In Depth Variant Analysis:  c.1613C>T (p.Pro538Leu)
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c.1613C>T
p.Pro538Leu (Legacy AA No. 520)
Variant Type:  
Point
Domain:  
Serine Protease
Codon Change: 
C>T
Variant Effect: 
Missense
No. of Patients Reported: 
9
Phenotype: 
II
Allele Count *: 
27
Allele Number *: 
282666
Allele Frequency *: 
0.000096
Variant Comments & Reference:
Mutant protein is expressed in 293 human kidney fibroblasts. Activated mutant has a modest catalytic defect in functional assays. The basis of catalytic defect that results from Pro538Leu alteration is due to subtle alterations in the oxyanion hole, which develops during conversion of zymogen to active enzyme, and results in a ~3.5-fold decrease in catalytic efficiency, consistent with the 70-80% loss of activity noted in conventional coagulation assays. Thus, Pro538 is important in maintaining the normal conformation of the FXI active site. Pro538 is conserved in FX and FVII, and its mutation in both these other proteins also causes Type II phenotypes.This variant was not activated by FXIIa. Gailani et al 2001 (Abstract), Gailani et al 2007, Saunders et al 2009, Esteban et al 2017Residue Information:
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Substitution Analysis:
Structural Implications:
Pro538 is an exposed residue  (surface accessibility value = 3 ).
Pro538 is in a random coil area of the FXI structure.
The DSSP assignment for this residue is ... C.
Pro538 is in a random coil area of the FXI structure.
The DSSP assignment for this residue is ... C.
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