میگالاستات هیدروکلراید

12.1 Mechanism of Action Migalastat is a pharmacological chaperone that reversibly binds to the active site of the alpha-galactosidase A (alpha-Gal A) protein (encoded by the galactosidase alpha gene, GLA ), which is deficient in Fabry disease. This binding stabilizes alpha-Gal A allowing its trafficking from the endoplasmic reticulum into the lysosome where it exerts its action. In the lysosome, at a lower pH and at a higher concentration of relevant substrates, migalastat dissociates from alpha-Gal A allowing it to break down the glycosphingolipids globotriaosylceramide (GL-3) and globotriaosylsphingosine (lyso-Gb 3 ). Certain GLA variants (mutations) causing Fabry disease result in the production of abnormally folded and less stable forms of the alpha-Gal A protein which, however, retain enzymatic activity. Those GLA variants, referred to as amenable variants, produce alpha-Gal A proteins that may be stabilized by migalastat thereby restoring their trafficking to lysosomes and their intralysosomal activity. In Vitro Amenability Assay In an in vitro assay (HEK-293 assay), Human Embryonic Kidney (HEK-293) cell lines were transfected with specific GLA variants which produced variant alpha-Gal A proteins. In the transfected cells, amenability of the GLA variants was assessed after a 5-day incubation with 10 micromol/L migalastat. A GLA variant was categorized as amenable if the resultant variant alpha-Gal A activity (measured in the cell lysates) met two criteria: 1) it showed a relative increase of at least 20% compared to the pre-treatment alpha-Gal A activity, and 2) it showed an absolute increase of at least 3% of the wild-type (normal) alpha-Gal A activity. The in vitro assay did not evaluate trafficking of the variant alpha-Gal A proteins into the lysosome or the dissociation of migalastat from the variant alpha-Gal A proteins within the lysosome. Also, the in vitro assay did not test whether a GLA variant causes Fabry disease or not. The GLA variants that are amenable to treatment with GALAFOLD, either based on the in vitro assay data or on the concept that synonymous nucleotide changes leading to the same variant alpha-Gal A protein as a confirmed amenable GLA variant are amenable without additional testing, are shown in Table 2 . In patients with multiple identified variants, the amenability assessment of each independent variant may not reflect the overall amenability classification of the combination of variants. The specific variant combination must be present within Table 2 (eg, c.[164A>T; 170A>T]) and on a single chromosome (males and females) to be considered amenable to treatment with GALAFOLD. When multiple variants are identified in a female, it is recommended to consult a clinical genetics professional to determine whether the variants are on a single GLA allele. Inclusion of GLA variants in this table does not reflect interpretation of their clinical significance in Fabry disease. Whether a certain amenable GLA variant in a patient with Fabry disease is disease-causing or not should be determined by the prescribing physician (in consultation with a clinical genetics professional, if needed) prior to treatment initiation. Consultation with a clinical genetics professional is strongly recommended in cases where the amenable GLA variant is of uncertain clinical significance (VUS, variant of uncertain significance) or may be benign (not causing Fabry disease). If a GLA variant does not appear in Table 2 , it is either non-amenable (if tested) or has not been tested for in vitro amenability. For further information, please contact Amicus Medical Information at 1-877-4AMICUS or medinfousa@amicusrx.com. Table 2: Amenable GLA Variants Based on the In Vitro Assay § Based on available published data, the GLA variant c.937G>T, (p.(D313Y)) is considered benign (not causing Fabry disease). Consultation with a clinical genetics professional is strongly recommended in patients with Fabry disease who have this GLA variant as additional evaluations may be indicated. † Multiple variant combination of two or more different variants on a single GLA allele that informs amenability. ‡ Synonymous variants are listed without testing in the in vitro amenability assay. GLA variant(s) with a different nucleotide change affecting the same amino acid position(s) as the tested GLA variant and predicted to encode the same variant alpha-Gal A enzyme are considered synonymous. ¶ c.761_763delTTG has been previously referred to as c.760_762delGTT. DNA Change (Long) DNA Change (Short) Protein Change (1-letter Code) Protein Change (3-letter Code) c.7C>G c.C7G p.(L3V) p.(Leu3Val) c.8T>C c.T8C p.(L3P) p.(Leu3Pro) c.[11G>T; 620A>C] † c.[G11T; A620C] † p.[(R4M; Y207S)] † p.[(Arg4Met; Tyr207Ser)] † c.37G>A c.G37A p.(A13T) p.(Ala13Thr) c.37G>C c.G37C p.(A13P) p.(Ala13Pro) c.43G>A c.G43A p.(A15T) p.(Ala15Thr) c.44C>G c.C44G p.(A15G) p.(Ala15Gly) c.53T>G c.T53G p.(F18C) p.(Phe18Cys) c.58G>C c.G58C p.(A20P) p.(Ala20Pro) c.59C>A c.C59A p.(A20D) p.(Ala20Asp) c.65T>G c.T65G p.(V22G) p.(Val22Gly) c.[70T>A; 1255A>G] † c.[T70A; A1255G] † p.[(W24R; N419D)] † p.[(Trp24Arg; Asn419Asp)] † c.70T>A or c.70T>C ‡ c.T70A or c.T70C ‡ p.(W24R) p.(Trp24Arg) c.70T>G c.T70G p.(W24G) p.(Trp24Gly) c.72G>C or c.72G>T ‡ c.G72C or c.G72T ‡ p.(W24C) p.(Trp24Cys) c.95T>C c.T95C p.(L32P) p.(Leu32Pro) c.97G>C c.G97C p.(D33H) p.(Asp33His) c.97G>T c.G97T p.(D33Y) p.(Asp33Tyr) c.98A>G c.A98G p.(D33G) p.(Asp33Gly) c.100A>C c.A100C p.(N34H) p.(Asn34His) c.100A>G c.A100G p.(N34D) p.(Asn34Asp) c.101A>C c.A101C p.(N34T) p.(Asn34Thr) c.101A>G c.A101G p.(N34S) p.(Asn34Ser) c.102T>A or c.102T>G ‡ c.T102A or c.T102G ‡ p.(N34K) p.(Asn34Lys) c.103G>A or c.103G>C ‡ c.G103A or c.G103C ‡ p.(G35R) p.(Gly35Arg) c.104G>A c.G104A p.(G35E) p.(Gly35Glu) c.104G>T c.G104T p.(G35V) p.(Gly35Val) c.107T>C c.T107C p.(L36S) p.(Leu36Ser) c.107T>G c.T107G p.(L36W) p.(Leu36Trp) c.108G>C or c.108G>T ‡ c.G108C or c.G108T ‡ p.(L36F) p.(Leu36Phe) c.109G>A c.G109A p.(A37T) p.(Ala37Thr) c.109G>T c.G109T p.(A37S) p.(Ala37Ser) c.110C>T c.C110T p.(A37V) p.(Ala37Val) c.122C>T c.C122T p.(T41I) p.(Thr41Ile) c.124A>C or c.124A>T ‡ c.A124C or c.A124T ‡ p.(M42L) p.(Met42Leu) c.124A>G c.A124G p.(M42V) p.(Met42Val) c.125T>A c.T125A p.(M42K) p.(Met42Lys) c.125T>C c.T125C p.(M42T) p.(Met42Thr) c.125T>G c.T125G p.(M42R) p.(Met42Arg) c.126G>A or c.126G>C ‡ or c.126G>T ‡ c.G126A or c.G126C ‡ or c.G126T ‡ p.(M42I) p.(Met42Ile) c.137A>C c.A137C p.(H46P) p.(His46Pro) c.142G>C c.G142C p.(E48Q) p.(Glu48Gln) c.152T>A c.T152A p.(M51K) p.(Met51Lys) c.153G>A or c.153G>T ‡ or c.153G>C ‡ c.G153A or c.G153T ‡ or c.G153C ‡ p.(M51I) p.(Met51Ile) c.157_158delinsCT c.157_158delinsCT p.(N53L) p.(Asn53Leu) c.157A>G c.A157G p.(N53D) p.(Asn53Asp) c.160C>T c.C160T p.(L54F) p.(Leu54Phe) c.161T>C c.T161C p.(L54P) p.(Leu54Pro) c.164A>G c.A164G p.(D55G) p.(Asp55Gly) c.164A>T c.A164T p.(D55V) p.(Asp55Val) c.[164A>T; 170A>T] † c.[A164T; A170T] † p.[(D55V; Q57L)] † p.[(Asp55Val; Gln57Leu)] † c.167G>A c.G167A p.(C56Y) p.(Cys56Tyr) c.167G>T c.G167T p.(C56F) p.(Cys56Phe) c.170A>G c.A170G p.(Q57R) p.(Gln57Arg) c.170A>T c.A170T p.(Q57L) p.(Gln57Leu) c.175G>A c.G175A p.(E59K) p.(Glu59Lys) c.178C>A c.C178A p.(P60T) p.(Pro60Thr) c.178C>T c.C178T p.(P60S) p.(Pro60Ser) c.179C>T c.C179T p.(P60L) p.(Pro60Leu) c.196G>A c.G196A p.(E66K) p.(Glu66Lys) c.197A>G c.A197G p.(E66G) p.(Glu66Gly) c.207C>A or c.207C>G ‡ c.C207A or c.C207G ‡ p.(F69L) p.(Phe69Leu) c.214A>G c.A214G p.(M72V) p.(Met72Val) c.216G>A or c.216G>T ‡ or c.216G>C ‡ c.G216A or c.G216T ‡ or c.G216C ‡ p.(M72I) p.(Met72Ile) c.218C>T c.C218T p.(A73V) p.(Ala73Val) c.227T>C c.T227C p.(M76T) p.(Met76Thr) c.239G>A c.G239A p.(G80D) p.(Gly80Asp) c.239G>T c.G239T p.(G80V) p.(Gly80Val) c.247G>A c.G247A p.(D83N) p.(Asp83Asn) c.253G>A c.G253A p.(G85S) p.(Gly85Ser) c.253_254delinsAA c.253_254delinsAA p.(G85N) p.(Gly85Asn) c.253_255delinsATG c.253_255delinsATG p.(G85M) p.(Gly85Met) c.254G>A c.G254A p.(G85D) p.(Gly85Asp) c.261G>C or c.261G>T ‡ c.G261C or c.G261T ‡ p.(E87D) p.(Glu87Asp) c.263A>G c.A263G p.(Y88C) p.(Tyr88Cys) c.265C>T c.C265T p.(L89F) p.(Leu89Phe) c.272T>C c.T272C p.(I91T) p.(Ile91Thr) c.288G>A or c.288G>T ‡ or c.288G>C ‡ c.G288A or c.G288T ‡ or c.G288C ‡ p.(M96I) p.(Met96Ile) c.289G>C c.G289C p.(A97P) p.(Ala97Pro) c.290C>T c.C290T p.(A97V) p.(Ala97Val) c.305C>T c.C305T p.(S102L) p.(Ser102Leu) c.311G>T c.G311T p.(G104V) p.(Gly104Val) c.316C>T c.C316T p.(L106F) p.(Leu106Phe) c.320A>G c.A320G p.(Q107R) p.(Gln107Arg) c.322G>A c.G322A p.(A108T) p.(Ala108Thr) c.326A>G c.A326G p.(D109G) p.(Asp109Gly) c.334C>G c.C334G p.(R112G) p.(Arg112Gly) c.335G>A c.G335A p.(R112H) p.(Arg112His) c.335G>T c.G335T p.(R112L) p.(Arg112Leu) c.337T>A c.T337A p.(F113I) p.(Phe113Ile) c.337T>C or c.339T>A ‡ or c.339T>G ‡ c.T337C or c.T339A ‡ or c.T339G ‡ p.(F113L) p.(Phe113Leu) c.352C>T c.C352T p.(R118C) p.(Arg118Cys) c.361G>A c.G361A p.(A121T) p.(Ala121Thr) c.368A>G c.A368G p.(Y123C) p.(Tyr123Cys) c.373C>T c.C373T p.(H125Y) p.(His125Tyr) c.374A>T c.A374T p.(H125L) p.(His125Leu) c.376A>G c.A376G p.(S126G) p.(Ser126Gly) c.376A>T c.A376T p.(S126C) p.(Ser126Cys) c.383G>A c.G383A p.(G128E) p.(Gly128Glu) c.399T>G c.T399G p.(I133M) p.(Ile133Met) c.404C>T c.C404T p.(A135V) p.(Ala135Val) c.408T>A or c.408T>G ‡ c.T408A or c.T408G ‡ p.(D136E) p.(Asp136Glu) c.416A>G c.A416G p.(N139S) p.(Asn139Ser) c.419A>C c.A419C p.(K140T) p.(Lys140Thr) c.427G>A c.G427A p.(A143T) p.(Ala143Thr) c.431G>A c.G431A p.(G144D) p.(Gly144Asp) c.431G>T c.G431T p.(G144V) p.(Gly144Val) c.434T>C c.T434C p.(F145S) p.(Phe145Ser) c.436C>T c.C436T p.(P146S) p.(Pro146Ser) c.437C>G c.C437G p.(P146R) p.(Pro146Arg) c.454T>C c.T454C p.(Y152H) p.(Tyr152His) c.454T>G c.T454G p.(Y152D) p.(Tyr152Asp) c.455A>G c.A455G p.(Y152C) p.(Tyr152Cys) c.465T>A or c.465T>G ‡ c.T465A or c.T465G ‡ p.(D155E) p.(Asp155Glu) c.466G>A c.G466A p.(A156T) p.(Ala156Thr) c.466G>T c.G466T p.(A156S) p.(Ala156Ser) c.467C>T c.C467T p.(A156V) p.(Ala156Val) c.471G>C or c.471G>T ‡ c.G471C or c.G471T ‡ p.(Q157H) p.(Gln157His) c.484T>G c.T484G p.(W162G) p.(Trp162Gly) c.493G>C c.G493C p.(D165H) p.(Asp165His) c.494A>G c.A494G p.(D165G) p.(Asp165Gly) c.496_497delinsTC c.496_497delinsTC p.(L166S) p.(Leu166Ser) c.496C>G c.C496G p.(L166V) p.(Leu166Val) c.496_497delinsGG c.496_497delinsGG p.(L166G) p.(Leu166Gly) c.499C>G c.C499G p.(L167V) p.(Leu167Val) c.506T>C c.T506C p.(F169S) p.(Phe169Ser) c.511G>A c.G511A p.(G171S) p.(Gly171Ser) c.520T>C c.T520C p.(C174R) p.(Cys174Arg) c.520T>G c.T520G p.(C174G) p.(Cys174Gly) c.525C>G or c.525C>A ‡ c.C525G or c.C525A ‡ p.(D175E) p.(Asp175Glu) c.539T>G c.T539G p.(L180W) p.(Leu180Trp) c.540G>T or c.540G>C ‡ c.G540T or c.G540C ‡ p.(L180F) p.(Leu180Phe) c.548G>A c.G548A p.(G183D) p.(Gly183Asp) c.548G>C c.G548C p.(G183A) p.(Gly183Ala) c.550T>A c.T550A p.(Y184N) p.(Tyr184Asn) c.551A>C c.A551C p.(Y184S) p.(Tyr184Ser) c.551A>G c.A551G p.(Y184C) p.(Tyr184Cys) c.553A>G c.A553G p.(K185E) p.(Lys185Glu) c.559_564dup c.559_564dup p.(M187_S188dup) p.(Met187_Ser188dup) c.559A>G c.A559G p.(M187V) p.(Met187Val) c.560T>C c.T560C p.(M187T) p.(Met187Thr) c.561G>A or c.561G>T ‡ or c.561G>C ‡ c.G561A or c.G561T ‡ or c.G561C ‡ p.(M187I) p.(Met187Ile) c.567G>C or c.567G>T ‡ c.G567C or c.G567T ‡ p.(L189F) p.(Leu189Phe) c.572T>A c.T572A p.(L191Q) p.(Leu191Gln) c.581C>T c.C581T p.(T194I) p.(Thr194Ile) c.584G>T c.G584T p.(G195V) p.(Gly195Val) c.586A>G c.A586G p.(R196G) p.(Arg196Gly) c.593T>C c.T593C p.(I198T) p.(Ile198Thr) c.595G>A c.G595A p.(V199M) p.(Val199Met) c.596T>C c.T596C p.(V199A) p.(Val199Ala) c.596T>G c.T596G p.(V199G) p.(Val199Gly) c.599A>G c.A599G p.(Y200C) p.(Tyr200Cys) c.602C>A c.C602A p.(S201Y) p.(Ser201Tyr) c.602C>T c.C602T p.(S201F) p.(Ser201Phe) c.608A>T c.A608T p.(E203V) p.(Glu203Val) c.609G>C or c.609G>T ‡ c.G609C or c.G609T ‡ p.(E203D) p.(Glu203Asp) c.611G>T c.G611T p.(W204L) p.(Trp204Leu) c.613C>A c.C613A p.(P205T) p.(Pro205Thr) c.613C>T c.C613T p.(P205S) p.(Pro205Ser) c.614C>T c.C614T p.(P205L) p.(Pro205Leu) c.619T>C c.T619C p.(Y207H) p.(Tyr207His) c.620A>C c.A620C p.(Y207S) p.(Tyr207Ser) c.623T>G c.T623G p.(M208R) p.(Met208Arg) c.628C>T c.C628T p.(P210S) p.(Pro210Ser) c.629C>T c.C629T p.(P210L) p.(Pro210Leu) c.638A>G c.A638G p.(K213R) p.(Lys213Arg) c.638A>T c.A638T p.(K213M) p.(Lys213Met) c.640C>T c.C640T p.(P214S) p.(Pro214Ser) c.641C>T c.C641T p.(P214L) p.(Pro214Leu) c.643A>G c.A643G p.(N215D) p.(Asn215Asp) c.644A>G c.A644G p.(N215S) p.(Asn215Ser) c.[644A>G; 937G>T § ] † c.[A644G; G937T § ] † p.[(N215S; D313Y § )] † p.[(Asn215Ser; Asp313Tyr § )] † c.644A>T c.A644T p.(N215I) p.(Asn215Ile) c.646T>G c.T646G p.(Y216D) p.(Tyr216Asp) c.647A>G c.A647G p.(Y216C) p.(Tyr216Cys) c.655A>C c.A655C p.(I219L) p.(Ile219Leu) c.656T>A c.T656A p.(I219N) p.(Ile219Asn) c.656T>C c.T656C p.(I219T) p.(Ile219Thr) c.657C>G c.C657G p.(I219M) p.(Ile219Met) c.659G>A c.G659A p.(R220Q) p.(Arg220Gln) c.659G>C c.G659C p.(R220P) p.(Arg220Pro) c.662A>C c.A662C p.(Q221P) p.(Gln221Pro) c.664T>G c.T664G p.(Y222D) p.(Tyr222Asp) c.671A>C c.A671C p.(N224T) p.(Asn224Thr) c.671A>G c.A671G p.(N224S) p.(Asn224Ser) c.673C>G c.C673G p.(H225D) p.(His225Asp) c.682A>C c.A682C p.(N228H) p.(Asn228His) c.683A>G c.A683G p.(N228S) p.(Asn228Ser) c.687T>G or c.687T>A ‡ c.T687G or c.T687A ‡ p.(F229L) p.(Phe229Leu) c.695T>C c.T695C p.(I232T) p.(Ile232Thr) c.712A>G c.A712G p.(S238G) p.(Ser238Gly) c.713G>A c.G713A p.(S238N) p.(Ser238Asn) c.716T>C c.T716C p.(I239T) p.(Ile239Thr) c.717A>G c.A717G p.(I239M) p.(Ile239Met) c.720G>C or c.720G>T ‡ c.G720C or c.G720T ‡ p.(K240N) p.(Lys240Asn) c.724A>G c.A724G p.(I242V) p.(Ile242Val) c.724A>T c.A724T p.(I242F) p.(Ile242Phe) c.725T>A c.T725A p.(I242N) p.(Ile242Asn) c.725T>C c.T725C p.(I242T) p.(Ile242Thr) c.728T>C c.T728C p.(L243S) p.(Leu243Ser) c.728T>G c.T728G p.(L243W) p.(Leu243Trp) c.729G>C or c.729G>T ‡ c.G729C or c.G729T ‡ p.(L243F) p.(Leu243Phe) c.730G>A c.G730A p.(D244N) p.(Asp244Asn) c.730G>C c.G730C p.(D244H) p.(Asp244His) c.733T>G c.T733G p.(W245G) p.(Trp245Gly) c.740C>G c.C740G p.(S247C) p.(Ser247Cys) c.747C>G or c.747C>A ‡ c.C747G or c.C747A ‡ p.(N249K) p.(Asn249Lys) c.749A>C c.A749C p.(Q250P) p.(Gln250Pro) c.749A>G c.A749G p.(Q250R) p.(Gln250Arg) c.750G>C c.G750C p.(Q250H) p.(Gln250His) c.758T>C c.T758C p.(I253T) p.(Ile253Thr) c.758T>G c.T758G p.(I253S) p.(Ile253Ser) c.761_763delTTG c.761_763delTTG [a.k.a. c.760_762delGTT ¶ ] p.(V254del) p.(Val254del) c.769G>C c.G769C p.(A257P) p.(Ala257Pro) c.770C>G c.C770G p.(A257G) p.(Ala257Gly) c.770C>T c.C770T p.(A257V) p.(Ala257Val) c.772G>C or c.772G>A ‡ c.G772C or c.G772A ‡ p.(G258R) p.(Gly258Arg) c.773G>T c.G773T p.(G258V) p.(Gly258Val) c.776C>A c.C776A p.(P259Q) p.(Pro259Gln) c.776C>G c.C776G p.(P259R) p.(Pro259Arg) c.776C>T c.C776T p.(P259L) p.(Pro259Leu) c.779G>A c.G779A p.(G260E) p.(Gly260Glu) c.779G>C c.G779C p.(G260A) p.(Gly260Ala) c.781G>A c.G781A p.(G261S) p.(Gly261Ser) c.781G>C c.G781C p.(G261R) p.(Gly261Arg) c.781G>T c.G781T p.(G261C) p.(Gly261Cys) c.788A>G c.A788G p.(N263S) p.(Asn263Ser) c.790G>T c.G790T p.(D264Y) p.(Asp264Tyr) c.794C>T c.C794T p.(P265L) p.(Pro265Leu) c.800T>C c.T800C p.(M267T) p.(Met267Thr) c.805G>A c.G805A p.(V269M) p.(Val269Met) c.805G>C c.G805C p.(V269L) p.(Val269Leu) c.806T>C c.T806C p.(V269A) p.(Val269Ala) c.809T>C c.T809C p.(I270T) p.(Ile270Thr) c.810T>G c.T810G p.(I270M) p.(Ile270Met) c.811G>A c.G811A p.(G271S) p.(Gly271Ser) c.[811G>A; 937G>T § ] † c.[G811A; G937T § ] † p.[(G271S; D313Y § )] † p.[(Gly271Ser; Asp313Tyr § )] † c.812G>A c.G812A p.(G271D) p.(Gly271Asp) c.812G>C c.G812C p.(G271A) p.(Gly271Ala) c.823C>G c.C823G p.(L275V) p.(Leu275Val) c.827G>A c.G827A p.(S276N) p.(Ser276Asn) c.829T>G c.T829G p.(W277G) p.(Trp277Gly) c.831G>C or c.831G>T ‡ c.G831C or c.G831T ‡ p.(W277C) p.(Trp277Cys) c.832A>T c.A832T p.(N278Y) p.(Asn278Tyr) c.835C>G c.C835G p.(Q279E) p.(Gln279Glu) c.838C>A c.C838A p.(Q280K) p.(Gln280Lys) c.840A>T or c.840A>C ‡ c.A840T or c.A840C ‡ p.(Q280H) p.(Gln280His) c.844A>G c.A844G p.(T282A) p.(Thr282Ala) c.845C>T c.C845T p.(T282I) p.(Thr282Ile) c.850A>G c.A850G p.(M284V) p.(Met284Val) c.851T>C c.T851C p.(M284T) p.(Met284Thr) c.860G>T c.G860T p.(W287L) p.(Trp287Leu) c.862G>C c.G862C p.(A288P) p.(Ala288Pro) c.866T>G c.T866G p.(I289S) p.(Ile289Ser) c.868A>C or c.868A>T ‡ c.A868C or c.A868T ‡ p.(M290L) p.(Met290Leu) c.869T>C c.T869C p.(M290T) p.(Met290Thr) c.870G>C or c.870G>A ‡ or c.870G>T ‡ c.G870C or c.G870A ‡ or c.G870T ‡ p.(M290I) p.(Met290Ile) c.871G>A c.G871A p.(A291T) p.(Ala291Thr) c.877C>A c.C877A p.(P293T) p.(Pro293Thr) c.881T>C c.T881C p.(L294S) p.(Leu294Ser) c.884T>G c.T884G p.(F295C) p.(Phe295Cys) c.886A>G c.A886G p.(M296V) p.(Met296Val) c.886A>C or c.886A>T ‡ c.A886C or c.A886T ‡ p.(M296L) p.(Met296Leu) c.887T>C c.T887C p.(M296T) p.(Met296Thr) c.888G>A or c.888G>T ‡ or c.888G>C ‡ c.G888A or c.G888T ‡ or c.G888C ‡ p.(M296I) p.(Met296Ile) c.893A>G c.A893G p.(N298S) p.(Asn298Ser) c.897C>G or c.897C>A ‡ c.C897G or c.C897A ‡ p.(D299E) p.(Asp299Glu) c.898C>T c.C898T p.(L300F) p.(Leu300Phe) c.899T>C c.T899C p.(L300P) p.(Leu300Pro) c.901C>G c.C901G p.(R301G) p.(Arg301Gly) c.902G>A c.G902A p.(R301Q) p.(Arg301Gln) c.902G>C c.G902C p.(R301P) p.(Arg301Pro) c.902G>T c.G902T p.(R301L) p.(Arg301Leu) c.907A>T c.A907T p.(I303F) p.(Ile303Phe) c.908T>A c.T908A p.(I303N) p.(Ile303Asn) c.908T>C c.T908C p.(I303T) p.(Ile303Thr) c.911G>A c.G911A p.(S304N) p.(Ser304Asn) c.911G>C c.G911C p.(S304T) p.(Ser304Thr) c.919G>A c.G919A p.(A307T) p.(Ala307Thr) c.922A>G c.A922G p.(K308E) p.(Lys308Glu) c.924A>C or c.924A>T ‡ c.A924C or c.A924T ‡ p.(K308N) p.(Lys308Asn) c.925G>C c.G925C p.(A309P) p.(Ala309Pro) c.926C>T c.C926T p.(A309V) p.(Ala309Val) c.928C>T c.C928T p.(L310F) p.(Leu310Phe) c.931C>G c.C931G p.(L311V) p.(Leu311Val) c.935A>G c.A935G p.(Q312R) p.(Gln312Arg) c.936G>C or c.936G>T ‡ c.G936C or c.G936T ‡ p.(Q312H) p.(Gln312His) c.937G>T § c.G937T § p.(D313Y § ) p.(Asp313Tyr § ) c.[937G>T § ; 1232G>A] † c.[G937T § ; G1232A] † p.[D313Y § ; G411D] † p.[Asp313Tyr § ; Gly411Asp] † c.938A>G c.A938G p.(D313G) p.(Asp313Gly) c.946G>A c.G946A p.(V316I) p.(Val316Ile) c.947T>G c.T947G p.(V316G) p.(Val316Gly) c.950T>C c.T950C p.(I317T) p.(Ile317Thr) c.955A>T c.A955T p.(I319F) p.(Ile319Phe) c.956T>C c.T956C p.(I319T) p.(Ile319Thr) c.958A>C c.A958C p.(N320H) p.(Asn320His) c.959A>T c.A959T p.(N320I) p.(Asn320Ile) c.962A>G c.A962G p.(Q321R) p.(Gln321Arg) c.962A>T c.A962T p.(Q321L) p.(Gln321Leu) c.963G>C or c.963G>T ‡ c.G963C or c.G963T ‡ p.(Q321H) p.(Gln321His) c.964G>A c.G964A p.(D322N) p.(Asp322Asn) c.964G>C c.G964C p.(D322H) p.(Asp322His) c.966C>A or c.966C>G ‡ c.C966A or c.C966G ‡ p.(D322E) p.(Asp322Glu) c.967C>A c.C967A p.(P323T) p.(Pro323Thr) c.968C>G c.C968G p.(P323R) p.(Pro323Arg) c.973G>A c.G973A p.(G325S) p.(Gly325Ser) c.973G>C c.G973C p.(G325R) p.(Gly325Arg) c.978G>C or c.978G>T ‡ c.G978C or c.G978T ‡ p.(K326N) p.(Lys326Asn) c.979C>G c.C979G p.(Q327E) p.(Gln327Glu) c.980A>T c.A980T p.(Q327L) p.(Gln327Leu) c.983G>C c.G983C p.(G328A) p.(Gly328Ala) c.989A>G c.A989G p.(Q330R) p.(Gln330Arg) c.1001G>A c.G1001A p.(G334E) p.(Gly334Glu) c.1010T>C c.T1010C p.(F337S) p.(Phe337Ser) c.1012G>A c.G1012A p.(E338K) p.(Glu338Lys) c.1013A>T c.A1013T p.(E338V) p.(Glu338Val) c.1016T>A c.T1016A p.(V339E) p.(Val339Glu) c.1027C>A c.C1027A p.(P343T) p.(Pro343Thr) c.1028C>T c.C1028T p.(P343L) p.(Pro343Leu) c.1033T>C c.T1033C p.(S345P) p.(Ser345Pro) c.1046G>C c.G1046C p.(W349S) p.(Trp349Ser) c.1055C>G c.C1055G p.(A352G) p.(Ala352Gly) c.1055C>T c.C1055T p.(A352V) p.(Ala352Val) c.1061T>A c.T1061A p.(I354K) p.(Ile354Lys) c.1066C>G c.C1066G p.(R356G) p.(Arg356Gly) c.1066C>T c.C1066T p.(R356W) p.(Arg356Trp) c.1067G>A c.G1067A p.(R356Q) p.(Arg356Gln) c.1067G>C c.G1067C p.(R356P) p.(Arg356Pro) c.1072G>C c.G1072C p.(E358Q) p.(Glu358Gln) c.1073A>C c.A1073C p.(E358A) p.(Glu358Ala) c.1073A>G c.A1073G p.(E358G) p.(Glu358Gly) c.1074G>T or c.1074G>C ‡ c.G1074T or c.G1074C ‡ p.(E358D) p.(Glu358Asp) c.1076T>C c.T1076C p.(I359T) p.(Ile359Thr) c.1078G>A c.G1078A p.(G360S) p.(Gly360Ser) c.1078G>C c.G1078C p.(G360R) p.(Gly360Arg) c.1078G>T c.G1078T p.(G360C) p.(Gly360Cys) c.1079G>A c.G1079A p.(G360D) p.(Gly360Asp) c.1082G>A c.G1082A p.(G361E) p.(Gly361Glu) c.1082G>C c.G1082C p.(G361A) p.(Gly361Ala) c.1084C>A c.C1084A p.(P362T) p.(Pro362Thr) c.1085C>T c.C1085T p.(P362L) p.(Pro362Leu) c.1087C>T c.C1087T p.(R363C) p.(Arg363Cys) c.1088G>A c.G1088A p.(R363H) p.(Arg363His) c.1102G>A c.G1102A p.(A368T) p.(Ala368Thr) c.1117G>A c.G1117A p.(G373S) p.(Gly373Ser) c.1124G>A c.G1124A p.(G375E) p.(Gly375Glu) c.1139C>T c.C1139T p.(P380L) p.(Pro380Leu) c.1153A>G c.A1153G p.(T385A) p.(Tyr385Ala) c.1163T>A c.T1163A p.(L388H) p.(Leu388His) c.1168G>A c.G1168A p.(V390M) p.(Val390Met) c.1172A>C c.A1172C p.(K391T) p.(Lys391Thr) c.1184G>A c.G1184A p.(G395E) p.(Gly395Glu) c.1184G>C c.G1184C p.(G395A) p.(Gly395Ala) c.1192G>A c.G1192A p.(E398K) p.(Glu398Lys) c.1202_1203insGACTTC c.1202_1203insGACTTC p.(T400_S401dup) p.(Thr400_Ser401dup) c.1208T>C c.T1208C p.(L403S) p.(Leu403Ser) c.1225C>A c.C1225A p.(P409T) p.(Pro409Thr) c.1225C>G c.C1225G p.(P409A) p.(Pro409Ala) c.1225C>T c.C1225T p.(P409S) p.(Pro409Ser) c.1228A>G c.A1228G p.(T410A) p.(Thr410Ala) c.1229C>T c.C1229T p.(T410I) p.(Thr410Ile) c.1232G>A c.G1232A p.(G411D) p.(Gly411Asp) c.1234A>C c.A1234C p.(T412P) p.(Thr412Pro) c.1235C>A c.C1235A p.(T412N) p.(Thr412Asn) c.1235C>T c.C1235T p.(T412I) p.(Thr412Ile) c.1253A>G c.A1253G p.(E418G) p.(Glu418Gly) c.1261A>G c.A1261G p.(M421V) p.(Met421Val)

12.2 فارماکودینامیک در مطالعه 1، 31 بیمار از 50 بیمار با واریانت های GLA سازگار (18 نفر در GALAFOLD، 13 در دارونما) ارزیابی لیزو-Gb 3 را پس از 6 ماه درمان داشتند. میانگین تغییر از پایه تا ماه 6 در lyso-Gb 3 پلاسما (nmol/L) 2.37- (محدوده 69.7-، 1.8) در بیمارانی که GALAFOLD مصرف می کردند و 0.53 (محدوده 21.5-، 16.3) در بیمارانی که دارونما مصرف می کردند، بود. در مرحله درمان با برچسب باز مطالعه 1، 13 بیمار که در ابتدا به مدت 6 ماه دارونما مصرف می کردند و به مدت 6 ماه دیگر به GALAFOLD تغییر داده بودند، میانگین تغییر در لیزو-Gb 3 (nmol/L) 2.72- (محدوده -61.1، 0.3-) داشتند. 18 بیمار که به مدت 6 ماه با GALAFOLD تحت درمان قرار گرفتند و سپس GALAFOLD را در مرحله درمان با برچسب باز مطالعه 1 به مدت 6 ماه دیگر ادامه دادند، هیچ تغییر دیگری در lyso-Gb 3 پلاسما مشاهده نشد. در مطالعه 2، 46 بیمار از 56 بیمار دارای واریانت های GLA قابل تحمل (31 نفر در GALAFOLD، 15 نفر تحت درمان جایگزینی آنزیمی (ERT)) پس از 18 ماه درمان، ارزیابی لیزو-Gb 3 را داشتند. میانگین تغییر از پایه تا ماه 18 در لیزو-Gb 3 پلاسما (nmol/L) 0.53 (محدوده 2.27-، 28.3) در بیماران تحت GALAFOLD و 0.03- (محدوده -11.9، 2.57) در بیماران تحت ERT بود. الکتروفیزیولوژی قلب با دوز تقریباً 8 برابر دوز توصیه شده، GALAFOLD فاصله QT را تا حد بالینی مرتبط طولانی نکرد.

12.3 فارماکوکینتیک جذب پس از یک دوز خوراکی 123 میلی گرمی GALAFOLD، فراهمی زیستی مطلق (AUC) میگالاستات تقریباً 75٪ و زمان رسیدن به حداکثر غلظت پلاسمایی (t max) تقریباً 3 ساعت بود. قرار گرفتن در معرض پلاسما میگالاستات (AUC 0-∞ و Cmax) افزایش متناسب با دوز را در دوزهای خوراکی از 75 میلی گرم تا 1250 میلی گرم (دوزهای 0.5 تا 8.3 برابر دوز توصیه شده توصیه شده) نشان داد. میگالاستات پس از تجویز 123 میلی گرم گالافولد یک روز در میان تجمع نمی یابد. تأثیر غذا: تجویز GALAFOLD یک ساعت قبل از مصرف پرچرب (850 کالری). 56٪ از چربی) یا وعده غذایی سبک (507 کالری؛ 30٪ از چربی)، یا یک ساعت پس از یک وعده غذایی سبک، میانگین AUC 0-∞ میگالاستات را 37٪ به 42٪ و Cmax را 15٪ تا 39٪ در مقایسه با حالت ناشتا کاهش داد [به مقدار مصرف و نحوه تجویز مراجعه کنید] (2. توزیع حجم ظاهری توزیع (Vz/F) میگالاستات در بیماران Fabry تقریباً 89 L (محدوده: 77 تا 133 L) در حالت پایدار بود. پس از تجویز [14C]-migalastat در محدوده غلظتی بین 1 تا 100 میکرومولار، اتصال پروتئین پلاسما قابل تشخیص وجود نداشت. متابولیسم حذف: بر اساس داده های in vivo، میگالاستات یک بستر برای یوریدین دی فسفات گلوکورونوزیل ترانسفراز (UDPGT)، یک مسیر حذف جزئی است. دفع: در یک مطالعه تعادل توده در افراد مرد سالم، پس از تجویز خوراکی 123 میلی‌گرم [14C]-میگالاستات، تقریباً 77٪ از کل دوز نشاندار شده رادیواکتیو در ادرار و 20٪ از کل دوز نشاندار شده رادیویی در مدفوع با بهبودی کلی 98٪ در عرض 96 ساعت پس از دوز بازیابی شد. در ادرار، میگالاستات بدون تغییر 80 درصد رادیواکتیویته را تشکیل می دهد که معادل 62 درصد دوز تجویز شده است. در مدفوع، میگالاستات بدون تغییر تنها جزء مرتبط با دارو بود. در پلاسما، میگالاستات بدون تغییر تقریباً 77 درصد از رادیواکتیویته پلاسما را تشکیل می‌دهد و سه متابولیت کونژوگه O-glucuronide هیدروژنه، M1 تا M3، روی هم تقریباً 13 درصد از رادیواکتیویته پلاسما را تشکیل می‌دهند که هیچ کدام بیش از 6 درصد از دوز نشاندار شده رادیواکتیو را تشکیل نمی‌دهند. تقریباً 9 درصد از کل رادیواکتیویته در پلاسما مشخص نشده بود. پس از یک دوز خوراکی 123 میلی گرم گالافولد، میگالاستات با میانگین نیمه عمر (t ½) تقریباً 4 ساعت و کلیرانس ظاهری 12.5 لیتر در ساعت از پلاسما پاک می شود. جمعیت‌های خاص بیماران مرد و زن: ویژگی‌های فارماکوکینتیک میگالاستات بین افراد سالم مرد و زن یا بیماران مبتلا به بیماری فابری تفاوت معنی‌داری نداشت. گروه های نژادی یا قومی: داده های بالینی نشان می دهد که هیچ تفاوت قومیتی در جمعیت بیماران مورد مطالعه با migalastat وجود ندارد. بیماران مبتلا به نارسایی کلیه: در یک مطالعه تک دوز در افراد با درجات مختلف نارسایی کلیوی، قرار گرفتن در معرض میگالاستات (AUC) در افراد با خفیف (eGFR 60 تا 90 میلی‌لیتر/دقیقه/1.73 میلی‌گرم در دقیقه، 5 میلی‌گرم فرات بر دقیقه) 5/1 میلی‌گرم در دقیقه (میلی‌گرم FR19 تا متوسط) 1.2، 1.8، و 4.3 برابر افزایش یافت. m2) و نارسایی شدید کلیوی (eGFR کمتر از 30 ml/min/1.73 m2) به ترتیب، در حالی که Cmax با شدت نارسایی کلیوی بدون تغییر باقی ماند. [به استفاده در جمعیت های خاص (8.6) مراجعه کنید]. مطالعات تداخل دارویی مطالعات آزمایشگاهی Migalastat یک مهارکننده یا القاکننده شناخته شده آنزیم های سیتوکروم P450 (CYP450) نیست و همچنین مهارکننده BCRP، MDR1، P-گلیکوپروتئین (P-gp)، یا BSEP1 OATB1، OATP1، OATB1، OATP1، OATB1، OATP1 و انتقال دهنده های انسانی نیست. ناقل های جذب انسان OAT3، OCT1، OCT2، MATE1 یا MATE2‑K. Migalastat زیرلایه P‑gp، BCRP، MDR1 یا MATE1، MATE2‑K، OAT1، OAT3، یا OCT2 نیست. Migalastat میل ترکیبی کمی برای SGLT1، به عنوان یک بستر و یک بازدارنده، نشان داد و هیچ فعالیتی برای SGLT2 نشان نداد. مطالعات بالینی: اثرات سایر داروها بر مصرف همزمان 190 میلی‌گرم کافئین میگالاستات، میانگین AUC 0-∞ میگالاستات را 55% و Cmax را 60% در مقایسه با بدون مصرف همزمان کافئین کاهش داد. T max میگالاستات تحت تأثیر مصرف همزمان کافئین قرار نگرفت. هیچ تغییر فارماکوکینتیک بالینی قابل توجهی برای میگالاستات در هنگام مصرف همزمان با ساکارز، آسپارتام یا استه سولفام پتاسیم مشاهده نشد [به دوز و نحوه تجویز (2.2) و تداخلات دارویی (7.1) مراجعه کنید.

Migalastat is a pharmacological chaperone that reversibly binds to the active site of the alpha-galactosidase A (alpha-Gal A) protein (encoded by the galactosidase alpha gene, GLA ), which is deficient in Fabry disease. This binding stabilizes alpha-Gal A allowing its trafficking from the endoplasmic reticulum into the lysosome where it exerts its action. In the lysosome, at a lower pH and at a higher concentration of relevant substrates, migalastat dissociates from alpha-Gal A allowing it to break down the glycosphingolipids globotriaosylceramide (GL-3) and globotriaosylsphingosine (lyso-Gb 3 ). Certain GLA variants (mutations) causing Fabry disease result in the production of abnormally folded and less stable forms of the alpha-Gal A protein which, however, retain enzymatic activity. Those GLA variants, referred to as amenable variants, produce alpha-Gal A proteins that may be stabilized by migalastat thereby restoring their trafficking to lysosomes and their intralysosomal activity. In Vitro Amenability Assay In an in vitro assay (HEK-293 assay), Human Embryonic Kidney (HEK-293) cell lines were transfected with specific GLA variants which produced variant alpha-Gal A proteins. In the transfected cells, amenability of the GLA variants was assessed after a 5-day incubation with 10 micromol/L migalastat. A GLA variant was categorized as amenable if the resultant variant alpha-Gal A activity (measured in the cell lysates) met two criteria: 1) it showed a relative increase of at least 20% compared to the pre-treatment alpha-Gal A activity, and 2) it showed an absolute increase of at least 3% of the wild-type (normal) alpha-Gal A activity. The in vitro assay did not evaluate trafficking of the variant alpha-Gal A proteins into the lysosome or the dissociation of migalastat from the variant alpha-Gal A proteins within the lysosome. Also, the in vitro assay did not test whether a GLA variant causes Fabry disease or not. The GLA variants that are amenable to treatment with GALAFOLD, either based on the in vitro assay data or on the concept that synonymous nucleotide changes leading to the same variant alpha-Gal A protein as a confirmed amenable GLA variant are amenable without additional testing, are shown in Table 2 . In patients with multiple identified variants, the amenability assessment of each independent variant may not reflect the overall amenability classification of the combination of variants. The specific variant combination must be present within Table 2 (eg, c.[164A>T; 170A>T]) and on a single chromosome (males and females) to be considered amenable to treatment with GALAFOLD. When multiple variants are identified in a female, it is recommended to consult a clinical genetics professional to determine whether the variants are on a single GLA allele. Inclusion of GLA variants in this table does not reflect interpretation of their clinical significance in Fabry disease. Whether a certain amenable GLA variant in a patient with Fabry disease is disease-causing or not should be determined by the prescribing physician (in consultation with a clinical genetics professional, if needed) prior to treatment initiation. Consultation with a clinical genetics professional is strongly recommended in cases where the amenable GLA variant is of uncertain clinical significance (VUS, variant of uncertain significance) or may be benign (not causing Fabry disease). If a GLA variant does not appear in Table 2 , it is either non-amenable (if tested) or has not been tested for in vitro amenability. For further information, please contact Amicus Medical Information at 1-877-4AMICUS or medinfousa@amicusrx.com. Table 2: Amenable GLA Variants Based on the In Vitro Assay § Based on available published data, the GLA variant c.937G>T, (p.(D313Y)) is considered benign (not causing Fabry disease). Consultation with a clinical genetics professional is strongly recommended in patients with Fabry disease who have this GLA variant as additional evaluations may be indicated. † Multiple variant combination of two or more different variants on a single GLA allele that informs amenability. ‡ Synonymous variants are listed without testing in the in vitro amenability assay. GLA variant(s) with a different nucleotide change affecting the same amino acid position(s) as the tested GLA variant and predicted to encode the same variant alpha-Gal A enzyme are considered synonymous. ¶ c.761_763delTTG has been previously referred to as c.760_762delGTT. DNA Change (Long) DNA Change (Short) Protein Change (1-letter Code) Protein Change (3-letter Code) c.7C>G c.C7G p.(L3V) p.(Leu3Val) c.8T>C c.T8C p.(L3P) p.(Leu3Pro) c.[11G>T; 620A>C] † c.[G11T; A620C] † p.[(R4M; Y207S)] † p.[(Arg4Met; Tyr207Ser)] † c.37G>A c.G37A p.(A13T) p.(Ala13Thr) c.37G>C c.G37C p.(A13P) p.(Ala13Pro) c.43G>A c.G43A p.(A15T) p.(Ala15Thr) c.44C>G c.C44G p.(A15G) p.(Ala15Gly) c.53T>G c.T53G p.(F18C) p.(Phe18Cys) c.58G>C c.G58C p.(A20P) p.(Ala20Pro) c.59C>A c.C59A p.(A20D) p.(Ala20Asp) c.65T>G c.T65G p.(V22G) p.(Val22Gly) c.[70T>A; 1255A>G] † c.[T70A; A1255G] † p.[(W24R; N419D)] † p.[(Trp24Arg; Asn419Asp)] † c.70T>A or c.70T>C ‡ c.T70A or c.T70C ‡ p.(W24R) p.(Trp24Arg) c.70T>G c.T70G p.(W24G) p.(Trp24Gly) c.72G>C or c.72G>T ‡ c.G72C or c.G72T ‡ p.(W24C) p.(Trp24Cys) c.95T>C c.T95C p.(L32P) p.(Leu32Pro) c.97G>C c.G97C p.(D33H) p.(Asp33His) c.97G>T c.G97T p.(D33Y) p.(Asp33Tyr) c.98A>G c.A98G p.(D33G) p.(Asp33Gly) c.100A>C c.A100C p.(N34H) p.(Asn34His) c.100A>G c.A100G p.(N34D) p.(Asn34Asp) c.101A>C c.A101C p.(N34T) p.(Asn34Thr) c.101A>G c.A101G p.(N34S) p.(Asn34Ser) c.102T>A or c.102T>G ‡ c.T102A or c.T102G ‡ p.(N34K) p.(Asn34Lys) c.103G>A or c.103G>C ‡ c.G103A or c.G103C ‡ p.(G35R) p.(Gly35Arg) c.104G>A c.G104A p.(G35E) p.(Gly35Glu) c.104G>T c.G104T p.(G35V) p.(Gly35Val) c.107T>C c.T107C p.(L36S) p.(Leu36Ser) c.107T>G c.T107G p.(L36W) p.(Leu36Trp) c.108G>C or c.108G>T ‡ c.G108C or c.G108T ‡ p.(L36F) p.(Leu36Phe) c.109G>A c.G109A p.(A37T) p.(Ala37Thr) c.109G>T c.G109T p.(A37S) p.(Ala37Ser) c.110C>T c.C110T p.(A37V) p.(Ala37Val) c.122C>T c.C122T p.(T41I) p.(Thr41Ile) c.124A>C or c.124A>T ‡ c.A124C or c.A124T ‡ p.(M42L) p.(Met42Leu) c.124A>G c.A124G p.(M42V) p.(Met42Val) c.125T>A c.T125A p.(M42K) p.(Met42Lys) c.125T>C c.T125C p.(M42T) p.(Met42Thr) c.125T>G c.T125G p.(M42R) p.(Met42Arg) c.126G>A or c.126G>C ‡ or c.126G>T ‡ c.G126A or c.G126C ‡ or c.G126T ‡ p.(M42I) p.(Met42Ile) c.137A>C c.A137C p.(H46P) p.(His46Pro) c.142G>C c.G142C p.(E48Q) p.(Glu48Gln) c.152T>A c.T152A p.(M51K) p.(Met51Lys) c.153G>A or c.153G>T ‡ or c.153G>C ‡ c.G153A or c.G153T ‡ or c.G153C ‡ p.(M51I) p.(Met51Ile) c.157_158delinsCT c.157_158delinsCT p.(N53L) p.(Asn53Leu) c.157A>G c.A157G p.(N53D) p.(Asn53Asp) c.160C>T c.C160T p.(L54F) p.(Leu54Phe) c.161T>C c.T161C p.(L54P) p.(Leu54Pro) c.164A>G c.A164G p.(D55G) p.(Asp55Gly) c.164A>T c.A164T p.(D55V) p.(Asp55Val) c.[164A>T; 170A>T] † c.[A164T; A170T] † p.[(D55V; Q57L)] † p.[(Asp55Val; Gln57Leu)] † c.167G>A c.G167A p.(C56Y) p.(Cys56Tyr) c.167G>T c.G167T p.(C56F) p.(Cys56Phe) c.170A>G c.A170G p.(Q57R) p.(Gln57Arg) c.170A>T c.A170T p.(Q57L) p.(Gln57Leu) c.175G>A c.G175A p.(E59K) p.(Glu59Lys) c.178C>A c.C178A p.(P60T) p.(Pro60Thr) c.178C>T c.C178T p.(P60S) p.(Pro60Ser) c.179C>T c.C179T p.(P60L) p.(Pro60Leu) c.196G>A c.G196A p.(E66K) p.(Glu66Lys) c.197A>G c.A197G p.(E66G) p.(Glu66Gly) c.207C>A or c.207C>G ‡ c.C207A or c.C207G ‡ p.(F69L) p.(Phe69Leu) c.214A>G c.A214G p.(M72V) p.(Met72Val) c.216G>A or c.216G>T ‡ or c.216G>C ‡ c.G216A or c.G216T ‡ or c.G216C ‡ p.(M72I) p.(Met72Ile) c.218C>T c.C218T p.(A73V) p.(Ala73Val) c.227T>C c.T227C p.(M76T) p.(Met76Thr) c.239G>A c.G239A p.(G80D) p.(Gly80Asp) c.239G>T c.G239T p.(G80V) p.(Gly80Val) c.247G>A c.G247A p.(D83N) p.(Asp83Asn) c.253G>A c.G253A p.(G85S) p.(Gly85Ser) c.253_254delinsAA c.253_254delinsAA p.(G85N) p.(Gly85Asn) c.253_255delinsATG c.253_255delinsATG p.(G85M) p.(Gly85Met) c.254G>A c.G254A p.(G85D) p.(Gly85Asp) c.261G>C or c.261G>T ‡ c.G261C or c.G261T ‡ p.(E87D) p.(Glu87Asp) c.263A>G c.A263G p.(Y88C) p.(Tyr88Cys) c.265C>T c.C265T p.(L89F) p.(Leu89Phe) c.272T>C c.T272C p.(I91T) p.(Ile91Thr) c.288G>A or c.288G>T ‡ or c.288G>C ‡ c.G288A or c.G288T ‡ or c.G288C ‡ p.(M96I) p.(Met96Ile) c.289G>C c.G289C p.(A97P) p.(Ala97Pro) c.290C>T c.C290T p.(A97V) p.(Ala97Val) c.305C>T c.C305T p.(S102L) p.(Ser102Leu) c.311G>T c.G311T p.(G104V) p.(Gly104Val) c.316C>T c.C316T p.(L106F) p.(Leu106Phe) c.320A>G c.A320G p.(Q107R) p.(Gln107Arg) c.322G>A c.G322A p.(A108T) p.(Ala108Thr) c.326A>G c.A326G p.(D109G) p.(Asp109Gly) c.334C>G c.C334G p.(R112G) p.(Arg112Gly) c.335G>A c.G335A p.(R112H) p.(Arg112His) c.335G>T c.G335T p.(R112L) p.(Arg112Leu) c.337T>A c.T337A p.(F113I) p.(Phe113Ile) c.337T>C or c.339T>A ‡ or c.339T>G ‡ c.T337C or c.T339A ‡ or c.T339G ‡ p.(F113L) p.(Phe113Leu) c.352C>T c.C352T p.(R118C) p.(Arg118Cys) c.361G>A c.G361A p.(A121T) p.(Ala121Thr) c.368A>G c.A368G p.(Y123C) p.(Tyr123Cys) c.373C>T c.C373T p.(H125Y) p.(His125Tyr) c.374A>T c.A374T p.(H125L) p.(His125Leu) c.376A>G c.A376G p.(S126G) p.(Ser126Gly) c.376A>T c.A376T p.(S126C) p.(Ser126Cys) c.383G>A c.G383A p.(G128E) p.(Gly128Glu) c.399T>G c.T399G p.(I133M) p.(Ile133Met) c.404C>T c.C404T p.(A135V) p.(Ala135Val) c.408T>A or c.408T>G ‡ c.T408A or c.T408G ‡ p.(D136E) p.(Asp136Glu) c.416A>G c.A416G p.(N139S) p.(Asn139Ser) c.419A>C c.A419C p.(K140T) p.(Lys140Thr) c.427G>A c.G427A p.(A143T) p.(Ala143Thr) c.431G>A c.G431A p.(G144D) p.(Gly144Asp) c.431G>T c.G431T p.(G144V) p.(Gly144Val) c.434T>C c.T434C p.(F145S) p.(Phe145Ser) c.436C>T c.C436T p.(P146S) p.(Pro146Ser) c.437C>G c.C437G p.(P146R) p.(Pro146Arg) c.454T>C c.T454C p.(Y152H) p.(Tyr152His) c.454T>G c.T454G p.(Y152D) p.(Tyr152Asp) c.455A>G c.A455G p.(Y152C) p.(Tyr152Cys) c.465T>A or c.465T>G ‡ c.T465A or c.T465G ‡ p.(D155E) p.(Asp155Glu) c.466G>A c.G466A p.(A156T) p.(Ala156Thr) c.466G>T c.G466T p.(A156S) p.(Ala156Ser) c.467C>T c.C467T p.(A156V) p.(Ala156Val) c.471G>C or c.471G>T ‡ c.G471C or c.G471T ‡ p.(Q157H) p.(Gln157His) c.484T>G c.T484G p.(W162G) p.(Trp162Gly) c.493G>C c.G493C p.(D165H) p.(Asp165His) c.494A>G c.A494G p.(D165G) p.(Asp165Gly) c.496_497delinsTC c.496_497delinsTC p.(L166S) p.(Leu166Ser) c.496C>G c.C496G p.(L166V) p.(Leu166Val) c.496_497delinsGG c.496_497delinsGG p.(L166G) p.(Leu166Gly) c.499C>G c.C499G p.(L167V) p.(Leu167Val) c.506T>C c.T506C p.(F169S) p.(Phe169Ser) c.511G>A c.G511A p.(G171S) p.(Gly171Ser) c.520T>C c.T520C p.(C174R) p.(Cys174Arg) c.520T>G c.T520G p.(C174G) p.(Cys174Gly) c.525C>G or c.525C>A ‡ c.C525G or c.C525A ‡ p.(D175E) p.(Asp175Glu) c.539T>G c.T539G p.(L180W) p.(Leu180Trp) c.540G>T or c.540G>C ‡ c.G540T or c.G540C ‡ p.(L180F) p.(Leu180Phe) c.548G>A c.G548A p.(G183D) p.(Gly183Asp) c.548G>C c.G548C p.(G183A) p.(Gly183Ala) c.550T>A c.T550A p.(Y184N) p.(Tyr184Asn) c.551A>C c.A551C p.(Y184S) p.(Tyr184Ser) c.551A>G c.A551G p.(Y184C) p.(Tyr184Cys) c.553A>G c.A553G p.(K185E) p.(Lys185Glu) c.559_564dup c.559_564dup p.(M187_S188dup) p.(Met187_Ser188dup) c.559A>G c.A559G p.(M187V) p.(Met187Val) c.560T>C c.T560C p.(M187T) p.(Met187Thr) c.561G>A or c.561G>T ‡ or c.561G>C ‡ c.G561A or c.G561T ‡ or c.G561C ‡ p.(M187I) p.(Met187Ile) c.567G>C or c.567G>T ‡ c.G567C or c.G567T ‡ p.(L189F) p.(Leu189Phe) c.572T>A c.T572A p.(L191Q) p.(Leu191Gln) c.581C>T c.C581T p.(T194I) p.(Thr194Ile) c.584G>T c.G584T p.(G195V) p.(Gly195Val) c.586A>G c.A586G p.(R196G) p.(Arg196Gly) c.593T>C c.T593C p.(I198T) p.(Ile198Thr) c.595G>A c.G595A p.(V199M) p.(Val199Met) c.596T>C c.T596C p.(V199A) p.(Val199Ala) c.596T>G c.T596G p.(V199G) p.(Val199Gly) c.599A>G c.A599G p.(Y200C) p.(Tyr200Cys) c.602C>A c.C602A p.(S201Y) p.(Ser201Tyr) c.602C>T c.C602T p.(S201F) p.(Ser201Phe) c.608A>T c.A608T p.(E203V) p.(Glu203Val) c.609G>C or c.609G>T ‡ c.G609C or c.G609T ‡ p.(E203D) p.(Glu203Asp) c.611G>T c.G611T p.(W204L) p.(Trp204Leu) c.613C>A c.C613A p.(P205T) p.(Pro205Thr) c.613C>T c.C613T p.(P205S) p.(Pro205Ser) c.614C>T c.C614T p.(P205L) p.(Pro205Leu) c.619T>C c.T619C p.(Y207H) p.(Tyr207His) c.620A>C c.A620C p.(Y207S) p.(Tyr207Ser) c.623T>G c.T623G p.(M208R) p.(Met208Arg) c.628C>T c.C628T p.(P210S) p.(Pro210Ser) c.629C>T c.C629T p.(P210L) p.(Pro210Leu) c.638A>G c.A638G p.(K213R) p.(Lys213Arg) c.638A>T c.A638T p.(K213M) p.(Lys213Met) c.640C>T c.C640T p.(P214S) p.(Pro214Ser) c.641C>T c.C641T p.(P214L) p.(Pro214Leu) c.643A>G c.A643G p.(N215D) p.(Asn215Asp) c.644A>G c.A644G p.(N215S) p.(Asn215Ser) c.[644A>G; 937G>T § ] † c.[A644G; G937T § ] † p.[(N215S; D313Y § )] † p.[(Asn215Ser; Asp313Tyr § )] † c.644A>T c.A644T p.(N215I) p.(Asn215Ile) c.646T>G c.T646G p.(Y216D) p.(Tyr216Asp) c.647A>G c.A647G p.(Y216C) p.(Tyr216Cys) c.655A>C c.A655C p.(I219L) p.(Ile219Leu) c.656T>A c.T656A p.(I219N) p.(Ile219Asn) c.656T>C c.T656C p.(I219T) p.(Ile219Thr) c.657C>G c.C657G p.(I219M) p.(Ile219Met) c.659G>A c.G659A p.(R220Q) p.(Arg220Gln) c.659G>C c.G659C p.(R220P) p.(Arg220Pro) c.662A>C c.A662C p.(Q221P) p.(Gln221Pro) c.664T>G c.T664G p.(Y222D) p.(Tyr222Asp) c.671A>C c.A671C p.(N224T) p.(Asn224Thr) c.671A>G c.A671G p.(N224S) p.(Asn224Ser) c.673C>G c.C673G p.(H225D) p.(His225Asp) c.682A>C c.A682C p.(N228H) p.(Asn228His) c.683A>G c.A683G p.(N228S) p.(Asn228Ser) c.687T>G or c.687T>A ‡ c.T687G or c.T687A ‡ p.(F229L) p.(Phe229Leu) c.695T>C c.T695C p.(I232T) p.(Ile232Thr) c.712A>G c.A712G p.(S238G) p.(Ser238Gly) c.713G>A c.G713A p.(S238N) p.(Ser238Asn) c.716T>C c.T716C p.(I239T) p.(Ile239Thr) c.717A>G c.A717G p.(I239M) p.(Ile239Met) c.720G>C or c.720G>T ‡ c.G720C or c.G720T ‡ p.(K240N) p.(Lys240Asn) c.724A>G c.A724G p.(I242V) p.(Ile242Val) c.724A>T c.A724T p.(I242F) p.(Ile242Phe) c.725T>A c.T725A p.(I242N) p.(Ile242Asn) c.725T>C c.T725C p.(I242T) p.(Ile242Thr) c.728T>C c.T728C p.(L243S) p.(Leu243Ser) c.728T>G c.T728G p.(L243W) p.(Leu243Trp) c.729G>C or c.729G>T ‡ c.G729C or c.G729T ‡ p.(L243F) p.(Leu243Phe) c.730G>A c.G730A p.(D244N) p.(Asp244Asn) c.730G>C c.G730C p.(D244H) p.(Asp244His) c.733T>G c.T733G p.(W245G) p.(Trp245Gly) c.740C>G c.C740G p.(S247C) p.(Ser247Cys) c.747C>G or c.747C>A ‡ c.C747G or c.C747A ‡ p.(N249K) p.(Asn249Lys) c.749A>C c.A749C p.(Q250P) p.(Gln250Pro) c.749A>G c.A749G p.(Q250R) p.(Gln250Arg) c.750G>C c.G750C p.(Q250H) p.(Gln250His) c.758T>C c.T758C p.(I253T) p.(Ile253Thr) c.758T>G c.T758G p.(I253S) p.(Ile253Ser) c.761_763delTTG c.761_763delTTG [a.k.a. c.760_762delGTT ¶ ] p.(V254del) p.(Val254del) c.769G>C c.G769C p.(A257P) p.(Ala257Pro) c.770C>G c.C770G p.(A257G) p.(Ala257Gly) c.770C>T c.C770T p.(A257V) p.(Ala257Val) c.772G>C or c.772G>A ‡ c.G772C or c.G772A ‡ p.(G258R) p.(Gly258Arg) c.773G>T c.G773T p.(G258V) p.(Gly258Val) c.776C>A c.C776A p.(P259Q) p.(Pro259Gln) c.776C>G c.C776G p.(P259R) p.(Pro259Arg) c.776C>T c.C776T p.(P259L) p.(Pro259Leu) c.779G>A c.G779A p.(G260E) p.(Gly260Glu) c.779G>C c.G779C p.(G260A) p.(Gly260Ala) c.781G>A c.G781A p.(G261S) p.(Gly261Ser) c.781G>C c.G781C p.(G261R) p.(Gly261Arg) c.781G>T c.G781T p.(G261C) p.(Gly261Cys) c.788A>G c.A788G p.(N263S) p.(Asn263Ser) c.790G>T c.G790T p.(D264Y) p.(Asp264Tyr) c.794C>T c.C794T p.(P265L) p.(Pro265Leu) c.800T>C c.T800C p.(M267T) p.(Met267Thr) c.805G>A c.G805A p.(V269M) p.(Val269Met) c.805G>C c.G805C p.(V269L) p.(Val269Leu) c.806T>C c.T806C p.(V269A) p.(Val269Ala) c.809T>C c.T809C p.(I270T) p.(Ile270Thr) c.810T>G c.T810G p.(I270M) p.(Ile270Met) c.811G>A c.G811A p.(G271S) p.(Gly271Ser) c.[811G>A; 937G>T § ] † c.[G811A; G937T § ] † p.[(G271S; D313Y § )] † p.[(Gly271Ser; Asp313Tyr § )] † c.812G>A c.G812A p.(G271D) p.(Gly271Asp) c.812G>C c.G812C p.(G271A) p.(Gly271Ala) c.823C>G c.C823G p.(L275V) p.(Leu275Val) c.827G>A c.G827A p.(S276N) p.(Ser276Asn) c.829T>G c.T829G p.(W277G) p.(Trp277Gly) c.831G>C or c.831G>T ‡ c.G831C or c.G831T ‡ p.(W277C) p.(Trp277Cys) c.832A>T c.A832T p.(N278Y) p.(Asn278Tyr) c.835C>G c.C835G p.(Q279E) p.(Gln279Glu) c.838C>A c.C838A p.(Q280K) p.(Gln280Lys) c.840A>T or c.840A>C ‡ c.A840T or c.A840C ‡ p.(Q280H) p.(Gln280His) c.844A>G c.A844G p.(T282A) p.(Thr282Ala) c.845C>T c.C845T p.(T282I) p.(Thr282Ile) c.850A>G c.A850G p.(M284V) p.(Met284Val) c.851T>C c.T851C p.(M284T) p.(Met284Thr) c.860G>T c.G860T p.(W287L) p.(Trp287Leu) c.862G>C c.G862C p.(A288P) p.(Ala288Pro) c.866T>G c.T866G p.(I289S) p.(Ile289Ser) c.868A>C or c.868A>T ‡ c.A868C or c.A868T ‡ p.(M290L) p.(Met290Leu) c.869T>C c.T869C p.(M290T) p.(Met290Thr) c.870G>C or c.870G>A ‡ or c.870G>T ‡ c.G870C or c.G870A ‡ or c.G870T ‡ p.(M290I) p.(Met290Ile) c.871G>A c.G871A p.(A291T) p.(Ala291Thr) c.877C>A c.C877A p.(P293T) p.(Pro293Thr) c.881T>C c.T881C p.(L294S) p.(Leu294Ser) c.884T>G c.T884G p.(F295C) p.(Phe295Cys) c.886A>G c.A886G p.(M296V) p.(Met296Val) c.886A>C or c.886A>T ‡ c.A886C or c.A886T ‡ p.(M296L) p.(Met296Leu) c.887T>C c.T887C p.(M296T) p.(Met296Thr) c.888G>A or c.888G>T ‡ or c.888G>C ‡ c.G888A or c.G888T ‡ or c.G888C ‡ p.(M296I) p.(Met296Ile) c.893A>G c.A893G p.(N298S) p.(Asn298Ser) c.897C>G or c.897C>A ‡ c.C897G or c.C897A ‡ p.(D299E) p.(Asp299Glu) c.898C>T c.C898T p.(L300F) p.(Leu300Phe) c.899T>C c.T899C p.(L300P) p.(Leu300Pro) c.901C>G c.C901G p.(R301G) p.(Arg301Gly) c.902G>A c.G902A p.(R301Q) p.(Arg301Gln) c.902G>C c.G902C p.(R301P) p.(Arg301Pro) c.902G>T c.G902T p.(R301L) p.(Arg301Leu) c.907A>T c.A907T p.(I303F) p.(Ile303Phe) c.908T>A c.T908A p.(I303N) p.(Ile303Asn) c.908T>C c.T908C p.(I303T) p.(Ile303Thr) c.911G>A c.G911A p.(S304N) p.(Ser304Asn) c.911G>C c.G911C p.(S304T) p.(Ser304Thr) c.919G>A c.G919A p.(A307T) p.(Ala307Thr) c.922A>G c.A922G p.(K308E) p.(Lys308Glu) c.924A>C or c.924A>T ‡ c.A924C or c.A924T ‡ p.(K308N) p.(Lys308Asn) c.925G>C c.G925C p.(A309P) p.(Ala309Pro) c.926C>T c.C926T p.(A309V) p.(Ala309Val) c.928C>T c.C928T p.(L310F) p.(Leu310Phe) c.931C>G c.C931G p.(L311V) p.(Leu311Val) c.935A>G c.A935G p.(Q312R) p.(Gln312Arg) c.936G>C or c.936G>T ‡ c.G936C or c.G936T ‡ p.(Q312H) p.(Gln312His) c.937G>T § c.G937T § p.(D313Y § ) p.(Asp313Tyr § ) c.[937G>T § ; 1232G>A] † c.[G937T § ; G1232A] † p.[D313Y § ; G411D] † p.[Asp313Tyr § ; Gly411Asp] † c.938A>G c.A938G p.(D313G) p.(Asp313Gly) c.946G>A c.G946A p.(V316I) p.(Val316Ile) c.947T>G c.T947G p.(V316G) p.(Val316Gly) c.950T>C c.T950C p.(I317T) p.(Ile317Thr) c.955A>T c.A955T p.(I319F) p.(Ile319Phe) c.956T>C c.T956C p.(I319T) p.(Ile319Thr) c.958A>C c.A958C p.(N320H) p.(Asn320His) c.959A>T c.A959T p.(N320I) p.(Asn320Ile) c.962A>G c.A962G p.(Q321R) p.(Gln321Arg) c.962A>T c.A962T p.(Q321L) p.(Gln321Leu) c.963G>C or c.963G>T ‡ c.G963C or c.G963T ‡ p.(Q321H) p.(Gln321His) c.964G>A c.G964A p.(D322N) p.(Asp322Asn) c.964G>C c.G964C p.(D322H) p.(Asp322His) c.966C>A or c.966C>G ‡ c.C966A or c.C966G ‡ p.(D322E) p.(Asp322Glu) c.967C>A c.C967A p.(P323T) p.(Pro323Thr) c.968C>G c.C968G p.(P323R) p.(Pro323Arg) c.973G>A c.G973A p.(G325S) p.(Gly325Ser) c.973G>C c.G973C p.(G325R) p.(Gly325Arg) c.978G>C or c.978G>T ‡ c.G978C or c.G978T ‡ p.(K326N) p.(Lys326Asn) c.979C>G c.C979G p.(Q327E) p.(Gln327Glu) c.980A>T c.A980T p.(Q327L) p.(Gln327Leu) c.983G>C c.G983C p.(G328A) p.(Gly328Ala) c.989A>G c.A989G p.(Q330R) p.(Gln330Arg) c.1001G>A c.G1001A p.(G334E) p.(Gly334Glu) c.1010T>C c.T1010C p.(F337S) p.(Phe337Ser) c.1012G>A c.G1012A p.(E338K) p.(Glu338Lys) c.1013A>T c.A1013T p.(E338V) p.(Glu338Val) c.1016T>A c.T1016A p.(V339E) p.(Val339Glu) c.1027C>A c.C1027A p.(P343T) p.(Pro343Thr) c.1028C>T c.C1028T p.(P343L) p.(Pro343Leu) c.1033T>C c.T1033C p.(S345P) p.(Ser345Pro) c.1046G>C c.G1046C p.(W349S) p.(Trp349Ser) c.1055C>G c.C1055G p.(A352G) p.(Ala352Gly) c.1055C>T c.C1055T p.(A352V) p.(Ala352Val) c.1061T>A c.T1061A p.(I354K) p.(Ile354Lys) c.1066C>G c.C1066G p.(R356G) p.(Arg356Gly) c.1066C>T c.C1066T p.(R356W) p.(Arg356Trp) c.1067G>A c.G1067A p.(R356Q) p.(Arg356Gln) c.1067G>C c.G1067C p.(R356P) p.(Arg356Pro) c.1072G>C c.G1072C p.(E358Q) p.(Glu358Gln) c.1073A>C c.A1073C p.(E358A) p.(Glu358Ala) c.1073A>G c.A1073G p.(E358G) p.(Glu358Gly) c.1074G>T or c.1074G>C ‡ c.G1074T or c.G1074C ‡ p.(E358D) p.(Glu358Asp) c.1076T>C c.T1076C p.(I359T) p.(Ile359Thr) c.1078G>A c.G1078A p.(G360S) p.(Gly360Ser) c.1078G>C c.G1078C p.(G360R) p.(Gly360Arg) c.1078G>T c.G1078T p.(G360C) p.(Gly360Cys) c.1079G>A c.G1079A p.(G360D) p.(Gly360Asp) c.1082G>A c.G1082A p.(G361E) p.(Gly361Glu) c.1082G>C c.G1082C p.(G361A) p.(Gly361Ala) c.1084C>A c.C1084A p.(P362T) p.(Pro362Thr) c.1085C>T c.C1085T p.(P362L) p.(Pro362Leu) c.1087C>T c.C1087T p.(R363C) p.(Arg363Cys) c.1088G>A c.G1088A p.(R363H) p.(Arg363His) c.1102G>A c.G1102A p.(A368T) p.(Ala368Thr) c.1117G>A c.G1117A p.(G373S) p.(Gly373Ser) c.1124G>A c.G1124A p.(G375E) p.(Gly375Glu) c.1139C>T c.C1139T p.(P380L) p.(Pro380Leu) c.1153A>G c.A1153G p.(T385A) p.(Tyr385Ala) c.1163T>A c.T1163A p.(L388H) p.(Leu388His) c.1168G>A c.G1168A p.(V390M) p.(Val390Met) c.1172A>C c.A1172C p.(K391T) p.(Lys391Thr) c.1184G>A c.G1184A p.(G395E) p.(Gly395Glu) c.1184G>C c.G1184C p.(G395A) p.(Gly395Ala) c.1192G>A c.G1192A p.(E398K) p.(Glu398Lys) c.1202_1203insGACTTC c.1202_1203insGACTTC p.(T400_S401dup) p.(Thr400_Ser401dup) c.1208T>C c.T1208C p.(L403S) p.(Leu403Ser) c.1225C>A c.C1225A p.(P409T) p.(Pro409Thr) c.1225C>G c.C1225G p.(P409A) p.(Pro409Ala) c.1225C>T c.C1225T p.(P409S) p.(Pro409Ser) c.1228A>G c.A1228G p.(T410A) p.(Thr410Ala) c.1229C>T c.C1229T p.(T410I) p.(Thr410Ile) c.1232G>A c.G1232A p.(G411D) p.(Gly411Asp) c.1234A>C c.A1234C p.(T412P) p.(Thr412Pro) c.1235C>A c.C1235A p.(T412N) p.(Thr412Asn) c.1235C>T c.C1235T p.(T412I) p.(Thr412Ile) c.1253A>G c.A1253G p.(E418G) p.(Glu418Gly) c.1261A>G c.A1261G p.(M421V) p.(Met421Val)