo/in vitro in vivo/in vitro in vivo/in vitro in vivo/in vitro in vivo/in vitro in vivo/in vitro in vivo/in vitro in vivo in vivo/in vitro in vivo/in vitro in vivo/in vitro (White et al., 1994; Lajic et al., 1999) (Tusie-Luna et al., 1991) no yes yes yes no yes no yes yes yes yes yes yes yes no yes yes yes (Pinto et al., 2003) (Ohlsson et al., 1999) (Krone et al., 2005) (Nunez et al., 1999) (Rodrigues et al., 1987) (White et al., 1994; Nikoshkov et al., 1997) (White et al., 1994; Usui et al., 2004) (Robins et al., 2007) (Grischuk et al., 2006) (Grischuk et al., 2006) (Barbaro et al., 2006) (Tusie-Luna et al., 1990) (Grischuk et al., 2006) (Grischuk et al., 2006) (Speiser et al., 1988) (Kapelari et al., 1999; Robins et al., 2005) (Tusie-Luna et al., 1990) (Kapelari et al., 1999; Robins et al., 2005) Leu 261 Pro Ser 268 Thr OMIM0005 CAH; hydroxylase polymorphism Val 281 Leu OMIM0002 CAH Val 281 Gly Met 283 Leu swiss:var_026067 CAH Gly 291 Ser swiss:var_001293 Gly 291 Cys swiss:var_026068 CAH Gly 291 Arg swiss:var_018365 CAH Leu 300 Phe swiss:var_026069 CAH; salt wasting form Ser 301 Tyr swiss:var_018366 CAH Trp 302 Arg CAH Val 304 Met swiss:var_026065 CAH CAH; salt wasting form CAH; salt wasting form; less then 1% activity in vivo no in vivo no in vivo in vivo/in vitro no in vivo in vivo/in vitro in vivo/in vitro in vivo in vivo/in vitro in vivo in vivo/in vitro Hyperandrogenism (due to 21hydroxylase deficiency; non-classic type; residual activity of 46% for conversion swiss:var_026070 of 17-hydroxyprogesterone and 26% for conversion of progesterone compared with the normal enzyme) Leu 317 Met swiss:var_026071 CAH Gln 319 Ter Arg 339 His Arg 341 Pro swiss:var_018367 CAH Arg 341 Trp swiss:var_001295 CAH (non-classic form; mild) Glu 351 Lys CAH (due to 21-hydroxylase deficiency, salt-wasting type) CAH (non-classic form; 50% swiss:var_001294 activity) rs7755898 CAH 11 yes no yes yes no yes no yes (Loke et al., 2001) (Wu and Chung, 1991) (Speiser et al., 1988) (Lajic et al., 2001) (Ezquieta et al., 2002) (Nikoshkov et al., 1998; Ohlsson et al., 1999) (Nunez et al., 1999) (Stikkelbroeck et al., 2003) (Lajic et al., 2001) (Stikkelbroeck et al., 2003) (Grischuk et al., 2006) (Lajic et al., 2002) in vivo/in vitro in vivo in vivo/in vitro in vivo/in vitro in vivo/in vitro in vivo in vivo/in vitro yes no yes yes no no yes (Deneux et al., 2001) (Globerman et al., 1988) (Helmberg et al., 1992) (Barbaro et al., 2006) (White et al., 1994) (Krone et al., 2005) in vivo/in vitro Arg 354 His swiss:var_026073 CAH Arg 354 Cys swiss:var_026072 CAH (salt wasting form) Arg 356 Pro swiss:var_001296 Arg 356 Gln Arg 357 Trp Ala 362 Val swiss:var_007924 CAH (no activity) Leu 363 Trp swiss:var_026074 CAH His 365 Tyr swiss:var_026075 CAH Ser Hyperandrogenism (due to 21hydroxylase deficiency; almost swiss:var_026076 completely abolished enzyme activity) Gly 375 CAH (salt wasting form; 0.15% activity) CAH (simple virilizing form; swiss:var_001297 mild; 0.65% activity) CAH (due to 21-hydroxylase rs7769409 deficiency) Glu 380 Asp swiss:var_001299 in CAH; salt wasting form Ala 391 Thr CAH Trp 406 Ter Arg 408 Cys OMIM0022 in CAH; salt wasting form in CAH; should lead to swiss:var_026077 complete impairment of enzymatic activity Gly 424 Ser swiss:var_026078 CAH Arg 426 Cys in CAH; exhibit only low swiss:var_026079 enzyme activity toward 17-hydroxyprogesterone Ala 434 Val CAH Arg 435 Cys swiss:var_026080 CAH Leu 446 Pro CAH Pro 454 Ser rs6445 CAH, due to 21-hydroxylase deficiency, nonclassic type 12 in vivo in vivo/in vitro in vivo/in vitro in vivo/in vitro in vivo/in vitro yes no yes yes yes yes in vivo no in vivo no in vivo/in vitro (Nunez et al., 1999) (Krone et al., 2000) (Lajic et al., 1997) (Lajic et al., 1997) (Chiou et al., 1990) (Ohlsson et al., 1999) (Levo and Partanen, 2001) (Zeng et al., 2004) (Lajic et al., 2002) yes in vivo in vivo/in vitro no yes in vivo no in vivo no in vivo no (Kirby-Keyser et al., 1997) (Robins et al., 2007) (Wedell and Luthman, 1993) (Billerbeck et al., 2002) in vivo/in vitro in vivo/in vitro in vivo in vivo/in vitro in vivo/in vitro (Billerbeck et al., 1999) (Grischuk et al., 2006) yes yes no yes yes (Krone et al., 2005) (Deneux et al., 2001) (Barbaro et al., 2006) (Nikoshkov et al., 1997) Arg 479 Leu swiss:var_026081 CAH Pro 482 Ser swiss:var_026082 Arg 483 Pro Arg 483 Trp swiss:var_026083 CAH (salt wasting form) Arg 483 Gln swiss:var_018368 CAH Phe 186 Leu CAH Cys 358 Arg CAH Gly 112 Glu Gly 145 Glu Thr 339 Met OMIM0013 CTX Arg 362 Cys OMIM0002 CTX Arg 362 Ser OMIM0008 CTX Arg 372 Gln OMIM0007 CTX Arg 395 Cys swiss:var_001303 CTX Arg 395 Ser swiss:var_012285 CTX Arg 405 Gln swiss:var_012286 CTX Arg 441 Gln OMIM0005 CTX Arg 441 Trp OMIM0006 CTX Arg 446 Cys OMIM0001 CTX Arg 474 Gln swiss:var_012287 CTX Arg 474 Trp swiss:var_012288 CTX in CAH; rediced enzyme activity to 70% of normal in CAH; moderate; 1-2% of swiss:var_001301 activity CYP26A1 OMIM0011 CTX swiss:var_016966 CTX CYP27A1 13 in vivo/in vitro in vivo/in vitro in vivo/in vitro in vivo in vivo/in vitro in vivo/in vitro in vivo/in vitro yes yes yes no yes yes yes in vivo no in vivo no in vivo in vivo/in vitro in vivo/in vitro in vivo/in vitro in vivo/in vitro in vivo/in vitro in vivo/in vitro in vivo/in vitro in vivo/in vitro in vivo/in vitro in vivo/in vitro in vivo/in vitro no yes yes yes yes yes yes no no yes no no (Robins et al., 2007) (Barbaro et al., 2004) (Nikoshkov et al., 1998) (Kharrat et al., 2004) (Robins et al., 2007) (Lee et al., 2007a) (Lee et al., 2007a) (Lamon-Fava et al., 2002) (Lamon-Fava et al., 2002) (Guyant-Marechal et al., 2005) (Cali et al., 1991) (Chen et al., 1998) (Chen et al., 1997) (Cali et al., 1991) (Chen et al., 1998) (Chen et al., 1997) (Kim et al., 1994) (Kim et al., 1994) (Cali et al., 1991) (Kim et al., 1994) (Kim et al., 1994) Arg 479 Cys in vivo/in vitro swiss:var_001304 CTX yes (Cali et al., 1991) (Guyant-Marechal et al., in vivo no 2005) in vivo/in Gln 65 His swiss:var_016969 VDDR-I (Wang et al., 1998) vitro yes VDDR I (complete loss of in vivo/in Arg 107 His swiss:var_016952 (Kitanaka et al., 1998) activity) vitro yes VDDR I (complete loss of in vivo/in Gly 125 Glu rs28934605 (Kitanaka et al., 1998) activity) vitro yes VDDR I (11% of wild-type in vivo/in Glu 189 Lys swiss:var_016967 (Wang et al., 1998) activity) vitro yes VDDR I (22% of wild-type in vivo/in Glu 189 Gly swiss:var_016954 (Wang et al., 2002) activity) vitro yes VDDR I (complete loss of in vivo/in Thr 321 Arg swiss:var_016955 (Kitanaka et al., 1999) activity) vitro yes in vivo/in Ser 323 Tyr swiss:var_016970 VDDR-I (Smith et al., 1999) vitro no VDDR I (complete loss of in vivo/in (Kitanaka et al., 1998) Arg 335 Pro rs28934606 activity) vitro yes VDDR I (2.3% of wild-type in vivo/in Leu 343 Phe swiss:var_016957 (Wang et al., 2002) activity) vitro yes CYP27B1 VDDR I (complete loss of in vivo/in (Kitanaka et al., 1998) Pro 382 Ser rs28934607 activity) vitro yes VDDR I (complete loss of in vivo/in (Wang et al., 1998) Arg 389 His swiss:var_016959 activity) vitro yes (Wang et al., 2002) VDDR I (complete loss of in vivo/in Arg 389 Gly swiss:var_016960 (Wang et al., 2002) activity) vitro yes VDDR I (complete loss of in vivo/in Arg 389 Cys swiss:var_016968 (Kitanaka et al., 1999) activity) vitro yes in vivo/in (Wang et al., 1998) Thr 409 Ile swiss:var_016961 VDDR I vitro yes (Wang et al., 2002) in vivo/in (Wang et al., 1998) Arg 429 Pro swiss:var_016971 VDDR I vitro yes in vivo/in (Wang et al., 1998) Arg 453 Cys swiss:var_016972 VDDR I vitro yes in vivo/in Val 478 Gly swiss:var_016973 VDDR I (Smith et al., 1999) vitro no in vivo/in Pro 497 Arg swiss:var_016974 VDDR I (Wang et al., 1998) vitro yes AH5 = Adrenal hyperplasia type 5; BCD = Bietti crystalline corneoretinal dystrophy; CTX = Cerebrotendinous xanthomatosis; CAH = Congenital adrenal hyperplasia; CMO-II = Corticosterone methyloxidase type II deficiency; CMO-I = Corticosterone methyloxidase type I deficiency; GLC3A = Primary congenital glaucoma type 3A; HETE = eicosatetraenoic acid; VDDR-1 = Vitamin D-dependent rickets type I. 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