Factor XI Variant Database

In Depth Variant Analysis: c.1165G>A (p.Val389Ile)

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c.1165G>A

p.Val389Ile (Legacy AA No. 371)

Variant Type:

Point

Domain:

Serine Protease

Codon Change:

G>A

Variant Effect:

Missense

No. of Patients Reported:

Phenotype:

Allele Count *:

Allele Number *:

Allele Frequency *:

Variant Comments & Reference:

Residue Val389 is located one residue following the cleavage site of FXI (P2' position, according to the convention of numbering position around the scissile bond), thus is part of the activation loop. FXI antigen levels, measured in both conditioned media and lysates of cells expressing the mutant protein (in either the heterozygous or homozygous state), were not significantly different from those measured in wild-type samples. FXI specific activity was measured in conditioned media. The specific activity of the FXI Val389Ile protein was significantly reduced when compared with the wildtype one (30% and 80% for the heterozygous and the homozygous conditions, respectively). Given the proximity of Val389 to the FXI activation site, a possible interference on FXI activation was hypothesized and this mutation was found to be associated with a defect both in FXI activation (slower than normal), and in FIX activation (slightly delayed), thus supporting the role of residues neighboring the active site in influencing and stabilizing the enzyme active state. Bozzao et al 2007

Patient Information: Show

Patient_ID	Age	Gender	Race	FXI:C%	FXI:Ag(%)	Inheritance	Other Variants	Severity	Comments	Reference
464	26	M	Italian	34	102	Heterozygote		Not Reported	Asymptomatic. Appendectomy, adenoidectomy and right knee arthroscopy had been without mishap. Patient's mother, born 1949, also had reduced FXI:C (43%) associated with normal FXI:Ag (132%), whereas the father, born 1947, had both functional and antigen FXI levels within normal range (96 and 134%, respectively).Mother had same Val371Ile in heterozygous state. Both parents were asymptomatic.	Bozzao et al 2007

Residue Information:

	Name	Type	Cyclic	Size	Position	Hydrophobicity	Charge
Wild Type	Val	aliphatic	acyclic	medium	buried	hydrophobic	neutral
Mutated	Ile	aliphatic	acyclic	large	buried	hydrophobic	neutral

Substitution Analysis:

Grantham Score : 29

PolyPhen-2 Prediction : Benign (SCORE: 0.087)

SIFT Prediction : Tolerated (SCORE: 0.08)

PROVEAN Prediction : Neutral (SCORE: -0.767)

Structural Implications:

Val389 is an exposed residue (surface accessibility value = 3 ).

Val389 is in a random coil area of the FXI structure.

The DSSP assignment for this residue is ... C.

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