In Depth Variant Analysis:  c.1608G>C (p.Lys536Asn)
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c.1608G>C
p.Lys536Asn (Legacy AA No. 518)
Variant Type:  
Point
Domain:  
Serine Protease
Codon Change: 
G>C
Variant Effect: 
Missense
No. of Patients Reported: 
4
Phenotype: 
I
Allele Count *: 
1
Allele Number *: 
251446
Allele Frequency *: 
0.000004
Variant Comments & Reference:
The novel missense mutation FXI Lys536Asn leads to the replacement of the Lys536 which is part of a LxxxxxPxxxxxxC motif (x-variable amino acid) that occurs in several subfamilies of serine proteases. Although this motif is highly conserved between FXI and pre-kallikrein (86% sequence identity), the Lys536 is not conserved. On the other hand, this residue is conserved in human, murine and bovine FXI indicating that this is a FXI-specific amino acid. A molecular model of FXI predicts that the side-chain of this residue is on the surface of the molecule, possibly H-bonded to W515. Replacement of the positively charged lysine side chain by the smaller, neutral side chain of asparagine may interfere with the folding of the FXI molecule and/or secretion, leading to low antigen level. Alternatively, the secreted FXI variant may have a shortened plasma half-life. Ventura et al 2000, Esteban et al 2017Residue Information:
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Substitution Analysis:
Structural Implications:
Lys536 is an exposed residue  (surface accessibility value = 5 ).
Lys536 is in a region of secondary structure within the FXI domains.
The DSSP assignment for this residue is ... E.
Lys536 is in a region of secondary structure within the FXI domains.
The DSSP assignment for this residue is ... E.
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