Galafold

(Migalastat Hydrochloride)

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Dosage & Administration

* Select adults with confirmed Fabry disease who have an amenable

GLA

variant for treatment with GALAFOLD. (

2.1 Patient Selection

Select adults with confirmed Fabry disease who have an amenable

GLA

variant for treatment with GALAFOLD

[see Clinical Pharmacology (12.1)]

Treatment is indicated for patients with an amenable

GLA

variant that is interpreted by a clinical genetics professional as causing Fabry disease (pathogenic, likely pathogenic) in the clinical context of the patient. 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).

)
* Treatment is indicated for patients with an amenable

GLA

variant is of uncertain clinical significance (VUS, variant of uncertain significance) or may be benign (not causing Fabry disease). (

2.1 Patient Selection

Select adults with confirmed Fabry disease who have an amenable

GLA

variant for treatment with GALAFOLD

[see Clinical Pharmacology (12.1)]

Treatment is indicated for patients with an amenable

GLA

variant is of uncertain clinical significance (VUS, variant of uncertain significance) or may be benign (not causing Fabry disease).

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-Gb₃). 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)

)
* The recommended dosage of GALAFOLD is 123 mg orally once every other day. Take GALAFOLD at the same time of day and do not take on consecutive days. Swallow capsule whole. Do not cut, crush, or chew the capsule. (

2.2 Recommended Dosage and Administration

The recommended dosage of GALAFOLD is 123 mg orally once every other day.

Take GALAFOLD at the same time of day and do not take on consecutive days.

Swallow capsule whole. Do not cut, crush, or chew the capsule.

Take GALAFOLD on an empty stomach. Do not consume food or caffeine at least 2 hours prior to and 2 hours after taking GALAFOLD to give a minimum 4 hour fast

[see Clinical Pharmacology (12.3)]

Water (plain, flavored, or sweetened), fruit juices without pulp, and caffeine-free carbonated beverages can be consumed during the fasting period.

)
* Take GALAFOLD on an empty stomach. Do not consume food or caffeine at least 2 hours prior to and 2 hours after taking GALAFOLD to give a minimum 4 hour fast. (

2.2 Recommended Dosage and Administration

The recommended dosage of GALAFOLD is 123 mg orally once every other day.

Take GALAFOLD at the same time of day and do not take on consecutive days.

Swallow capsule whole. Do not cut, crush, or chew the capsule.

Take GALAFOLD on an empty stomach. Do not consume food or caffeine at least 2 hours prior to and 2 hours after taking GALAFOLD to give a minimum 4 hour fast

[see Clinical Pharmacology (12.3)]

Water (plain, flavored, or sweetened), fruit juices without pulp, and caffeine-free carbonated beverages can be consumed during the fasting period.

)
* If the GALAFOLD dose is missed, take the missed dose if it is within 12 hours of the time that the dose should have been taken. If more than 12 hours have passed, take GALAFOLD at the next planned dosing day and time following the original every-other-day dosing schedule. (

2.3 Recommendations for a Missed Dose

If the GALAFOLD dose is missed, take the missed dose if it is within 12 hours of the time that the dose should have been taken. If more than 12 hours have passed, take GALAFOLD at the next planned dosing day and time following the original every-other-day dosing schedule.

)

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Galafold Prescribing Information

GALAFOLD is indicated for the treatment of adults with a confirmed diagnosis of Fabry disease and an amenable galactosidase alpha gene (

GLA

) variant based on in vitro assay data

[see

2.1 Patient Selection

Select adults with confirmed Fabry disease who have an amenable

GLA

variant for treatment with GALAFOLD

[see Clinical Pharmacology (12.1)]

Treatment is indicated for patients with an amenable

GLA

variant is of uncertain clinical significance (VUS, variant of uncertain significance) or may be benign (not causing Fabry disease).

and

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

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 causes Fabry disease or not.

The

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 is of uncertain clinical significance (VUS, variant of uncertain significance) or may be benign (not causing Fabry disease).

If a

GLA

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)

]

This indication is approved under accelerated approval based on reduction in kidney interstitial capillary cell globotriaosylceramide (KIC GL-3) substrate

[see

14 CLINICAL STUDIES

Study AT1001‑011 (referred to as Study 1; NCT00925301) included a 6‑month randomized, double‑blind, placebo‑controlled phase followed by a 6‑month open‑label treatment phase and a 12‑month open‑label extension phase. Patients received 123 mg GALAFOLD orally every other day taken without consuming food 2 hours before and 2 hours after each dose to give a minimum 4‑hour fast

[see Dosage and Administration (2.2)]

A total of 67 patients with Fabry disease who were naïve to GALAFOLD and enzyme replacement therapy (ERT) or were previously treated with ERT (agalsidase beta or non‑U.S. approved agalsidase alfa) and had been off ERT for at least 6 months were randomized in a 1:1 ratio to receive either GALAFOLD 123 mg every other day or placebo for the first 6 months. In the second 6 months, all patients were treated with GALAFOLD.

Results - Patients with Fabry Disease with Amenable

GLA

Variants

Of the 67 enrolled patients, 50 patients (32 females, 18 males) had amenable

GLA

variants based on the in vitro amenability assay

[see Clinical Pharmacology (12.1)]

. The median age of this population was 45 years (range from 16 to 68 years old); 65 were White (97%), and 2 were other racial group (3%). The major efficacy outcome measure of the average number of GL‑3 inclusions per kidney interstitial capillary (KIC) in renal biopsy samples was assessed by light microscopy before and after treatment.

Efficacy was evaluated after 6 months of treatment in 45 of 50 patients with amenable

GLA

variants (29 females and 16 males) and with available histology data both at baseline and month 6. Of the 45 evaluable patients, 25 received GALAFOLD (18 females, 7 males) and 20 received placebo (11 females, 9 males). The proportion of patients with ≥ 50% reduction from baseline in the average number of GL‑3 inclusions per KIC and the median changes from baseline in the average number of GL‑3 inclusions per KIC after 6 months of treatment in Study 1 are shown in Table 3.

Table 3: Changes from Baseline to Month 6 in Average Number of GL‑3 Inclusions per KIC in Adults with Fabry Disease with Amenable GLA Variants in Study 1 (N = 45)
	GALAFOLD n/N (%) with ≥ 50% reduction Median change from baseline (range)	Placebo n/N (%) with ≥ 50% reduction Median change from baseline (range)
All patients (N = 45)	13/25 (52%) -0.04 (-1.94, 0.26)	9/20 (45%) -0.03 (-1.00, 1.69)
Females (N = 29)	8/18 (44%) -0.02 (-0.46, 0.26)	5/11 (46%) -0.03 (-0.35, 0.10)
Males (N = 16)	5/7 (71%) -1.10 (-1.94, -0.02)	4/9 (44%) -0.03 (-1.00, 1.69)
Patients with baseline GL-3 ≥ 0.3 (N = 17; 9 males, 8 females)	7/9 (78%) -0.91 (-1.94, 0.19)	2/8 (25%) -0.02 (-1.00, 1.69)
Patients with baseline GL-3 < 0.3 (N = 28; 7 males, 21 females)	6/16 (38%) -0.02 (-0.10, 0.26)	7/12 (58%) -0.05 (-0.16, 0.14)

Results - Patients with Fabry Disease with Non‑Amenable

GLA

Variants

Of the 67 enrolled patients in Study 1, 17 patients had non‑amenable

GLA

variants. These patients had no change from baseline in the average number of GL‑3 inclusions per KIC after 6 months of treatment.

]

. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Select adults with confirmed Fabry disease who have an amenable
GLA
variant for treatment with GALAFOLD. (
2.1 Patient Selection
Select adults with confirmed Fabry disease who have an amenable
GLA
variant for treatment with GALAFOLD
[see Clinical Pharmacology (12.1)]
.
Treatment is indicated for patients with an amenable
GLA
variant that is interpreted by a clinical genetics professional as causing Fabry disease (pathogenic, likely pathogenic) in the clinical context of the patient. 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).
)

Treatment is indicated for patients with an amenable

GLA

variant is of uncertain clinical significance (VUS, variant of uncertain significance) or may be benign (not causing Fabry disease). (

2.1 Patient Selection

Select adults with confirmed Fabry disease who have an amenable

GLA

variant for treatment with GALAFOLD

[see Clinical Pharmacology (12.1)]

Treatment is indicated for patients with an amenable

GLA

variant is of uncertain clinical significance (VUS, variant of uncertain significance) or may be benign (not causing Fabry disease).

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

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 causes Fabry disease or not.

The

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 is of uncertain clinical significance (VUS, variant of uncertain significance) or may be benign (not causing Fabry disease).

If a

GLA

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)

)

The recommended dosage of GALAFOLD is 123 mg orally once every other day. Take GALAFOLD at the same time of day and do not take on consecutive days. Swallow capsule whole. Do not cut, crush, or chew the capsule. (
2.2 Recommended Dosage and Administration
The recommended dosage of GALAFOLD is 123 mg orally once every other day.
Take GALAFOLD at the same time of day and do not take on consecutive days.
Swallow capsule whole. Do not cut, crush, or chew the capsule.
Take GALAFOLD on an empty stomach. Do not consume food or caffeine at least 2 hours prior to and 2 hours after taking GALAFOLD to give a minimum 4 hour fast
[see Clinical Pharmacology (12.3)]
.
Water (plain, flavored, or sweetened), fruit juices without pulp, and caffeine-free carbonated beverages can be consumed during the fasting period.
)
Take GALAFOLD on an empty stomach. Do not consume food or caffeine at least 2 hours prior to and 2 hours after taking GALAFOLD to give a minimum 4 hour fast. (
2.2 Recommended Dosage and Administration
The recommended dosage of GALAFOLD is 123 mg orally once every other day.
Take GALAFOLD at the same time of day and do not take on consecutive days.
Swallow capsule whole. Do not cut, crush, or chew the capsule.
Take GALAFOLD on an empty stomach. Do not consume food or caffeine at least 2 hours prior to and 2 hours after taking GALAFOLD to give a minimum 4 hour fast
[see Clinical Pharmacology (12.3)]
.
Water (plain, flavored, or sweetened), fruit juices without pulp, and caffeine-free carbonated beverages can be consumed during the fasting period.
)
If the GALAFOLD dose is missed, take the missed dose if it is within 12 hours of the time that the dose should have been taken. If more than 12 hours have passed, take GALAFOLD at the next planned dosing day and time following the original every-other-day dosing schedule. (
2.3 Recommendations for a Missed Dose
If the GALAFOLD dose is missed, take the missed dose if it is within 12 hours of the time that the dose should have been taken. If more than 12 hours have passed, take GALAFOLD at the next planned dosing day and time following the original every-other-day dosing schedule.
)

Risk Summary

There were three pregnant women with Fabry disease exposed to GALAFOLD in clinical trials. As such, the available data are not sufficient to assess drug associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental effects were observed

(see

Data

)

The background risk for major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

There is a study that collects data on pregnant women with Fabry disease, either exposed or unexposed to GALAFOLD. Healthcare providers are encouraged to register patients or obtain additional information by contacting the Pregnancy Coordinating Center at 1-888-239-0758, emailing fabrypregnancy@ubc.com, or visiting www.fabrypregnancyregistry.com.

Data

Animal Data

No adverse developmental effects were observed with oral administration of migalastat to pregnant rats and rabbits during organogenesis at doses up to 26 and 54 times, respectively, the recommended dose based on AUC. No effects on post-natal development were observed following oral administration of up to 500 mg/kg migalastat twice daily to pregnant rats (16 times the recommended dose based on AUC) during organogenesis and through lactation.

Most common adverse drug reactions ≥ 10% are: headache, nasopharyngitis, urinary tract infection, nausea, and pyrexia. (

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical trials, 139 patients with Fabry disease (79 females, 60 males, 92% Caucasian, ages 16 to 72 years), who were naïve to GALAFOLD or previously treated with enzyme replacement therapy, were exposed to at least one dose of GALAFOLD. Of the 139 patients, 127 patients were exposed to GALAFOLD 123 mg every other day for 6 months and 123 patients were exposed for greater than one year. The clinical trials included one randomized, double-blind, placebo-controlled clinical trial of 6 months duration followed by a 6-month open-label treatment phase (Study 1)

[see Clinical Studies (14)]

. A second trial was a randomized, open-label, active-controlled clinical trial of 18 months duration in patients with Fabry disease receiving enzyme replacement therapy who were randomized to either switch to GALAFOLD or continue enzyme replacement therapy (Study 2; NCT01218659). In addition, there were two open-label, long-term extension trials.

The most common adverse reactions reported with GALAFOLD (≥ 10%) during the 6-month placebo-controlled, double-blind phase of Study 1 were headache, nasopharyngitis, urinary tract infection, nausea, and pyrexia.

Table 1shows adverse reactions that occurred in at least 5% of patients treated with GALAFOLD during the 6-month placebo-controlled, double-blind phase of Study 1.

Table 1: Adverse Reactions* in Patients with Fabry Disease (Study 1)
* Adverse reactions were those that occurred in at least 5% of patients treated with GALAFOLD. ** Included urinary tract infection, cystitis, and kidney infection
Adverse Reaction	GALAFOLD % (N = 34)	Placebo % (N = 33)
Headache	35%	21%
Nasopharyngitis	18%	6%
Urinary tract infection**	15%	0
Nausea	12%	6%
Pyrexia	12%	3%
Abdominal pain	9%	3%
Back pain	9%	0
Cough	9%	0
Diarrhea	9%	3%
Epistaxis	9%	3%

Adverse reactions that occurred in > 5% of patients who received GALAFOLD in the 6-month open-label treatment phase of Study 1, in Study 2, and in the long-term extension trials (N = 115, mean duration of treatment 2.7 years) included those in Table 1with the addition of vomiting.

)

To report SUSPECTED ADVERSE REACTIONS, contact Amicus Therapeutics at 1-877-4AMICUS or FDA at 1-800-FDA-1088 or

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