Factor XI Variant Database

In Depth Variant Analysis: c.688T>A (p.Cys230Ser)

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c.688T>A

p.Cys230Ser (Legacy AA No. 212)

Variant Type:

Point

Domain:

Apple 3

Codon Change:

T>A

Variant Effect:

Missense

No. of Patients Reported:

Phenotype:

Allele Count *:

Allele Number *:

Allele Frequency *:

Variant Comments & Reference:

Cys230Ser in exon 7 suppresses a disulphide bond that maintains the 220-226 loop in the tertiary structure of the third apple domain. It is also possible that free cysteine affects other disulphide bonds such as the 226-255 bond. Aberrant or absent disulphide bonds may disrupt the protein structure leading to impaired secretion or function or increased clearance of misfolded proteins. Another mutation involving Cys230 has been described (Cys230Arg). The Cys230 residue is buried. As a consequence, the size or charge of the substituting Arg residue may contribute to protein structure disruption. In Cys230Ser however, neither size nor charge can account for the structure disruption, rather the suppression of disulphide bridges is likely to be the determinant of altered secretion. Quelin et al 2009

Patient Information: Show

Patient_ID	Gender	Race	FXI:C%	Inheritance	Other Variants	Severity	Comments	Reference
419	F	French	<1	Compound heterozygote	c.403G>T (p.Glu135*)	Severe	Transfusion for bleeding complications and post-operative bruising following ovariectomy	Quelin et al 2009
420	F		<1	Compound heterozygote	c.403G>T (p.Glu135*)	Severe	Patient sufferes from spontaneous bruising and gingivorrhagia.Post-operative bleeding following cholecystectomy requiring no therapeutic intervention. Ovarian bruising following obstetric delivery.	Quelin et al 2009
421	F	French	38	Heterozygote		Not Reported	Bleeding following tooth extraction - requiring no therapeutic intervention. No spontaneous bleeding symptoms.	Quelin et al 2009
422	F	French	35	Heterozygote		Not Reported	Easy bruising	Quelin et al 2009

Residue Information:

	Name	Type	Cyclic	Size	Position	Hydrophobicity	Charge
Wild Type	Cys	-	acyclic	medium	buried	hydrophilic	neutral
Mutated	Ser	-	acyclic	small	surface	hydrophilic	neutral

Substitution Analysis:

Grantham Score : 112

PolyPhen-2 Prediction : Probably Damaging (SCORE: 1.000)

SIFT Prediction : Probably Damaging (SCORE: 0.00)

PROVEAN Prediction : Deleterious (SCORE: -5.489)

Structural Implications:

Cys230 is a buried residue (surface accessibility value = 0 ).

Cys230 is in a region of secondary structure within the FXI domains.

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

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