Migalastat Hydrochloride

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 [email protected]. 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)