Galafold 123 mg tvrdé kapsuly

Farmakoterapeutická skupina: Iné liečivá pre tráviaci trakt a metabolizmus, rôzne liečivá tráviaceho traktu a metabolizmu, ATC kód: A16AX14 Fabryho choroba je progresívna porucha lyzozómovej akumulácie viazaná na chromozóm X, ktorá postihuje mužov aj ženy. Mutácie v géne GLA zapríčinené Fabryho chorobou vedú k nedostatku lyzozómového enzýmu α-galaktozidázy A (α-Gal A), ktorý je potrebný pre metabolizmus glykosfingolipidového substrátu (napr. GL-3, lyzo-Gb 3 ). Znížená aktivita α-Gal A je preto spojená s progresívnou akumuláciou substrátu v citlivých orgánoch a tkanivách, čo vedie k morbidite a mortalite spojenej s Fabryho chorobou. Mechanizmus účinku Určité mutácie GLA môžu viesť k vytváraniu abnormálne zvinutých a nestabilných mutantných foriem α-Gal A. Migalastát je farmakologický šaperón, ktorý je vytvorený tak, že sa selektívne a reverzibilne viaže s vysokou afinitou na aktívne miesta určitých mutantných foriem α-Gal A, ktorých genotypy sa nazývajú príslušné mutácie. Naviazanie migalastátu stabilizuje tieto mutantné formy α-Gal A v endoplazmatickom retikule a uľahčuje ich náležitú migráciu do lyzozómov. Disociácia migalastátu v lyzozómoch obnovuje aktivitu α-Gal A, čo vedie ku katabolizmu GL-3 a podobných substrátov. Mutácie GLA príslušné na liečbu liekom Galafold sú uvedené ďalej v tabuľke 2. Mutácie GLA sú k dispozícii aj poskytovateľom zdravotnej starostlivosti na adrese www.galafoldamenabilitytable.com. Uvedené zmeny nukleotidov predstavujú potenciálne zmeny v sekvencii DNA, ktoré vedú k mutácii aminokyselín. Mutácia aminokyselín (zmena v sekvencii bielkovín) je pri určovaní významu najrelevantnejšia. Ak je na rovnakom chromozóme (u mužov aj žien) prítomná dvojitá mutácia, pacient je vhodný na liečbu, ak je dvojitá mutácia uvedená v tabuľke 2 v rámci jednej položky (napr. D55V/Q57L). Ak je dvojitá mutácia prítomná na rôznych chromozómoch (len u žien), pacientka je vhodná na liečbu, ak je v tabuľke 2 uvedená ktorákoľvek z daných dvoch mutácií. 6 Zmena nukleotidov (dlhý) Zmena nukleotidov (krátky) Zmena sekvencie proteínov c.7C>G c.C7G L3V c.8T>C c.T8C L3P c.[11G>T; 620A>C] c.G11T/A620C R4M/Y207S c.13A>G c.A13G N5D c.15C>G c.C15G N5K c.16C>A c.C16A P6T c.16C>T c.C16T P6S c.17C>A c.C17A P6Q c.17C>G c.C17G P6R c.17C>T c.C17T P6L c.19G>A c.G19A E7K c.20A>T c.A20T E7V c.21A>T c.A21T E7D c.22C>A c.C22A L8I c.23T>A c.T23A L8Q c.23T>C c.T23C L8P c.25C>T c.C25T H9Y c.26A>G c.A26G H9R c.26A>T c.A26T H9L c.27T>A c.T27A H9Q c.28C>A c.C28A L10M c.28C>G c.C28G L10V c.29T>A c.T29A L10Q c.29T>C c.T29C L10P c.29T>G c.T29G L10R c.31G>A c.G31A G11S c.31G>C c.G31C G11R c.31G>T c.G31T G11C c.32G>A c.G32A G11D c.32G>T c.G32T G11V c.34T>A c.T34A C12S c.34T>C c.T34C C12R c.34T>G c.T34G C12G c.35G>A c.G35A C12Y c.37G>A c.G37A A13T c.37G>C c.G37C A13P c.38C>A c.C38A A13E c.38C>G c.C38G A13G c.40C>G c.C40G L14V c.40C>T c.C40T L14F c.41T>A c.T41A L14H c.43G>A c.G43A A15T c.44C>G c.C44G A15G c.49C>A c.C49A R17S c.49C>G c.C49G R17G c.49C>T c.C49T R17C c.50G>A c.G50A R17H c.50G>C c.G50C R17P 7 Zmena nukleotidov (dlhý) Zmena nukleotidov (krátky) Zmena sekvencie proteínov c.52T>A c.T52A F18I c.53T>G c.T53G F18C c.54C>G c.C54G F18L c.58G>C c.G58C A20P c.59C>A c.C59A A20D c.59C>G c.C59G A20G c.62T>A c.T62A L21H c.64G>A c.G64A V22I c.64G>C c.G64C V22L c.64G>T c.G64T V22F c.65T>C c.T65C V22A c.65T>G c.T65G V22G c.67T>A c.T67A S23T c.67T>C c.T67C S23P c.[70T>A; 1255A>G] c.T70A/A1255G W24R/N419D c.70T>C alebo c.70T>A c.T70C alebo c.T70A W24R c.70T>G c.T70G W24G c.71G>C c.G71C W24S c.72G>C alebo c.72G>T c.G72C alebo c.G72T W24C c.73G>C c.G73C D25H c.77T>A c.T77A I26N c.79C>A c.C79A P27T c.79C>G c.C79G P27A c.79C>T c.C79T P27S c.80C>T c.C80T P27L c.82G>C c.G82C G28R c.82G>T c.G82T G28W c.83G>A c.G83A G28E c.85G>C c.G85C A29P c.86C>A c.C86A A29D c.86C>G c.C86G A29G c.86C>T c.C86T A29V c.88A>G c.A88G R30G c.94C>A c.C94A L32M c.94C>G c.C94G L32V c.95T>A c.T95A L32Q c.95T>C c.T95C L32P c.95T>G c.T95G L32R c.97G>C c.G97C D33H c.97G>T c.G97T D33Y c.98A>C c.A98C D33A c.98A>G c.A98G D33G c.98A>T c.A98T D33V c.99C>G c.C99G D33E c.100A>C c.A100C N34H c.100A>G c.A100G N34D c.101A>C c.A101C N34T c.101A>G c.A101G N34S 8 Zmena nukleotidov (dlhý) Zmena nukleotidov (krátky) Zmena sekvencie proteínov c.102T>G alebo c.102T>A c.T102G alebo c.T102A N34K c.103G>C alebo c.103G>A c.G103C alebo c.G103A G35R c.104G>A c.G104A G35E c.104G>C c.G104C G35A c.104G>T c.G104T G35V c.106T>A c.T106A L36M c.106T>G c.T106G L36V c.107T>C c.T107C L36S c.107T>G c.T107G L36W c.108G>C alebo c.108G>T c.G108C alebo c.G108T L36F c.109G>A c.G109A A37T c.109G>T c.G109T A37S c.110C>A c.C110A A37E c.110C>G c.C110G A37G c.110C>T c.C110T A37V c.112A>G c.A112G R38G c.112A>T c.A112T R38W c.113G>T c.G113T R38M c.114G>C c.G114C R38S c.115A>G c.A115G T39A c.115A>T c.A115T T39S c.116C>A c.C116A T39K c.116C>G c.C116G T39R c.116C>T c.C116T T39M c.121A>G c.A121G T41A c.122C>A c.C122A T41N c.122C>G c.C122G T41S c.122C>T c.C122T T41I c.124A>C alebo c.124A>T c.A124C alebo c.A124T M42L c.124A>G c.A124G M42V c.125T>A c.T125A M42K c.125T>C c.T125C M42T c.125T>G c.T125G M42R c.126G>A alebo c.126G>C alebo c.126G>T c.G126A alebo c.G126C alebo c.G126T M42I c.128G>C c.G128C G43A c.133C>A c.C133A L45M c.133C>G c.C133G L45V c.136C>A c.C136A H46N c.136C>G c.C136G H46D c.137A>C c.A137C H46P c.138C>G c.C138G H46Q c.142G>C c.G142C E48Q c.143A>C c.A143C E48A c.149T>A c.T149A F50Y c.151A>G c.A151G M51V c.152T>A c.T152A M51K c.152T>C c.T152C M51T 9 Zmena nukleotidov (dlhý) Zmena nukleotidov (krátky) Zmena sekvencie proteínov c.152T>G c.T152G M51R c.153G>A alebo c.153G>T alebo c.153G>C c.G153A alebo c.G153T alebo c.G153C M51I c.157A>C c.A157C N53H c.[157A>C; 158A>T] c.A157C/A158T N53L c.157A>G c.A157G N53D c.157A>T c.A157T N53Y c.158A>C c.A158C N53T c.158A>G c.A158G N53S c.158A>T c.A158T N53I c.159C>G alebo c.159C>A c.C159G alebo c.C159A N53K c.160C>G c.C160G L54V c.[160C>G; 937G>T] c.C160G/G937T L54V/D313Y c.160C>T c.C160T L54F c.161T>A c.T161A L54H c.161T>C c.T161C L54P c.161T>G c.T161G L54R c.163G>C c.G163C D55H c.163G>T c.G163T D55Y c.164A>C c.A164C D55A c.164A>G c.A164G D55G c.164A>T c.A164T D55V c.[164A>T; 170A>T] c.A164T/A170T D55V/Q57L c.165C>G c.C165G D55E c.167G>A c.G167A C56Y c.167G>T c.G167T C56F c.168C>G c.C168G C56W c.170A>G c.A170G Q57R c.170A>T c.A170T Q57L c.172G>A c.G172A E58K c.175G>A c.G175A E59K c.175G>C c.G175C E59Q c.176A>C c.A176C E59A c.176A>G c.A176G E59G c.176A>T c.A176T E59V c.177G>C c.G177C E59D c.178C>A c.C178A P60T c.178C>G c.C178G P60A c.178C>T c.C178T P60S c.179C>A c.C179A P60Q c.179C>G c.C179G P60R c.179C>T c.C179T P60L c.182A>T c.A182T D61V c.183T>A c.T183A D61E c.184_185insTAG c.184_185insTAG S62delinsLA c.184T>C c.T184C S62P c.184T>G c.T184G S62A c.185C>A c.C185A S62Y 10 Zmena nukleotidov (dlhý) Zmena nukleotidov (krátky) Zmena sekvencie proteínov c.185C>G c.C185G S62C c.185C>T c.C185T S62F c.190A>C c.A190C I64L c.190A>G c.A190G I64V c.193A>G c.A193G S65G c.193A>T c.A193T S65C c.195T>A c.T195A S65R c.196G>A c.G196A E66K c.197A>G c.A197G E66G c.197A>T c.A197T E66V c.198G>C c.G198C E66D c.199A>C c.A199C K67Q c.199A>G c.A199G K67E c.200A>C c.A200C K67T c.200A>T c.A200T K67M c.201G>C c.G201C K67N c.202C>A c.C202A L68I c.205T>A c.T205A F69I c.206T>A c.T206A F69Y c.207C>A alebo c.207C>G c.C207A alebo c.C207G F69L c.208A>T c.A208T M70L c.209T>A c.T209A M70K c.209T>G c.T209G M70R c.210G>C c.G210C M70I c.211G>C c.G211C E71Q c.212A>C c.A212C E71A c.212A>G c.A212G E71G c.212A>T c.A212T E71V c.213G>C c.G213C E71D c.214A>G c.A214G M72V c.214A>T c.A214T M72L c.215T>C c.T215C M72T c.216G>A alebo c.216G>T alebo c.216G>C c.G216A alebo c.G216T alebo c.G216C M72I c.217G>A c.G217A A73T c.217G>T c.G217T A73S c.218C>T c.C218T A73V c.[218C>T; 525C>G] c.C218T/C525G A73V/D175E c.220G>A c.G220A E74K c.221A>G c.A221G E74G c.221A>T c.A221T E74V c.222G>C c.G222C E74D c.223C>T c.C223T L75F c.224T>C c.T224C L75P c.226A>G c.A226G M76V c.227T>C c.T227C M76T c.229G>A c.G229A V77I c.229G>C c.G229C V77L 11 Zmena nukleotidov (dlhý) Zmena nukleotidov (krátky) Zmena sekvencie proteínov c.232T>C c.T232C S78P c.233C>T c.C233T S78L c.235G>A c.G235A E79K c.235G>C c.G235C E79Q c.236A>C c.A236C E79A c.236A>G c.A236G E79G c.236A>T c.A236T E79V c.237A>T c.A237T E79D c.238G>A c.G238A G80S c.238G>T c.G238T G80C c.239G>A c.G239A G80D c.239G>C c.G239C G80A c.239G>T c.G239T G80V c.242G>T c.G242T W81L c.244A>G c.A244G K82E c.245A>C c.A245C K82T c.245A>G c.A245G K82R c.245A>T c.A245T K82M c.246G>C c.G246C K82N c.247G>A c.G247A D83N c.248A>C c.A248C D83A c.248A>G c.A248G D83G c.248A>T c.A248T D83V c.249T>A c.T249A D83E c.250G>A c.G250A A84T c.250G>C c.G250C A84P c.250G>T c.G250T A84S c.251C>A c.C251A A84E c.251C>G c.C251G A84G c.251C>T c.C251T A84V c.253G>A c.G253A G85S c.[253G>A; 254G>A] c.G253A/G254A G85N c.[253G>A; 254G>T; 255T>G] c.G253A/G254T/T255G G85M c.253G>C c.G253C G85R c.253G>T c.G253T G85C c.254G>A c.G254A G85D c.254G>C c.G254C G85A c.257A>T c.A257T Y86F c.260A>G c.A260G E87G c.261G>C alebo c.261G>T c.G261C alebo c.G261T E87D c.262T>A c.T262A Y88N c.262T>C c.T262C Y88H c.263A>C c.A263C Y88S c.263A>G c.A263G Y88C c.265C>G c.C265G L89V c.265C>T c.C265T L89F c.271A>C c.A271C I91L c.271A>T c.A271T I91F 12 Zmena nukleotidov (dlhý) Zmena nukleotidov (krátky) Zmena sekvencie proteínov c.272T>C c.T272C I91T c.272T>G c.T272G I91S c.273T>G c.T273G I91M c.286A>G c.A286G M96V c.286A>T c.A286T M96L c.287T>C c.T287C M96T c.288G>A alebo c.288G>T aleboc.288G>C c.G288A alebo c.G288T aleboc.G288C M96I c.289G>A c.G289A A97T c.289G>C c.G289C A97P c.289G>T c.G289T A97S c.290C>A c.C290A A97D c.290C>T c.C290T A97V c.293C>A c.C293A P98H c.293C>G c.C293G P98R c.293C>T c.C293T P98L c.295C>G c.C295G Q99E c.296A>C c.A296C Q99P c.296A>G c.A296G Q99R c.296A>T c.A296T Q99L c.301G>C c.G301C D101H c.302A>C c.A302C D101A c.302A>G c.A302G D101G c.302A>T c.A302T D101V c.303T>A c.T303A D101E c.304T>A c.T304A S102T c.304T>C c.T304C S102P c.304T>G c.T304G S102A c.305C>T c.C305T S102L c.310G>A c.G310A G104S c.311G>A c.G311A G104D c.311G>C c.G311C G104A c.311G>T c.G311T G104V c.313A>G c.A313G R105G c.314G>A c.G314A R105K c.314G>C c.G314C R105T c.314G>T c.G314T R105I c.316C>A c.C316A L106I c.316C>G c.C316G L106V c.316C>T c.C316T L106F c.317T>A c.T317A L106H c.317T>C c.T317C L106P c.319C>A c.C319A Q107K c.319C>G c.C319G Q107E c.320A>G c.A320G Q107R c.321G>C c.G321C Q107H c.322G>A c.G322A A108T c.323C>A c.C323A A108E 13 Zmena nukleotidov (dlhý) Zmena nukleotidov (krátky) Zmena sekvencie proteínov c.323C>T c.C323T A108V c.325G>A c.G325A D109N c.325G>C c.G325C D109H c.325G>T c.G325T D109Y c.326A>C c.A326C D109A c.326A>G c.A326G D109G c.327C>G c.C327G D109E c.328C>A c.C328A P110T c.334C>G c.C334G R112G c.335G>A c.G335A R112H c.335G>T c.G335T R112L c.337T>A c.T337A F113I c.337T>C alebo c.339T>A alebo c.339T>G c.T337C alebo c.T339A alebo c.T339G F113L c.337T>G c.T337G F113V c.338T>A c.T338A F113Y c.341C>T c.C341T P114L c.343C>A c.C343A H115N c.343C>G c.C343G H115D c.346G>C c.G346C G116R c.350T>C c.T350C I117T c.351T>G c.T351G I117M c.352C>T c.C352T R118C c.361G>A c.G361A A121T c.362C>T c.C362T A121V c.367T>A c.T367A Y123N c.367T>G c.T367G Y123D c.368A>C c.A368C Y123S c.368A>G c.A368G Y123C c.368A>T c.A368T Y123F c.370G>A c.G370A V124I c.371T>G c.T371G V124G c.373C>A c.C373A H125N c.373C>G c.C373G H125D c.373C>T c.C373T H125Y c.374A>G c.A374G H125R c.374A>T c.A374T H125L c.376A>G c.A376G S126G c.376A>T c.A376T S126C c.377G>T c.G377T S126I c.379A>G c.A379G K127E c.383G>A c.G383A G128E c.383G>C c.G383C G128A c.385C>G c.C385G L129V c.388A>C c.A388C K130Q c.389A>T c.A389T K130M c.390G>C c.G390C K130N c.391C>G c.C391G L131V 14 Zmena nukleotidov (dlhý) Zmena nukleotidov (krátky) Zmena sekvencie proteínov c.397A>C c.A397C I133L c.397A>G c.A397G I133V c.397A>T c.A397T I133F c.398T>C c.T398C I133T c.399T>G c.T399G I133M c.[399T>G; 434T>C] c.T399G/T434C I133M/F145S c.403G>A c.G403A A135T c.403G>T c.G403T A135S c.404C>A c.C404A A135E c.404C>G c.C404G A135G c.404C>T c.C404T A135V c.406G>A c.G406A D136N c.407A>C c.A407C D136A c.407A>T c.A407T D136V c.408T>A alebo c.408T>G c.T408A alebo c.T408G D136E c.409G>A c.G409A V137I c.409G>C c.G409C V137L c.410T>A c.T410A V137D c.410T>C c.T410C V137A c.410T>G c.T410G V137G c.413G>C c.G413C G138A c.415A>C c.A415C N139H c.415A>T c.A415T N139Y c.416A>G c.A416G N139S c.416A>T c.A416T N139I c.417T>A c.T417A N139K c.418A>C c.A418C K140Q c.418A>G c.A418G K140E c.419A>C c.A419C K140T c.419A>G c.A419G K140R c.419A>T c.A419T K140I c.420A>T c.A420T K140N c.421A>T c.A421T T141S c.427G>A c.G427A A143T c.428C>A c.C428A A143E c.428C>G c.C428G A143G c.428C>T c.C428T A143V c.430G>A c.G430A G144S c.430G>C c.G430C G144R c.430G>T c.G430T G144C c.431G>A c.G431A G144D c.431G>C c.G431C G144A c.431G>T c.G431T G144V c.433T>G c.T433G F145V c.434T>A c.T434A F145Y c.434T>C c.T434C F145S c.434T>G c.T434G F145C c.435C>G c.C435G F145L 15 Zmena nukleotidov (dlhý) Zmena nukleotidov (krátky) Zmena sekvencie proteínov c.436C>A c.C436A P146T c.436C>G c.C436G P146A c.436C>T c.C436T P146S c.437C>A c.C437A P146H c.437C>G c.C437G P146R c.437C>T c.C437T P146L c.440G>C c.G440C G147A c.442A>G c.A442G S148G c.442A>T c.A442T S148C c.443G>C c.G443C S148T c.446T>G c.T446G F149C c.449G>A c.G449A G150E c.449G>T c.G449T G150V c.451T>G c.T451G Y151D c.452A>C c.A452C Y151S c.452A>G c.A452G Y151C c.454T>A c.T454A Y152N c.454T>C c.T454C Y152H c.454T>G c.T454G Y152D c.455A>C c.A455C Y152S c.455A>G c.A455G Y152C c.455A>T c.A455T Y152F c.457G>A c.G457A D153N c.457G>C c.G457C D153H c.457G>T c.G457T D153Y c.458A>C c.A458C D153A c.458A>T c.A458T D153V c.465T>A alebo c.465T>G c.T465A alebo c.T465G D155E c.466G>A c.G466A A156T c.466G>T c.G466T A156S c.467C>G c.C467G A156G c.467C>T c.C467T A156V c.469C>A c.C469A Q157K c.469C>G c.C469G Q157E c.470A>C c.A470C Q157P c.470A>T c.A470T Q157L c.471G>C alebo c.471G>T c.G471C alebo c.G471T Q157H c.472A>G c.A472G T158A c.472A>T c.A472T T158S c.473C>A c.C473A T158N c.473C>T c.C473T T158I c.475T>A c.T475A F159I c.475T>G c.T475G F159V c.476T>A c.T476A F159Y c.476T>G c.T476G F159C c.477T>A c.T477A F159L c.478G>A c.G478A A160T c.478G>T c.G478T A160S 16 Zmena nukleotidov (dlhý) Zmena nukleotidov (krátky) Zmena sekvencie proteínov c.479C>A c.C479A A160D c.479C>G c.C479G A160G c.479C>T c.C479T A160V c.481G>A c.G481A D161N c.481G>C c.G481C D161H c.481G>T c.G481T D161Y c.482A>T c.A482T D161V c.484T>G c.T484G W162G c.485G>C c.G485C W162S c.490G>A c.G490A V164I c.490G>T c.G490T V164L c.491T>C c.T491C V164A c.493G>A c.G493A D165N c.493G>C c.G493C D165H c.494A>C c.A494C D165A c.494A>G c.A494G D165G c.495T>A c.T495A D165E c.496_497delinsTC c.496_497delinsTC L166S c.496C>A c.C496A L166M c.496C>G c.C496G L166V c.[496C>G; 497T>G] c.C496G/T497G L166G c.497T>A c.T497A L166Q c.499C>A c.C499A L167I c.499C>G c.C499G L167V c.505T>A c.T505A F169I c.505T>G c.T505G F169V c.506T>A c.T506A F169Y c.506T>C c.T506C F169S c.506T>G c.T506G F169C c.507T>A c.T507A F169L c.511G>A c.G511A G171S c.512G>C c.G512C G171A c.512G>T c.G512T G171V c.517T>C c.T517C Y173H c.518A>C c.A518C Y173S c.518A>G c.A518G Y173C c.518A>T c.A518T Y173F c.520T>C c.T520C C174R c.520T>G c.T520G C174G c.523G>C c.G523C D175H c.523G>T c.G523T D175Y c.524A>G c.A524G D175G c.524A>T c.A524T D175V c.525C>G alebo c.525C>A c.C525G alebo c.C525A D175E c.526A>T c.A526T S176C c.528T>A c.T528A S176R c.529T>A c.T529A L177M c.529T>G c.T529G L177V 17 Zmena nukleotidov (dlhý) Zmena nukleotidov (krátky) Zmena sekvencie proteínov c.530T>C c.T530C L177S c.530T>G c.T530G L177W c.531G>C c.G531C L177F c.532G>A c.G532A E178K c.532G>C c.G532C E178Q c.533A>C c.A533C E178A c.533A>G c.A533G E178G c.538T>A c.T538A L180M c.538T>G c.T538G L180V c.539T>C c.T539C L180S c.539T>G c.T539G L180W c.540G>C alebo c.540G>T c.G540C alebo c.G540T L180F c.541G>A c.G541A A181T c.541G>C c.G541C A181P c.542C>T c.C542T A181V c.544G>T c.G544T D182Y c.545A>C c.A545C D182A c.545A>G c.A545G D182G c.545A>T c.A545T D182V c.546T>A c.T546A D182E c.548G>A c.G548A G183D c.548G>C c.G548C G183A c.550T>A c.T550A Y184N c.550T>C c.T550C Y184H c.551A>C c.A551C Y184S c.551A>G c.A551G Y184C c.551A>T c.A551T Y184F c.553A>C c.A553C K185Q c.553A>G c.A553G K185E c.554A>C c.A554C K185T c.554A>T c.A554T K185M c.555G>C c.G555C K185N c.556C>A c.C556A H186N c.556C>G c.C556G H186D c.556C>T c.C556T H186Y c.557A>T c.A557T H186L c.558C>G c.C558G H186Q c.559_564dup c.559_564dup p.M187_S188dup c.559A>T c.A559T M187L c.559A>G c.A559G M187V c.560T>C c.T560C M187T c.561G>T alebo c.561G>A alebo c.561G>C c.G561T alebo c.G561A alebo c.G561C M187I c.562T>A c.T562A S188T c.562T>C c.T562C S188P c.562T>G c.T562G S188A c.563C>A c.C563A S188Y c.563C>G c.C563G S188C 18 Zmena nukleotidov (dlhý) Zmena nukleotidov (krátky) Zmena sekvencie proteínov c.563C>T c.C563T S188F c.565T>G c.T565G L189V c.566T>C c.T566C L189S c.567G>C alebo c.567G>T c.G567C alebo c.G567T L189F c.568G>A c.G568A A190T c.568G>T c.G568T A190S c.569C>A c.C569A A190D c.569C>G c.C569G A190G c.569C>T c.C569T A190V c.571C>A c.C571A L191M c.571C>G c.C571G L191V c.572T>A c.T572A L191Q c.574A>C c.A574C N192H c.574A>G c.A574G N192D c.575A>C c.A575C N192T c.575A>G c.A575G N192S c.576T>A c.T576A N192K c.577A>G c.A577G R193G c.577A>T c.A577T R193W c.578G>C c.G578C R193T c.578G>T c.G578T R193M c.[578G>T; 936G>C] c.G578T/G936C R193M/Q312H c.580A>C c.A580C T194P c.580A>G c.A580G T194A c.580A>T alebo c.581C>G c.A580T alebo c.C581G T194S c.581C>A c.C581A T194N c.581C>T c.C581T T194I c.583G>A c.G583A G195S c.583G>C c.G583C G195R c.583G>T c.G583T G195C c.584G>T c.G584T G195V c.586A>G c.A586G R196G c.587G>A c.G587A R196K c.587G>C c.G587C R196T c.587G>T c.G587T R196I c.589A>G c.A589G S197G c.589A>T c.A589T S197C c.590G>A c.G590A S197N c.590G>C c.G590C S197T c.590G>T c.G590T S197I c.593T>C c.T593C I198T c.593T>G c.T593G I198S c.594T>G c.T594G I198M c.595G>A c.G595A V199M c.595G>C c.G595C V199L c.596T>A c.T596A V199E c.596T>C c.T596C V199A c.596T>G c.T596G V199G 19 Zmena nukleotidov (dlhý) Zmena nukleotidov (krátky) Zmena sekvencie proteínov c.598T>A c.T598A Y200N c.599A>C c.A599C Y200S c.599A>G c.A599G Y200C c.601T>A c.T601A S201T c.601T>G c.T601G S201A c.602C>A c.C602A S201Y c.602C>G c.C602G S201C c.602C>T c.C602T S201F c.[602C>T; 937G>T] c.C602T/G937T S201F/D313Y c.607G>C c.G607C E203Q c.608A>C c.A608C E203A c.608A>G c.A608G E203G c.608A>T c.A608T E203V c.609G>C alebo c.609G>T c.G609C alebo c.G609T E203D c.610T>G c.T610G W204G c.611G>C c.G611C W204S c.611G>T c.G611T W204L c.613C>A c.C613A P205T c.613C>T c.C613T P205S c.614C>T c.C614T P205L c.616C>A c.C616A L206I c.616C>G c.C616G L206V c.616C>T c.C616T L206F c.617T>A c.T617A L206H c.617T>G c.T617G L206R c.619T>C c.T619C Y207H c.620A>C c.A620C Y207S c.620A>T c.A620T Y207F c.623T>A c.T623A M208K c.623T>G c.T623G M208R c.625T>A c.T625A W209R c.625T>G c.T625G W209G c.627G>C c.G627C W209C c.628C>A c.C628A P210T c.628C>T c.C628T P210S c.629C>A c.C629A P210H c.629C>T c.C629T P210L c.631T>C c.T631C F211L c.631T>G c.T631G F211V c.632T>A c.T632A F211Y c.632T>C c.T632C F211S c.632T>G c.T632G F211C c.635A>C c.A635C Q212P c.636A>T c.A636T Q212H c.637A>C c.A637C K213Q c.637A>G c.A637G K213E c.638A>G c.A638G K213R c.638A>T c.A638T K213M 20 Zmena nukleotidov (dlhý) Zmena nukleotidov (krátky) Zmena sekvencie proteínov c.640C>A c.C640A P214T c.640C>G c.C640G P214A c.640C>T c.C640T P214S c.641C>A c.C641A P214H c.641C>G c.C641G P214R c.641C>T c.C641T P214L c.643A>C c.A643C N215H c.643A>G c.A643G N215D c.643A>T c.A643T N215Y c.644A>C c.A644C N215T c.644A>G c.A644G N215S c.[644A>G; 937G>T] c.A644G/G937T N215S/D313Y c.644A>T c.A644T N215I c.645T>A c.T645A N215K c.646T>A c.T646A Y216N c.646T>C c.T646C Y216H c.646T>G c.T646G Y216D c.647A>C c.A647C Y216S c.647A>G c.A647G Y216C c.647A>T c.A647T Y216F c.649A>C c.A649C T217P c.649A>G c.A649G T217A c.649A>T c.A649T T217S c.650C>A c.C650A T217K c.650C>G c.C650G T217R c.650C>T c.C650T T217I c.652G>A c.G652A E218K c.652G>C c.G652C E218Q c.653A>C c.A653C E218A c.653A>G c.A653G E218G c.653A>T c.A653T E218V c.654A>T c.A654T E218D c.655A>C c.A655C I219L c.655A>T c.A655T I219F c.656T>A c.T656A I219N c.656T>C c.T656C I219T c.656T>G c.T656G I219S c.657C>G c.C657G I219M c.659G>A c.G659A R220Q c.659G>C c.G659C R220P c.659G>T c.G659T R220L c.661C>A c.C661A Q221K c.661C>G c.C661G Q221E c.662A>C c.A662C Q221P c.662A>G c.A662G Q221R c.662A>T c.A662T Q221L c.663G>C c.G663C Q221H c.664T>A c.T664A Y222N 21 Zmena nukleotidov (dlhý) Zmena nukleotidov (krátky) Zmena sekvencie proteínov c.664T>C c.T664C Y222H c.664T>G c.T664G Y222D c.665A>C c.A665C Y222S c.665A>G c.A665G Y222C c.670A>C c.A670C N224H c.671A>C c.A671C N224T c.671A>G c.A671G N224S c.673C>G c.C673G H225D c.679C>G c.C679G R227G c.682A>C c.A682C N228H c.682A>G c.A682G N228D c.683A>C c.A683C N228T c.683A>G c.A683G N228S c.683A>T c.A683T N228I c.685T>A c.T685A F229I c.686T>A c.T686A F229Y c.686T>C c.T686C F229S c.687T>A alebo c.687T>G c.T687A alebo c.T687G F229L c.688G>C c.G688C A230P c.689C>A c.C689A A230D c.689C>G c.C689G A230G c.689C>T c.C689T A230V c.694A>C c.A694C I232L c.694A>G c.A694G I232V c.695T>C c.T695C I232T c.696T>G c.T696G I232M c.698A>C c.A698C D233A c.698A>G c.A698G D233G c.698A>T c.A698T D233V c.699T>A c.T699A D233E c.703T>A c.T703A S235T c.703T>G c.T703G S235A c.710A>T c.A710T K237I c.712A>G c.A712G S238G c.712A>T c.A712T S238C c.713G>A c.G713A S238N c.713G>C c.G713C S238T c.713G>T c.G713T S238I c.715A>T c.A715T I239L c.716T>C c.T716C I239T c.717A>G c.A717G I239M c.718A>G c.A718G K240E c.719A>G c.A719G K240R c.719A>T c.A719T K240M c.720G>C alebo c.720G>T c.G720C alebo c.G720T K240N c.721A>T c.A721T S241C c.722G>C c.G722C S241T c.722G>T c.G722T S241I 22 Zmena nukleotidov (dlhý) Zmena nukleotidov (krátky) Zmena sekvencie proteínov c.724A>C c.A724C I242L c.724A>G c.A724G I242V c.724A>T c.A724T I242F c.725T>A c.T725A I242N c.725T>C c.T725C I242T c.725T>G c.T725G I242S c.726C>G c.C726G I242M c.727T>A c.T727A L243M c.727T>G c.T727G L243V c.728T>C c.T728C L243S c.728T>G c.T728G L243W c.729G>C alebo c.729G>T c.G729C alebo c.G729T L243F c.730G>A c.G730A D244N c.730G>C c.G730C D244H c.730G>T c.G730T D244Y c.731A>C c.A731C D244A c.731A>G c.A731G D244G c.731A>T c.A731T D244V c.732C>G c.C732G D244E c.733T>G c.T733G W245G c.735G>C c.G735C W245C c.736A>G c.A736G T246A c.737C>A c.C737A T246K c.737C>G c.C737G T246R c.737C>T c.C737T T246I c.739T>A c.T739A S247T c.739T>G c.T739G S247A c.740C>A c.C740A S247Y c.740C>G c.C740G S247C c.740C>T c.C740T S247F c.742T>G c.T742G F248V c.743T>A c.T743A F248Y c.743T>G c.T743G F248C c.744T>A c.T744A F248L c.745A>C c.A745C N249H c.745A>G c.A745G N249D c.745A>T c.A745T N249Y c.746A>C c.A746C N249T c.746A>G c.A746G N249S c.746A>T c.A746T N249I c.747C>G alebo c.747C>A c.C747G alebo c.C747A N249K c.748C>A c.C748A Q250K c.748C>G c.C748G Q250E c.749A>C c.A749C Q250P c.749A>G c.A749G Q250R c.749A>T c.A749T Q250L c.750G>C c.G750C Q250H c.751G>A c.G751A E251K 23 Zmena nukleotidov (dlhý) Zmena nukleotidov (krátky) Zmena sekvencie proteínov c.751G>C c.G751C E251Q c.752A>G c.A752G E251G c.752A>T c.A752T E251V c.754A>G c.A754G R252G c.757A>G c.A757G I253V c.757A>T c.A757T I253F c.758T>A c.T758A I253N c.758T>C c.T758C I253T c.758T>G c.T758G I253S c.760-762delGTT alebo c.761-763del c.760_762delGTT alebo c.761_763del p.V254del c.760G>T c.G760T V254F c.761T>A c.T761A V254D c.761T>C c.T761C V254A c.761T>G c.T761G V254G c.763G>A c.G763A D255N c.763G>C c.G763C D255H c.763G>T c.G763T D255Y c.764A>C c.A764C D255A c.764A>T c.A764T D255V c.765T>A c.T765A D255E c.766G>C c.G766C V256L c.767T>A c.T767A V256D c.767T>G c.T767G V256G c.769G>A c.G769A A257T c.769G>C c.G769C A257P c.769G>T c.G769T A257S c.770C>G c.C770G A257G c.770C>T c.C770T A257V c.772G>C alebo c.772G>A c.G772C alebo c.G772A G258R c.773G>A c.G773A G258E c.773G>T c.G773T G258V c.775C>A c.C775A P259T c.775C>G c.C775G P259A c.775C>T c.C775T P259S c.776C>A c.C776A P259Q c.776C>G c.C776G P259R c.776C>T c.C776T P259L c.778G>T c.G778T G260W c.779G>A c.G779A G260E c.779G>C c.G779C G260A c.781G>A c.G781A G261S c.781G>C c.G781C G261R c.781G>T c.G781T G261C c.782G>C c.G782C G261A c.787A>C c.A787C N263H c.788A>C c.A788C N263T c.788A>G c.A788G N263S 24 Zmena nukleotidov (dlhý) Zmena nukleotidov (krátky) Zmena sekvencie proteínov c.790G>A c.G790A D264N c.790G>C c.G790C D264H c.790G>T c.G790T D264Y c.793C>G c.C793G P265A c.794C>A c.C794A P265Q c.794C>T c.C794T P265L c.799A>G c.A799G M267V c.799A>T c.A799T M267L c.800T>C c.T800C M267T c.802T>A c.T802A L268I c.804A>T c.A804T L268F c.805G>A c.G805A V269M c.805G>C c.G805C V269L c.806T>C c.T806C V269A c.808A>C c.A808C I270L c.808A>G c.A808G I270V c.809T>C c.T809C I270T c.809T>G c.T809G I270S c.810T>G c.T810G I270M c.811G>A c.G811A G271S c.[811G>A; 937G>T] c.G811A/G937T G271S/D313Y c.812G>A c.G812A G271D c.812G>C c.G812C G271A c.814A>G c.A814G N272D c.818T>A c.T818A F273Y c.823C>A c.C823A L275I c.823C>G c.C823G L275V c.827G>A c.G827A S276N c.827G>C c.G827C S276T c.829T>G c.T829G W277G c.830G>T c.G830T W277L c.831G>T alebo c.831G>C c.G831T alebo c.G831C W277C c.832A>T c.A832T N278Y c.833A>T c.A833T N278I c.835C>G c.C835G Q279E c.838C>A c.C838A Q280K c.839A>G c.A839G Q280R c.839A>T c.A839T Q280L c.840A>T alebo c.840A>C c.A840T alebo c.A840C Q280H c.841G>C c.G841C V281L c.842T>A c.T842A V281E c.842T>C c.T842C V281A c.842T>G c.T842G V281G c.844A>G c.A844G T282A c.844A>T c.A844T T282S c.845C>T c.C845T T282I c.847C>G c.C847G Q283E c.848A>T c.A848T Q283L 25 Zmena nukleotidov (dlhý) Zmena nukleotidov (krátky) Zmena sekvencie proteínov c.849G>C c.G849C Q283H c.850A>G c.A850G M284V c.850A>T c.A850T M284L c.851T>C c.T851C M284T c.852G>C c.G852C M284I c.853G>A c.G853A A285T c.854C>G c.C854G A285G c.854C>T c.C854T A285V c.856C>G c.C856G L286V c.856C>T c.C856T L286F c.857T>A c.T857A L286H c.860G>T c.G860T W287L c.862G>C c.G862C A288P c.862G>T c.G862T A288S c.863C>G c.C863G A288G c.863C>T c.C863T A288V c.865A>C c.A865C I289L c.865A>G c.A865G I289V c.866T>C c.T866C I289T c.866T>G c.T866G I289S c.868A>C alebo c.868A>T c.A868C alebo c.A868T M290L c.868A>G c.A868G M290V c.869T>C c.T869C M290T c.870G>A alebo c.870G>C aleboc.870G>T c.G870A alebo c.G870C aleboc.G870T M290I c.871G>A c.G871A A291T c.871G>T c.G871T A291S c.872C>G c.C872G A291G c.874G>T c.G874T A292S c.875C>G c.C875G A292G c.877C>A c.C877A P293T c.880T>A c.T880A L294I c.880T>G c.T880G L294V c.881T>C c.T881C L294S c.882A>T c.A882T L294F c.883T>A c.T883A F295I c.883T>G c.T883G F295V c.884T>A c.T884A F295Y c.884T>C c.T884C F295S c.884T>G c.T884G F295C c.886A>G c.A886G M296V c.886A>T alebo c.886A>C c.A886T alebo c.A886C M296L c.887T>C c.T887C M296T c.888G>A alebo c.888G>T alebo c.888G>C c.G888A alebo c.G888T alebo c.G888C M296I c.889T>A c.T889A S297T c.892A>G c.A892G N298D c.893A>C c.A893C N298T 26 Zmena nukleotidov (dlhý) Zmena nukleotidov (krátky) Zmena sekvencie proteínov c.893A>G c.A893G N298S c.893A>T c.A893T N298I c.895G>A c.G895A D299N c.895G>C c.G895C D299H c.897C>G alebo c.897C>A c.C897G alebo c.C897A D299E c.898C>A c.C898A L300I c.898C>G c.C898G L300V c.898C>T c.C898T L300F c.899T>C c.T899C L300P c.901C>G c.C901G R301G c.902G>A c.G902A R301Q c.902G>C c.G902C R301P c.902G>T c.G902T R301L c.904C>A c.C904A H302N c.904C>G c.C904G H302D c.904C>T c.C904T H302Y c.905A>T c.A905T H302L c.907A>G c.A907G I303V c.907A>T c.A907T I303F c.908T>A c.T908A I303N c.908T>C c.T908C I303T c.908T>G c.T908G I303S c.911G>A c.G911A S304N c.911G>C c.G911C S304T c.911G>T c.G911T S304I c.916C>G c.C916G Q306E c.917A>C c.A917C Q306P c.917A>T c.A917T Q306L c.919G>A c.G919A A307T c.919G>C c.G919C A307P c.919G>T c.G919T A307S c.920C>A c.C920A A307D c.920C>G c.C920G A307G c.920C>T c.C920T A307V c.922A>C c.A922C K308Q c.922A>G c.A922G K308E c.923A>G c.A923G K308R c.923A>T c.A923T K308I c.924A>T alebo c.924A>C c.A924T alebo c.A924C K308N c.925G>A c.G925A A309T c.925G>C c.G925C A309P c.926C>A c.C926A A309D c.926C>T c.C926T A309V c.928C>A c.C928A L310I c.928C>G c.C928G L310V c.928C>T c.C928T L310F c.931C>A c.C931A L311I c.931C>G c.C931G L311V 27 Zmena nukleotidov (dlhý) Zmena nukleotidov (krátky) Zmena sekvencie proteínov c.934C>A c.C934A Q312K c.934C>G c.C934G Q312E c.935A>G c.A935G Q312R c.935A>T c.A935T Q312L c.936G>T alebo c.936G>C c.G936T alebo c.G936C Q312H c.937G>T c.G937T D313Y c.[937G>T; 1232G>A] c.G937T/G1232A D313Y/G411D c.938A>G c.A938G D313G c.938A>T c.A938T D313V c.939T>A c.T939A D313E c.940A>G c.A940G K314E c.941A>C c.A941C K314T c.941A>T c.A941T K314M c.942G>C c.G942C K314N c.943G>A c.G943A D315N c.943G>C c.G943C D315H c.943G>T c.G943T D315Y c.944A>C c.A944C D315A c.944A>G c.A944G D315G c.944A>T c.A944T D315V c.946G>A c.G946A V316I c.946G>C c.G946C V316L c.947T>C c.T947C V316A c.947T>G c.T947G V316G c.949A>C c.A949C I317L c.949A>G c.A949G I317V c.950T>C c.T950C I317T c.951T>G c.T951G I317M c.952G>A c.G952A A318T c.952G>C c.G952C A318P c.953C>A c.C953A A318D c.953C>T c.C953T A318V c.955A>T c.A955T I319F c.956T>C c.T956C I319T c.957C>G c.C957G I319M c.958A>C c.A958C N320H c.959A>C c.A959C N320T c.959A>G c.A959G N320S c.959A>T c.A959T N320I c.961C>A c.C961A Q321K c.962A>G c.A962G Q321R c.962A>T c.A962T Q321L c.963G>C alebo c.963G>T c.G963C alebo c.G963T Q321H c.964G>A c.G964A D322N c.964G>C c.G964C D322H c.965A>C c.A965C D322A c.965A>T c.A965T D322V c.966C>A alebo c.966C>G c.C966A alebo c.C966G D322E 28 Zmena nukleotidov (dlhý) Zmena nukleotidov (krátky) Zmena sekvencie proteínov c.967C>A c.C967A P323T c.968C>G c.C968G P323R c.970T>G c.T970G L324V c.971T>G c.T971G L324W c.973G>A c.G973A G325S c.973G>C c.G973C G325R c.973G>T c.G973T G325C c.974G>C c.G974C G325A c.974G>T c.G974T G325V c.976A>C c.A976C K326Q c.976A>G c.A976G K326E c.977A>C c.A977C K326T c.977A>G c.A977G K326R c.977A>T c.A977T K326M c.978G>C alebo c.978G>T c.G978C alebo c.G978T K326N c.979C>G c.C979G Q327E c.980A>C c.A980C Q327P c.980A>T c.A980T Q327L c.981A>T alebo c.981A>C c.A981T alebo c.A981C Q327H c.983G>C c.G983C G328A c.985T>A c.T985A Y329N c.985T>C c.T985C Y329H c.985T>G c.T985G Y329D c.986A>G c.A986G Y329C c.986A>T c.A986T Y329F c.988C>A c.C988A Q330K c.988C>G c.C988G Q330E c.989A>C c.A989C Q330P c.989A>G c.A989G Q330R c.990G>C c.G990C Q330H c.991C>G c.C991G L331V c.992T>A c.T992A L331H c.992T>C c.T992C L331P c.992T>G c.T992G L331R c.994A>G c.A994G R332G c.995G>C c.G995C R332T c.995G>T c.G995T R332I c.996A>T c.A996T R332S c.997C>G c.C997G Q333E c.998A>C c.A998C Q333P c.998A>T c.A998T Q333L c.1000G>C c.G1000C G334R c.1001G>A c.G1001A G334E c.1001G>T c.G1001T G334V c.1003G>T c.G1003T D335Y c.1004A>C c.A1004C D335A c.1004A>G c.A1004G D335G c.1004A>T c.A1004T D335V 29 Zmena nukleotidov (dlhý) Zmena nukleotidov (krátky) Zmena sekvencie proteínov c.1005C>G c.C1005G D335E c.1006A>G c.A1006G N336D c.1006A>T c.A1006T N336Y c.1007A>C c.A1007C N336T c.1007A>G c.A1007G N336S c.1007A>T c.A1007T N336I c.1009T>G c.T1009G F337V c.1010T>A c.T1010A F337Y c.1010T>C c.T1010C F337S c.1010T>G c.T1010G F337C c.1011T>A c.T1011A F337L c.1012G>A c.G1012A E338K c.1013A>C c.A1013C E338A c.1013A>G c.A1013G E338G c.1013A>T c.A1013T E338V c.1014A>T c.A1014T E338D c.1015G>A c.G1015A V339M c.1016T>A c.T1016A V339E c.1016T>C c.T1016C V339A c.1021G>C c.G1021C E341Q c.1022A>C c.A1022C E341A c.1027C>A c.C1027A P343T c.1027C>G c.C1027G P343A c.1027C>T c.C1027T P343S c.1028C>T c.C1028T P343L c.1030C>G c.C1030G L344V c.1030C>T c.C1030T L344F c.1031T>G c.T1031G L344R c.1033T>C c.T1033C S345P c.1036G>T c.G1036T G346C c.1037G>A c.G1037A G346D c.1037G>C c.G1037C G346A c.1037G>T c.G1037T G346V c.1039T>A c.T1039A L347I c.1043C>A c.C1043A A348D c.1046G>C c.G1046C W349S c.1046G>T c.G1046T W349L c.1047G>C c.G1047C W349C c.1048G>A c.G1048A A350T c.1048G>T c.G1048T A350S c.1049C>G c.C1049G A350G c.1049C>T c.C1049T A350V c.1052T>A c.T1052A V351E c.1052T>C c.T1052C V351A c.1054G>A c.G1054A A352T c.1054G>T c.G1054T A352S c.1055C>G c.C1055G A352G c.1055C>T c.C1055T A352V 30 Zmena nukleotidov (dlhý) Zmena nukleotidov (krátky) Zmena sekvencie proteínov c.1057A>T c.A1057T M353L c.1058T>A c.T1058A M353K c.1058T>C c.T1058C M353T c.1061T>A c.T1061A I354K c.1061T>G c.T1061G I354R c.1063A>C c.A1063C N355H c.1063A>G c.A1063G N355D c.1063A>T c.A1063T N355Y c.1064A>G c.A1064G N355S c.1066C>G c.C1066G R356G c.1066C>T c.C1066T R356W c.1067G>A c.G1067A R356Q c.1067G>C c.G1067C R356P c.1067G>T c.G1067T R356L c.1069C>G c.C1069G Q357E c.1072G>C c.G1072C E358Q c.1073A>C c.A1073C E358A c.1073A>G c.A1073G E358G c.1074G>T alebo c.1074G>C c.G1074T alebo c.G1074C E358D c.1075A>C c.A1075C I359L c.1075A>G c.A1075G I359V c.1075A>T c.A1075T I359F c.1076T>A c.T1076A I359N c.1076T>C c.T1076C I359T c.1076T>G c.T1076G I359S c.1078G>A c.G1078A G360S c.1078G>C c.G1078C G360R c.1078G>T c.G1078T G360C c.1079G>A c.G1079A G360D c.1079G>C c.G1079C G360A c.1082G>A c.G1082A G361E c.1082G>C c.G1082C G361A c.1084C>A c.C1084A P362T c.1084C>G c.C1084G P362A c.1084C>T c.C1084T P362S c.1085C>A c.C1085A P362H c.1085C>G c.C1085G P362R c.1085C>T c.C1085T P362L c.1087C>A c.C1087A R363S c.1087C>G c.C1087G R363G c.1087C>T c.C1087T R363C c.1088G>A c.G1088A R363H c.1088G>T c.G1088T R363L c.1090T>C c.T1090C S364P c.1091C>G c.C1091G S364C c.1093T>A c.T1093A Y365N c.1093T>G c.T1093G Y365D c.1094A>C c.A1094C Y365S 31 Zmena nukleotidov (dlhý) Zmena nukleotidov (krátky) Zmena sekvencie proteínov c.1094A>T c.A1094T Y365F c.1096A>C c.A1096C T366P c.1096A>T c.A1096T T366S c.1097C>A c.C1097A T366N c.1097C>T c.C1097T T366I c.1099A>C c.A1099C I367L c.1099A>T c.A1099T I367F c.1101C>G c.C1101G I367M c.1102G>A c.G1102A A368T c.1102G>C c.G1102C A368P c.1103C>G c.C1103G A368G c.1105G>A c.G1105A V369I c.1105G>C c.G1105C V369L c.1105G>T c.G1105T V369F c.1106T>C c.T1106C V369A c.1106T>G c.T1106G V369G c.1108G>A c.G1108A A370T c.1108G>C c.G1108C A370P c.1109C>A c.C1109A A370D c.1109C>G c.C1109G A370G c.1109C>T c.C1109T A370V c.1111T>A c.T1111A S371T c.1112C>G c.C1112G S371C c.1117G>A c.G1117A G373S c.1117G>T c.G1117T G373C c.1118G>C c.G1118C G373A c.1120A>G c.A1120G K374E c.1121A>C c.A1121C K374T c.1121A>G c.A1121G K374R c.1121A>T c.A1121T K374I c.1123G>C c.G1123C G375R c.1124G>A c.G1124A G375E c.1124G>C c.G1124C G375A c.1126G>A c.G1126A V376M c.1126G>C c.G1126C V376L c.1127T>A c.T1127A V376E c.1127T>G c.T1127G V376G c.1129G>A c.G1129A A377T c.1129G>C c.G1129C A377P c.1129G>T c.G1129T A377S c.1130C>G c.C1130G A377G c.1135A>G c.A1135G N379D c.1136A>C c.A1136C N379T c.1136A>T c.A1136T N379I c.1137T>A c.T1137A N379K c.1138C>A c.C1138A P380T c.1138C>G c.C1138G P380A c.1139C>A c.C1139A P380H 32 Zmena nukleotidov (dlhý) Zmena nukleotidov (krátky) Zmena sekvencie proteínov c.1139C>G c.C1139G P380R c.1139C>T c.C1139T P380L c.1142C>A c.C1142A A381D c.1147T>A c.T1147A F383I c.1148T>A c.T1148A F383Y c.1148T>G c.T1148G F383C c.1150A>T c.A1150T I384F c.1151T>C c.T1151C I384T c.1152C>G c.C1152G I384M c.1153A>G c.A1153G T385A c.1154C>T c.C1154T T385I c.1156C>A c.C1156A Q386K c.1157A>T c.A1157T Q386L c.1158G>C c.G1158C Q386H c.1159C>A c.C1159A L387I c.1159C>T c.C1159T L387F c.1160T>A c.T1160A L387H c.1160T>G c.T1160G L387R c.1162C>A c.C1162A L388I c.1162C>G c.C1162G L388V c.1162C>T c.C1162T L388F c.1163T>A c.T1163A L388H c.1163T>G c.T1163G L388R c.1168G>A c.G1168A V390M c.1171A>C c.A1171C K391Q c.1171A>G c.A1171G K391E c.1172A>C c.A1172C K391T c.1172A>G c.A1172G K391R c.1172A>T c.A1172T K391I c.1173A>T c.A1173T K391N c.1174A>G c.A1174G R392G c.1174A>T c.A1174T R392W c.1175G>A c.G1175A R392K c.1175G>C c.G1175C R392T c.1175G>T c.G1175T R392M c.1177A>C c.A1177C K393Q c.1177A>G c.A1177G K393E c.1178A>C c.A1178C K393T c.1179G>C c.G1179C K393N c.1180C>A c.C1180A L394I c.1181T>A c.T1181A L394Q c.1181T>C c.T1181C L394P c.1181T>G c.T1181G L394R c.1183G>C c.G1183C G395R c.1184G>A c.G1184A G395E c.1184G>C c.G1184C G395A c.1186T>A c.T1186A F396I c.1186T>G c.T1186G F396V 33 Zmena nukleotidov (dlhý) Zmena nukleotidov (krátky) Zmena sekvencie proteínov c.1187T>G c.T1187G F396C c.1188C>G c.C1188G F396L c.1189T>A c.T1189A Y397N c.1189T>C c.T1189C Y397H c.1190A>C c.A1190C Y397S c.1190A>G c.A1190G Y397C c.1190A>T c.A1190T Y397F c.1192G>A c.G1192A E398K c.1192G>C c.G1192C E398Q c.1193A>G c.A1193G E398G c.1195T>A c.T1195A W399R c.1195T>G c.T1195G W399G c.1198A>C c.A1198C T400P c.1198A>G c.A1198G T400A c.1198A>T c.A1198T T400S c.1199C>A c.C1199A T400N c.1199C>T c.C1199T T400I c.1201T>A c.T1201A S401T c.1201T>G c.T1201G S401A c.1202_1203insGACTTC c.1202_1203insGACTTC p.T400_S401dup c.1202C>T c.C1202T S401L c.1204A>G c.A1204G R402G c.1204A>T c.A1204T R402W c.1205G>C c.G1205C R402T c.1205G>T c.G1205T R402M c.1206G>C c.G1206C R402S c.1207T>G c.T1207G L403V c.1208T>C c.T1208C L403S c.1209A>T c.A1209T L403F c.1210A>G c.A1210G R404G c.1211G>A c.G1211A R404K c.1211G>C c.G1211C R404T c.1211G>T c.G1211T R404I c.1212A>T c.A1212T R404S c.1213A>G c.A1213G S405G c.1216C>G c.C1216G H406D c.1217A>T c.A1217T H406L c.1218C>G c.C1218G H406Q c.1219A>T c.A1219T I407L c.1220T>C c.T1220C I407T c.1221A>G c.A1221G I407M c.1222A>C c.A1222C N408H c.1222A>G c.A1222G N408D c.1222A>T c.A1222T N408Y c.1223A>C c.A1223C N408T c.1225C>A c.C1225A P409T c.1225C>G c.C1225G P409A 34 Zmena nukleotidov (dlhý) Zmena nukleotidov (krátky) Zmena sekvencie proteínov c.1225C>T c.C1225T P409S c.1226C>T c.C1226T P409L c.1228A>G c.A1228G T410A c.1228A>T c.A1228T T410S c.1229C>T c.C1229T T410I c.1231G>A c.G1231A G411S c.1231G>T c.G1231T G411C c.1232G>A c.G1232A G411D c.1232G>C c.G1232C G411A c.1232G>T c.G1232T G411V c.1234A>C c.A1234C T412P c.1234A>G c.A1234G T412A c.1234A>T c.A1234T T412S c.1235C>A c.C1235A T412N c.1235C>T c.C1235T T412I c.1237G>A c.G1237A V413I c.1237G>T c.G1237T V413F c.1238T>G c.T1238G V413G c.1240T>G c.T1240G L414V c.1242G>C c.G1242C L414F c.1243C>A c.C1243A L415I c.1244T>A c.T1244A L415H c.1246C>G c.C1246G Q416E c.1247A>T c.A1247T Q416L c.1248G>C c.G1248C Q416H c.1249C>A c.C1249A L417I c.1252G>A c.G1252A E418K c.1252G>C c.G1252C E418Q c.1253A>C c.A1253C E418A c.1253A>G c.A1253G E418G c.1254A>T c.A1254T E418D c.1255A>G c.A1255G N419D c.1255A>T c.A1255T N419Y c.1256A>C c.A1256C N419T c.1256A>G c.A1256G N419S c.1256A>T c.A1256T N419I c.1258A>C c.A1258C T420P c.1258A>T c.A1258T T420S c.1259C>A c.C1259A T420K c.1259C>G c.C1259G T420R c.1261A>G c.A1261G M421V c.1261A>T c.A1261T M421L c.1262T>A c.T1262A M421K c.1262T>C c.T1262C M421T c.1262T>G c.T1262G M421R c.1263G>C c.G1263C M421I c.1265A>C c.A1265C Q422P c.1267A>T c.A1267T M423L 35 Zmena nukleotidov (dlhý) Zmena nukleotidov (krátky) Zmena sekvencie proteínov c.1268T>A c.T1268A M423K c.1268T>C c.T1268C M423T c.1269G>C c.G1269C M423I c.1271C>T c.C1271T S424L c.1275A>C c.A1275C L425F c.1279G>A c.G1279A D427N c.1286T>G c.T1286G L429R Farmakodynamické účinky Liečba liekom Galafold vo farmakodynamických štúdiách fázy 2 zvyčajne viedla u väčšiny pacientov k zvýšeniu endogénnej aktivity α-Gal A v bielych krvinkách a tiež v koži a obličkách. U pacientov s príslušnými mutáciami sa zvyčajne znížila hladina GL-3 v moči a v intersticiálnej oblasti kapilár obličiek. Klinická účinnosť a bezpečnosť Klinická účinnosť a bezpečnosť lieku Galafold boli hodnotené v dvoch hlavných klinických štúdiách fázy 3 a v dvoch otvorených predĺžených (open-label extension - OLE) klinických štúdiách. Všetci pacienti dostávali odporúčané dávky 123 mg lieku Galafold každý druhý deň. Prvá klinická štúdia fázy 3 (ATTRACT) bola randomizovaná, otvorená štúdia s aktívnym komparátorom, v ktorom sa hodnotila účinnosť a bezpečnosť lieku Galafold v porovnaní s enzýmovou substitučnou liečbou (ERT) (beta-agalzidáza, alfa-agalzidáza) u 52 mužov a žien s Fabryho chorobou, ktorí dostávali ERT pred vstupom do klinickej štúdie a ktorí mali príslušné mutácie (klinická štúdia u pacientov, ktorí mali skúsenosti s ERT). Klinická štúdia bola rozdelená do dvoch etáp. V prvej, 18-mesačnej etape boli pacienti so skúsenosťou s ERT randomizovaní a prechádzali z liečby ERT na liečbu liekom Galafold alebo sa naďalej liečili ERT. Druhou etapou bolo voliteľné 12-mesačné otvorené predĺženie, počas ktorého všetci pacienti dostávali Galafold. Druhá klinická štúdia fázy 3 (FACETS) bola šesťmesačná, randomizovaná, dvojito zaslepená štúdia kontrolovaná placebom (až do šiesteho mesiaca) s 18-mesačným otvoreným obdobím na vyhodnotenie účinnosti a bezpečnosti lieku Galafold u 50 mužov a žien s Fabryho chorobou bez predchádzajúcej liečby ERT alebo ktorí dostávali ERT v minulosti a prestali ju užívať najmenej na šesť mesiacov, a ktorí mali príslušné mutácie (štúdia s pacientmi bez predchádzajúcej liečby ERT). Do prvej OLE klinickej štúdie (AT1001-041) boli zaradení pacienti zo štúdií v 2. a 3. fáze a bola dokončená. Stredná hodnota rozsahu expozície dávky 123 mg migalastátu každý druhý deň, ktorá bola uvedená na trh u pacientov, ktorí ukončili štúdiu AT1001-041 bola 3,57 (± 1,23) roka (n=85). Maximálna expozícia bola 5,6 roka. Do druhej OLE klinickej štúdie (AT1001-042) boli zaradení pacienti, ktorí prešli zo štúdie OLE AT1001-041 alebo priamo zo štúdie ATTRACT v 3. fáze. Stredná hodnota rozsahu expozície dávky 123 mg lieku Galafold každý druhý deň, ktorá bola uvedená na trh, u pacientov v tejto štúdii bola 32,3 (± 12,3) mesiaca (n = 82). Maximálna expozícia bola 51,9 mesiaca. Funkcia obličiek V klinickej štúdii u pacientov, ktorí mali skúsenosti s ERT, funkcia obličiek ostala stabilná až do 18 mesiacov liečby liekom Galafold. Priemerná anualizovaná miera zmeny eGFR CKD-EPI bola -0,40 ml/min/1,73 m 2 (95 % IS: -2,272; 1,478; n=34) v skupine užívajúcej Galafold v porovnaní s -1,03 36 ml/min/1,73 m 2 (95 % IS: -3,636; 1,575; n=18) v skupine, ktorá dostávala ERT. Priemerná anualizovaná miera zmeny eGFR CKD-EPI u pacientov liečených počas tridsiatich mesiacov liekom Galafold od začiatku liečby bola -1,72 ml/min/1,73 m 2 (95 % IS: -2,653; -0,782; n=31). V klinickej štúdii u pacientov bez predchádzajucej liečbyERT a v otvorenom predĺžení ostala funkcia obličiek stabilná do 5 rokov liečby liekom Galafold. Po priemerne 3,4 roka liečby bola priemerná anualizovaná miera zmeny eGFRCKD-EPI -0,74 ml/min/1,73 m 2 (95 % IS: -1,89; 0,40; n=41). Počas počiatočného šesťmesačného obdobia kontrolovaného placebom sa nepozorovali klinicky významné rozdiely. Boli zosumarizované údaje anualizovanej miery zmeny eGFR CKD-EPI u pacientov bez predchádzajúcej liečby ERT a u pacientov, ktorí mali skúsenosti s ERT s príslušnými mutáciami, pričom výsledky preukázali pretrvávanie renálnej stabilizácie až 8,6 roka v anulizovanej miere zmeny. Po priemernej dĺžke 5,2 roka mali pacienti bez predchádzajúcej liečby ERT priemernú anualizovanú mieru zmeny od začiatku -1,71 ml/min/1,73 m 2 (95 % IS: -2,83, -0,60; n = 47). Po priemernej dĺžke 4,3 roka mali pacienti, ktorí mali skúsenosti s ERT, priemernú anualizovanú mieru zmeny od začiatku -1,78 ml/min/1,73 m 2 (95 % IS: -3,76; 0,20; n = 49). Index hmotnosti ľavej komory (LVMi) V klinickej štúdii u pacientov, ktorí mali skúsenosti s ERT, sa po 18 mesiacoch liečby liekom Galafold pozorovalo štatisticky významné zníženie LVMi (p < 0,05). Východiskové hodnoty boli 95,3 g/m 2 pre skupinu s liekom Galafold a 92,9 g/m 2 pre skupinu s ERT a priemerná zmena východiskového LVMi v 18. mesiaci predstavovala -6,6 (95 % interval spoľahlivosti: -11,0; -2,1; n=31) pre Galafold a -2,0 (95 % interval spoľahlivosti: -11,0; 7,0; n=13) pre ERT. Zmena LVMi (g/m 2 ) od začiatku do 18. mesiaca u pacientov s hypertrofiou ľavej komory (ženy s LVMi na začiatku > 95 g/m 2 a muži s LVMi na začiatku > 115 g/m 2 ) bola -8,4 (95 % IS: -15,7; 2,6; n=13) pre Galafold a 4,5 (95 % IS: -10,7; 18,4; n=5) pre ERT. Po tridsiatich mesiacoch liečby liekom Galafold bola priemerná zmena LVMi od začiatku -3,8 (95 % IS: -8,9; 1,3; n=28) a priemerná zmena LVMi od začiatku u pacientov s hypertrofiou ľavej komory bola -10,0 (95 % IS: -16,6; -3,3; n=10). V klinickej štúdii u pacientov bez predchádzajúcej liečbyERT, liečba liekom Galafold viedla k štatisticky významnému zníženiu LVMi (p < 0,05); priemerná zmena LVMi od začiatku do 18. – 24. mesiaca bola -7,7 (95 % IS: -15,4; -0,01; n=27). Po sledovaní v OLE bola priemerná zmena LVMi od začiatku do 36. mesiaca -8,3 (95 % IS: -17,1; 0,4; n=25) a do 48. mesiaca -9,1 (95% IS: -20,3; 2,0; n=18). Priemerná zmena LVMi od začiatku do 18. – 24. mesiaca u pacientov s hypertrofiou ľavej komory na začiatku (ženy s LVMi na začiatku > 95 g/m 2 alebo muži s LVMi na začiatku > 115 g/m 2 ) bola -18,6 (95 % IS: -38,2; 1,0; n=8). Po sledovaní v OLE bola priemerná zmena LVMi od začiatku do 36. mesiaca u pacientov s hypertrofiou ľavej komory na začiatku -30,0 (95 % IS: -57,9; -2,2; n=4) a do 48. mesiaca 33,1 (95 % IS: -60,9; -5,4; n=4). Počas počiatočného šesťmesačného obdobia kontrolovaného placebom sa nepozorovali klinicky významné rozdiely LVMi. V klinických štúdiách u pacientov, ktorí mali skúsenosti s ERT, a u pacientov bez predchádzajúcej liečby ERT po sledovaní v OLE klinickej štúdie AT1001-042 bola priemerná zmena LVMi od začiatku AT1001- 042 1,2 g/m 2 (95 % IS: -5,3; 7,7; n = 15) a -5,6 g/m 2 (95 % IS: -28,5; 17,2; n = 4) v uvedenom poradí u pacientov liečených liekom Galafold s priemerom 2,4 a 2,9 roka (najviac 4,0 a 4,3 roka v uvedenom poradí). Substrát ochorenia V klinickej štúdii u pacientov, ktorí mali skúsenosti s ERT, plazmatická hladina lyzo-Gb3 mierne vzrástla, no zostala nízka u pacientov s príslušnýmimutáciami, liečenými liekom Galafold počas trvania 30-mesačnej štúdie. Plazmatická hladina lyzo-Gb3 taktiež ostala nízka až 18 mesiacov u pacientov, ktorí dostávali ERT. 37 V klinickej štúdii u pacientov bez predchádzajúcej liečby ERT, Galafold preukázal štatisticky významné zníženia plazmatických koncentrácií lyzo-Gb3 a inklúzií GL-3 v intersticiálnej oblasti kapilár obličiek u pacientov s príslušnými mutáciami. Pacienti randomizovaní na liečbu liekom Galafold v 1. štádiu preukázali štatisticky výraznejšie významné zníženie (±SEM) priemerného ukladania GL-3 v intersticiálnej oblasti kapilár (–0,25 ± 0,10; –39 %) v šiestom mesiaci v porovnaní s placebom (+0,07 ± 0,13; +14 %) (p = 0,008). Pacienti randomizovaní na liečbu placebom v 1. štádiu, ktorí prešli na liek Galafold v šiestom mesiaci (2. štádium) tiež preukázali štatisticky významné zníženia inklúzií GL-3 v intersticiálnej oblasti kapilár v 12. mesiaci (-0,33 ± 0,15; –58 %) (p = 0,014). Počas 12 mesiacov liečby liekom Galafold sa pozorovali kvalitatívne zníženia hladiny GL-3 vo viacerých typoch renálnych buniek: v podocytoch, mezangiálnych bunkách a v glomerulárnych endotelových bunkách. Zložené klinické výsledky V klinickej štúdii u pacientov, ktorí mali skúsenosti s ERT, sa uskutočnila analýza zloženého klinického výsledku, ktorý sa skladal z renálnych, srdcových a cerebrovaskulárnych udalostí alebo úmrtia, pričom frekvencia udalostí pozorovaných v skupine liečenej liekom Galafold bola 29 % v porovnaní so 44 % v skupine, ktorá dostávala ERT počas osemnástich mesiacov. Frekvencia udalostí u pacientov liečených liekom Galafold počas tridsiatich mesiacov (32 %) bola podobná ako u pacientov liečených liekom Galafold počas osemnástich mesiacov. Výsledok udávaný pacientmi – stupnica hodnotenia gastrointestinálnych symptómov V klinickej štúdii u pacientov bez predchádzajúcej liečbyERT, analýzy stupnice hodnotenia gastrointestinálnych symptómov preukázali, že liečba liekom Galafold sa spájala so štatisticky významnými (p < 0,05) zlepšeniami od začiatku do šiesteho mesiaca v porovnaní s placebom, pokiaľ ide o hnačku a reflux u pacientov, ktorí mali na začiatku symptómy. Počas otvorenej predĺženej fázy sa pozorovali štatisticky významné (p < 0,05) zlepšenia oproti začiatku, pokiaľ ide o hnačku a trávenie a pozoroval sa trend zlepšenia, pokiaľ ide o zápchu. Pediatrická populácia V klinickej štúdii AT1001-020, 1-ročnom, nezaslepenom, nekontrolovanom, multicentrickom klinickom skúšaní v 3b. fáze, sa bezpečnosť, FK, farmakodynamika (FD) a účinnosť liečby migalastátom hodnotili u 21 dospievajúcich účastníkov (vo veku 12 až < 18 rokov a s telesnou hmotnosťou ≥ 45 kg) s Fabryho chorobou, a ktorí majú príslušné mutácie génového kódovania α-galaktozidázy A (GLA). Účastníci predtým neužívali enzýmovú substitučnú liečbu (ERT) alebo ukončili ERT najmenej 14 dní pred skríningom. Priemerná hodnota počtu rokov od potvrdenia diagnózy Fabryho choroby bol 9,6 (± 4,25) roka. Po 1 roku boli výsledky účinnosti u dospievajúcich s rovnakou dávkovacou schémou ako u dospelých konzistentné, čo sa týka renálnych, srdcových a farmakodynamických výsledkov, ako aj odpovedí na výsledky hlásené pacientmi. Celková stredná hodnota (SD) zmeny oproti východiskovému stavu v eGFR bola -1,6 (15,4) ml/min/1,73 m 2 (n = 19). Celková stredná hodnota (SD) zmeny oproti východiskovému stavu v LVMi bola -3,9 (13,5) g/m 2 (n = 18). Hodnota LVMi sa znížila u 10 účastníkov a zvýšila sa u 8 účastníkov, ale u všetkých účastníkov zostala po 12 mesiacoch v normálnych rozmedziach. Východisková plazmatická hladina lyso-Gb3 bola 12,00 ng/ml a celková stredná hodnota (SD) zmeny oproti východiskovému stavu v plazmatickej hladine lyso-Gb3 bola -0,06 (32,9) (n = 19). Zníženie plazmatickej hladiny lyso-Gb3 oproti východiskovému stavu bolo pozorované u účastníkov bez predchádzajúcej liečby ERT (medián -2,23 ng/ml, n = 9) a hladiny zostali celkovo stabilizované u účastníkov so skúsenosťami s ERT (medián 0,54 ng/ml, n = 10). Vo výsledkoch hlásených pacientmi nedošlo k žiadnym významným zmenám. Európska agentúra pre lieky udelila odklad z povinnosti predložiť výsledky štúdií s liekom Galafold v jednej alebo vo viacerých podskupinách pediatrickej populácie v liečbe Fabryho choroby (informácie o použití v pediatrickej populácii, pozri časť 4.2 ). 38