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Mutations in Transthyretin Gene (TTR)

Name (Protein Variant incl. 20-aa signal peptide) Sequence Variant (mRNA) Codon Change Location Reported Phenotype Ethnic Group References
Gly6Ser (p.Gly26Ser) c.76G>AGGT>AGTExon 2non-amyloidogenicCaucasian Jacobson (1994) Hum Mutat 3, 254
Cys10Arg (p.Cys30Arg) c.88T>CTGT>CGTExon 2AN, E, H, PNAmerican (Hungarian) Uemichi (1992) J Med Genet 29, 888
Leu12Pro (p.Leu32Pro) c.95T>CCTG>CCGExon 2PN, AN, H, LM, LBritish Brett (1999) Brain 122, 183
p.Met13Ile (p.Met33Ile) c.99G>CATG>ATCExon 2non-amyloidogenicGerman Altland (1999) The 4th International Symposium on FAP and Other TTR Related Disorders.
Asp18Asn (p.Asp38Asn) c.112G>AGAT>AATExon 2HAmerican Connors (2003) Amyloid 10, 160
Asp18Gly (p.Asp38Gly) c.113A>GGAT>GGTExon 2LMHungarian Vidal (1996) Am J Pathol 148, 361
Asp18Glu (p.Asp38Glu) c.114T>A or GGAT> GAA/GExon 2PNSouth American Connors (2004) Amyloid 11, 61
Ala19Asp (p. Ala39Asp) c.116C>AGCT >GATExon 2HCaucasian Ferreira (2013) PLoS One; 8(12):e82484
Val20Ile (p.Val40Ile) c.118G>AGTC>ATCExon 2CTS, HGerman, American Jenne (1996) Proc Natl Acad Sci U S A 93, 6302
Arg21Gln (p.Arg41Gln) c.122G>ACGA>CAAExon 2H, NFrench S. Valleix. Personal communication.
Ser23Asn (p.Ser43Asn) c.128G>AAGT >AATExon 2E, H, PNPortuguese, American Connors (1999) Amyloid 6, 114
Pro24Ser (p.Pro44Ser) c.130C>TCCT >TCTExon 2CTS, H, PNAmerican Uemichi (1995) J Med Genet 32, 279
Ala25Ser (p.Ala45Ser) c.133G>TGCC>TCCExon 2H, PNAmerican Yazatic (2002) Muscle Nerve 25, 244
Ala25Thr (p.Ala45Thr) c.133G>AGCC>ACCExon 2CNS, PNJapanese Sekijima (2003) Lab Invest 83, 409
Val28Met (p.Val48Met) c.142G>AGTG>ATGExon 2PNPortuguese Carvalho (2000) Muscle Nerve 23, 1016
Val30Leu (p.Val50Leu) c.148G>CGTG>CTGExon 2AN, H, K, PNJapanese, American Murakami (1992) Biochem Biophys Res Commun 187, 397
Val30Met (p.Val50Met) c.148G>AGTG>ATGExon 2AN, E, LM, PNAmerican Chinese, Japanese, European Saraiva (1984) J Clin Invest 74, 104
Val30Ala (p.Val50Ala) c.149T>CGTG>GCGExon 2AN, HAmerican (German) Jones (1992) Clin Genet 41, 70
Val30Gly (p.Val50Gly) c.149T>GGTG>GGGExon 2CNS, E, LMAmerican Peterson (1997) Ann Neurol 41, 307
Val30Leu (p.Val50Leu) c.148G>CGTG>TTGExon 2AN, H, PNFinish Suhr (2016) XVth International Symposium on Amyloidosis
Val32Ala (p.Val52Ala) c.155T>CGTG>GCGExon 2AN, H, PNChinese Pica (2005) Muscle Nerve 32, 223
Val32Gly (p.Val52Gly) c.155T>GGTG>GGGExon 2AN, PNFrench Plante-Bordeneuve (2003) J Med Genet 40, e120
Phe33Ile (p.Phe53Ile) c.157T>ATTC>ATCExon 2E, PNJewish Jacobson (1988) Biochem Biophys Res Commun 153(1):198
Phe33Leu (p.Phe53Leu) c.157T>CTTC>CTCExon 2PN, C, ANAmerican, Polish Li (1991) Neurology 41:893; Suhr (2016) XVth International Symposium on Amyloidosis
Phe33Val (p.Phe53Val) c.157T>GTTC>GTCExon 2PNChinese, British Tachibana (1999) Amyloid 6(4):282
Phe33Cys (p.Phe53Cys) c.158T>GTTC>TGCExon 2CTS, E, K,A HAmerican Connors (2003) Amyloid 10, 160
Arg34Gly (p.Arg54Gly) c.160A>GAGA>GGAExon 2EKosovo Levy J, Hawkins PN, Rowczenio D, Godfrey T, Stawell R, Zamir E.
Arg34Thr (p.Arg54Thr) c.161G>CAGA > ACAExon 2H, PNItalian Patrosso (1998) Am J Med Genet 77, 135
Lys35Asn (p.Lys55Asn) c.165G>C or TAAG>AAC/TExon 2AN, H, PNFrench Reilly (1995) Brain 118, 849
Lys35Thr (p.Lys55Thr) c.164A>C AAG>ACGExon 2EChinese Long (2012) Ophthalmic Genet 33(1):28-33
Ala36Asp (p.Ala56Asp) c.167C>AGCT>GATExon 3H, PNJapanese Nomura (2016) XVth International Symposium on Amyloidosis
Ala36Pro (p.Ala56Pro) c.166G>CGCT>CCTExon 2CTS, E, PNGreek, Italian, Jewish, American Jones (1991) Am J Hum Genet 48, 979
Asp38Ala (p.Asp58Ala) c.173A>CGAT>GCTExon 2AN, H, PNJapanese Yazaki (2000), Biochem Biophys Res Commun, 274(3):702
Asp38Val (p.Asp58Val) c.173A>TGAT>GTTExon 2H, PNGuianese Lachmann (2002) N Engl J Med 346, 1786
Asp39Val (p.Asn59Val) c.176A>TGAC>GTCExon 2HGerman Eriksson (2009) Am J Surg Pathol 33 (1):58
Trp41Leu (p.Trp61Leu) c.182G>TTGG>TTGExon 2EAmerican (Russian) Yazaki (2002) Amyloid 9, 263
Glu42Gly (p.Glu62Gly) c.185A>GGAG>GGGExon 2AN, H, PNJapanese, Russian, American Ueno (1990) Biochem Biophys Res Commun 169, 1117
Glu42Asp (p.Glu62Asp) c.186G>C or TGAG>GAC/TExon 2HFrench Dupuy (1998) Amyloid 5, 285
Phe44Tyr (p.Phe64Tyr) c.191T>ATTT>TATExon 2AN, PNFrench Plante-Bordeneuve (2003) J Med Genet 40, e120
Phe44Ser (p.Phe64Ser) c.191T>CTTT>TCTExon 2AN, H, PNAmerican Klein (1998) Neurology 51, 1462
Phe44Leu (p.Phe64Leu) c.190T>CTTT>CTTExon 2HCaucasian Unpublished
Ala45Ser (p.Ala65Ser) c.193G>TGCC>TCCExon 2HSwedish Janunger (2000) Amyloid 7, 137
Ala45Thr (p.Ala65Thr) c.193G>AGCC >ACCExon 2HIrish, Italian, American Saraiva (1992) Am J Hum Genet 50, 1027
Ala45Asp (p.Ala65Asp) c.194C>AGCC >GACExon 2H, PNIrish, American Saraiva (1995) Hum Mutat 5, 191
Ala45Gly (p.Ala65Gly) c.194C>GGCC>GGCExon 2HDutch Klaassen (2017) Cardiovasc Pathol. 29:19-22
Gly47Arg (p.Gly67Arg) c.199G>CGGG>CGGExon 2AN, PNJapanese Murakami (1992) Biochem Biophys Res Commun 182, 520
Gly47Arg (p.Gly67Arg) c.199G>AGGG>AGGExon 2H, PNItalian Ferlini (2000) Clin Genet 57, 284
Gly47Ala (p.Gly67Ala) c.200G>CGGG>GCGExon 2AN, H, PNGerman, Italian, French Ferlini (1994) Hum Mutat 4, 61
Gly47Glu (p.Gly67Glu) c.200G>AGGG>GAGExon 2H, K, PNGerman, Italian Pelo (2002) Amyloid 9, 35
Gly47Val (p.Gly67Val) c.200G>TGGG>GTGExon 2AN, CTS, H, PNSri Lankan Booth (1993) Amyloid, 456
Thr49Ala (p.Thr69Ala) c.205A>GACC>GCCExon 3CTS, H, PNItalian, French Almeida (1992) Hum Mutat 1, 211
Thr49Pro (p.Thr69Pro) c.205A>CACC>CCCExon 3H, LMAmerican Nakagawa (2008) J Neurol , 272(1-2):186; Connors (2003) Amyloid 10, 160;
Thr49Ile (p.Thr69Ile) c.206C>TACC>ATCExon 3H, PNJapanese Nakamura (1999) Hum Hered 49, 186
Thr49Ser (p.Thr69Ser) c.206C>GACC>AGCExon 3PNIndian Rowczenio (2010) XII International Symposium on Amyloidosis
Ser50Arg (p.Ser70Arg) c.210T>AAGT>AGAExon 3H, PNMexican Dasgupta (2016) XVth International Symposium on Amyloidosis
Ser50Arg (p.Ser70Arg) c.210T>GAGT>AGGExon 3AN, H, PNItalian, French, Japanese Ueno (1990) Biochem Biophys Res Commun 169, 1117
Ser50Ile (p.Ser70Ile) c.209G>TAGT>ATTExon 3AN, H, PNJapanese, Spanish Saeki (1992) FEBS Lett 308, 35
Glu51Gly (p.Glu71Gly) c.212A>GGAG>GGGExon 3HAmerican Connors (2003) Amyloid 10, 160
Ser52Pro (p.Ser72Pro) c.214T>CTCT>CCTExon 3AN, H, K, PNBritish Stangou (1998) Transplantation 66(2):229
Gly53Arg (p.Gly73Arg) c.217G>AGGA>AGAExon 3LMAmerican Liepnieks (2011) Amyloid 18; 1:162
Gly53Glu (p.Gly73Glu) c.218G>AGGA>GAAExon 3CNS, LM, NFrench Ellie (2001) Neurology 57, 135
Gly53Ala (p.Gly73Ala) c.218G>CGGA>GCAExon 3AN, E, H, PN, LMBritish Douglass (2007) J Neurol Neurosurg Psychiatry 78, 193
Glu54Leu (p.Glu74Leu) c.220_221 GA>TTGAG>TTGExon 3HBelgian Rowczenio (2006) XI International Symposium on Amyloidosis
Glu54Lys (p.Glu74Lys) c.220G>AGAG>AAGExon 3AN, H, PNJapanese Togashi (1999) Neurology 53, 637
Glu54Gly (p.Glu74Gly) c.221A>GGAG>GGGExon 3AN, E, PNBritish Reilly (1995) Brain 118, 849
Glu54Asp (p.Glu74Asp) c.222G>TGAG>GACExon 3Not listedGerman Eriksson (2009) Am J Surg Pathol 33 (1):58
Glu54Gln (p.Glu74Gln) c.220G>CGAG>CAGExon 3H, PNRomanian Coriu D, XIII International Symposium on Amyloisosis
Leu55Gln (p.Leu75Gln) c.224T>ACTG>CAGExon 3AN, E, PNAmerican (Spanish) Yazaki (2002) Amyloid 9, 268
Leu55Arg (p.Leu75Arg) c.224T>GCTG>CGGExon 3LM, PN, EChinese, German Long (2012) Ophthalmic Genet 33(1):28-33 Connors (2003) Amyloid 10, 160
Leu55Pro (p.Leu75Pro) c.224T>CCTG>CCGExon 3AN, E, H, PNTaiwanese, American (Dutch, German) Jacobson (1992) Hum Genet 89, 353
His56Arg (p.His76Arg) c.227A>GCAT>CGTExon 3HAmerican Jacobson (1999) TTR Locus-specific database Unpublished
Gly57Arg (p.Gly77Arg) c.229G>AGGG>AGGExon 3HSwedish Suhr (2009) Amyloid 16(4):208-14.
Leu58Arg (p.Leu78Arg) c.233T>GCTC>CGCExon 3AN, CTS, E, HJapanese Saeki (1991) Biochem Biophys Res Commun 180, 380
Leu58His (p.Leu78His) c.233T>ACTC>CACExon 3CTS, HGerman, American (MD) Nichols (1989) Genomics 5, 535
Thr59Arg (p.Thr79Arg) c.236C>GACA>AGAExon 3HJapanese Watanabe (2016) XVth International Symposium on Amyloidosis
Thr59Lys (p.Thr79Lys) c.236C>AACA>AAAExon 3AN, H, PNItalian, American (Asian) Saraiva (1995) Hum Mutat 5, 191
Thr60Ala (p.Thr80Ala) c.238A>GACT>GCTExon 3CTS, H, PNAustralian, German, Irish, British, American Wallace (1986) J Clin Invest 78, 6
Glu61Lys (p.Glu81Lys) c.241G>AGAG>AAGExon 3PNJapanese Shiomi (1993) Biochem Biophys Res Commun 194, 1090
Glu61Gly (p.Glu81Gly) c.242A>GGAG>GGGExon 3CTS, H, PNAmerican (English/Dutch) Rosenzweig (2007) Amyloid 14, 65
Glu62Lys (p.Glu82Lys) c.243G>AGAG>AAGExon 3HCaucasian Briani (2012) J Neurol.; 259(10):2226-8.
Phe64Ile(p.Phe84Ile) c.250T>ATTT>ATTExon 3H, PN, ANCaucasian Tarquini (2007) Amyloid 14(4):289
Phe64Leu(p.Phe84Leu) c.250T>CTTT>CTTExon 3CTS, H, PNItalian, American Li (1991) Neurology 41, 893
Phe64Ser (p.Phe84Ser) c.251T>CTTT>TCTExon 3E, LM, PN, CNSCanadian (Italian), British Uemichi (1999) Arch Neurol 56, 1152
Gly67Arg (p.Gly87Arg) c.259G>CGGG>CGGExon 3E, ANBangladeshi S. Valleix. ARiA III Symposium, Portugal 2014
Gly67Glu (p.Gly87Glu) c.260G>AGGG>GAGExon 3H, PNChinese Mak (2007) Amyloid, 14, 293
Ile68Leu (p.Ile88Leu) c.262A>T/CATA >C/TTAExon 3HGerman, American Almeida (1991) Basic Res Cardiol 86, 567
Tyr69His (p.Tyr89His) c.265T>CTAC>CACExon 3EScottish, American Zeldenrust (1994) Amyloid, 1, 17
Tyr69Ile (p.Tyr89Ile) c.265-266 TA>ATTAC >ATCExon 3CTS, HJapanese Takei (2003) Amyloid 10, 25
Lys70Asn (p.Lys90Asn) c.270A>C/TAAA>AAC/TExon 3CTS, E, PNGerman, American Izumoto (1992) Neurology 42, 2094
Val71Ala (p.Val91Ala) c.272T>CGTG>GCGExon 3CTS, E, PNFrench, Spanish Almeida (1993) Hum Mutat 2, 420.
Glu72Gly (p.Glu92Gly) c.275A>GGAA >GGAExon 3HCaucasian Unpublished, Personal Communication
Ile73Val (p.Ile93Val) c.277A>GATA>GTAExon 3AN, PNBangladeshi Booth (1997) Hum Mutat 12, 135
Asp74His (p.Asp94His) c.280G>CGAC>CACExon 3non-amyloidogenicGerman Uemichi (1994) Amyloid, 1, 149
Ser77Phe (p.Ser97Phe) c.290C>TTCT>TTTExon 3AN, PNFrench Plante-Bordeneuve (1998) Neurology 51, 708
Ser77Tyr (p.Ser97Tyr) c.290C>ATCT>TATExon 3H, K, PNFrench, German, American (IL,TX) Wallace (1988) J Clin Invest 81, 189
Tyr78Phe (p.Tyr98Phe) c.293A>TTAC>TTCExon 3CTS, S, PNFrench (Italian) Magy (2003) Amyloid 10, 29
Ala81Thr (p.Ala101Thr) c.301G>AGCA>ACAExon 3HAmerican Connors (2003) Amyloid 10, 160
Ala81Val (p.Ala101Val) c.302C>TGCA>GTAExon 3HRussian, Polish Rowczenio (2006) XI International Symposium on Amyloidosis
Gly83Arg (p.Gly103Arg) c.307G>CGGC>CGCExon 3EChinese Xie Y (2012) Zhonghua Yi Xue Yi Chuan Xue Za Zhi.; 29(1):13-5.
Ile84Asn (p.Ile104Asn) c.311T>AATC>AACExon 3CTS, E, HAmerican Skinner (1992) Ophthalmology 99, 503
Ile84Ser (p.Ile104Ser) c.311T>GATC>AGCExon 3CTS, E, H, LMHungarian, Swiss, American Dwulet (1986) J Clin Invest 78, 880
Ile84Thr (p.Ile104Thr) c.311T>CATC>ACCExon 3H, PNGerman, British Stangou (1998) Transplantation 66, 229
His88Arg (p.His108Arg) c.323A>GCAT>CGTExon 3HSwedish Holmgren (2005) Amyloid 12, 184
Glu89Gln (p.Glu109Gln) c.325G>CGAG>CAGExon 3CTS, H, PNItaly Almeida (1992) Hum Mutat 1, 211
Glu89Lys (p.Glu109Lys) c.325G>AGAG>AAGExon 3AN, H, PNAmerican Nakamura (2000) Amyloid 7, 46
His90Asn (p.His110Asn) c.328C>ACAT>AATExon 3non-amyloidogenicGerman, Portuguese Skare (1994) Clin Genet 45, 281
His90Asp (p.His110Asp) c.328C>GCAT>GATExon 3HBritish Rowczenio (2006) XI International Symposium on Amyloidosis
Ala91Ser (p.Ala111Ser) c.331G>TGCA>TCAExon 3AN, CTS, H, PNFrench Misrahi (1998) Hum Mutat 12, 71
Gln92Lys (p.Gln112Lys) c.334G>AGAG>AAGExon 3HJapanese Saito (2001) Hum Pathol 32, 237
Val93Met (p.Val113Met) c.367G>A GTG>ATGExon 4PNMalian Lozern (2008) The VIIth International Symposium on FAP and Other TTR Related Disorders.
Val94Ala (p.Val114Ala) c.341T>CGTA>GCAExon 4AN, H, PNGerman, Greek (Cyprus) Kristen (2007) Amyloid 14(4): 283
Ala97Ser (p.Ala117Ser) c.349G>TGCC>TCCExon 4PN, H, E, ANChinese, Taiwanese Tachibana (1999) Amyloid 6, 282
Ala97Gly (p.Ala117Gly) c.350C>GGCC>GGCExon 4H, PNJapanese Yasuda (1994) J Neurol Sci 121, 97
Gly101Ser (p.Gly121Ser) c.361G>AGGC>AGCExon 4non-amyloidJapanese Kishikawa M et al (1988) Hum Mutat 12, 363
Pro102Arg (p.Pro122Arg) c.365C>GCCC>CGCExon 4non-amyloidGerman Altland (1999) The 4th International Symposium on FAP and Other TTR Related Disorders.
Arg103Ser (p. Arg123Ser) c.367C>ACGC>AGCExon 4HAmerican Connors (2003) Amyloid 10, 160
Arg104Cys (p.Arg124Cys) c.370C>TCGC>TGCExon 4non-amyloid,American Torres (1996) Neuromuscular DisordVol 6, S21,
Arg104His (p.Arg124His) c.371G>ACGC>CACExon 4non-amyloidJapanese, American Terazaki (1999) Biochem Biophys Res Commun 264, 365
Ile107Val (p.Ile127Val) c.379A>GATT>GTTExon 4CTS, H, PNGerman, American Jacobson (1994) Hum Mutat 3, 399
Ile107Phe (p.Ile127Phe) c.379A>TATT>TTTExon 4AN, PNBritish Rowczenio (2006) XI International Symposium on Amyloidosis
Ile107Met (p.Ile127Met) c.381T>GATT>ATGExon 4H, PNGerman Connors (2003) Amyloid 10, 160
Ala108Ala (p.Ala128Ala) c.384C>TGCC>GCTExon 4non-amyloidogenicPortuguese Palha (1997) Amyloid 4,52
Ala109Ser (p.Ala129Ser) c.385G>TGCC>TCCExon 4PNJapanese Date (1997) J Neurol Sci 150, 143
Ala109Thr (p.Ala129Thr) c.385G>AGCC>ACCExon 4non-amyloidogenicPortuguese Moses (1990) J Clin Invest 86, 2025
Ala109Val (p.Ala129Val) c.386C>TGCC>GTCExon 4non-amyloidogenicAmerican Izumoto (1993) J Rheumatol 20 188
Leu111Met (p.Leu131Met) c.391C>ACTG>ATGExon 4CTS, HDanish Nordlie (1988) Scand J Immunol 27, 119
Ser112Ile (p.Ser132Ile) c.395G>TAGC>ATCExon 4H, PNItalian De Lucia (1993) Clin Neuropathol 12, S44
Pro113Thr (p.Pro133Thr) c.397C>ACCC>ACCExon 4HFrench S. Valleix. ARiA III Symposium, Portugal 2014
Tyr114Cys (p.Tyr134Cys) c.401A>GTAC>TGCExon 4AN, E, H, LM, PNJapanese Ueno (1990) Biochem Biophys Res Commun 169, 143
Tyr114His (p.Tyr134His) c.400T>CTAC>CACExon 4CTSJapanese Murakami (1994) Neurology 44, 315
Tyr116Ser (p.Tyr136Ser) c.407A>CTAT>TCTExon 4AN, PN, CTSFrench Misrahi (1997) Hum Mutat 12, 71
Thr119Met (p.Thr139Met) c.416C>TACG>ATGExon 4non-amyloidogenicPortuguese, American Harrison (1991) Am J Med Genet 39, 442
Ala120Ser (p.Ala140Ser) c.418G>TGCT>TCTExon 4AN, H, PNCaribbean Lachmann (2002) N Engl J Med 346, 1786
Val122del (p. Val142del) c.424_426del GTC Exon 4CNS, CTS, H, PNAmerican (Ecuador/ Spain) Uemichi (1997) Neurology 48
Val122Ile (p.Val142Ile) c.424G>AGTC>ATCExon 4HAfrican, Portuguese, American Jacobson (1990) Am J Hum Genet 47, 127
Val122Ala (p.Val142Ala) c.425T>CGTC>GCCExon 4E, H, PNBritish, American Theberge (1999) Amyloid 6, 54
Pro125Ser (p.Pro145Ser) c.433C>TCCC>TCCExon 4non-amyloidogenicItalian Ferlini (1996) Neuromuscular Disord Vol 6, S23,

 

Abbreviation Key:

AN = autonomic neuropathy;
CTS = carpal tunnel syndrome;
E = eye;
H = heart;
K = kidney;
L = liver;
LM = leptomeningeal;
N = neuropathy;
PN = polyneuropathy;
CNS = central nervous system