Table 2 Novel missense mutations... | American Society of Hematology

Table 2

Novel missense mutations detected in Spanish HA patients

Exon	Domain	Mutation		Clinical severity	Family history	Conservation in FVIII/FV/Cp	PolyPhen prediction	Predicted structural and/or functional implication
Exon	Domain	Nucleotide	Protein	Clinical severity	Family history	Conservation in FVIII/FV/Cp	PolyPhen prediction	Predicted structural and/or functional implication
2*	A1	c.248C>G	p.Pro64Arg	Mild	Positive	Yes/yes/no	Probably damaging	Impaired FX binding
4	A1	c.556G>A	p.Asp167Asn	Severe	Positive	Yes/yes/yes	Benign	Eliminates H-bond network/Disrupts domain structure
4	A1	c.584T>C	p.Leu176Pro	Severe	Sporadic	Yes/yes/yes	Possibly damaging	Creates cavity in protein core/disrupts secondary structure
6	A1	c.762A>G	p.Asn235Ser	Severe	Sporadic	Yes/yes/yes	Benign	Eliminates H-bond network/disrupts domain structure
6	A1	c.782T>C	p.Leu242Pro	Moderate	Sporadic	Yes/cons/yes	Possibly damaging	Creates cavity in protein core
7	A1	c.839G>A	p.Gly261Asp	Mild	Sporadic	Yes/no/yes	Possibly damaging	Introduces acidic side chain in unfavorable environment
8*	A2	c.1180G>T	p.Ala375Ser	Mild	Positive	Yes/no/no	Benign	Change at P_3′ position/delayed factor VIII activation
9	A2	c.1421G>T	p.Gly455Val	Mild	NA	Yes/no/no	Probably damaging	Steric clashes with mostly aliphatic residues
10	A2	c.1487C>G	p.Pro477Arg	Severe	Sporadic	Yes/yes/yes	Probably damaging	Major disruption of protein core
11*	A2	c.1538G>T	p.Gly494Val	Moderate	Positive	Yes/no/no	Probably damaging	Impaired FX binding/enhanced binding to LRP
11	A2	c.1706C>G	p.Pro550Arg	Severe	Sporadic	Yes/no/yes	Probably damaging	Major disruption of protein core
13	A2	c.1910A>T	p.Asn618Ile	Moderate	Sporadic	Yes/yes/yes	Probably damaging	Eliminates stabilizing H-bond interactions
14	A3	c.5159C>T	p.Ala1701Val	Mild	Positive	Yes/yes/yes	Benign	Steric clashes with mostly aromatic or polar residues
15	A3	c.5286T>A	p.Phe1743Leu	Moderate	Sporadic	Yes/yes/yes	Possibly damaging	Creates small cavity in domain core/Disrupts loop conformation
22	C1	C.6301C>G	p.His2082Asp	Mild	Positive	Yes/no/—	Probably damaging	Disrupts interactions between domains A3 and C1
22	C1	C.6317A>C	p.Gln2087Pro	Severe	Positive	Yes/yes/—	Possibly damaging	Eliminates H-bond network/disrupts domain structure
22	C1	C.6427A>G	p.Met2124Val	Mild	Sporadic	Yes/yes/—	Possibly damaging	Creates small cavity in protein core
23	C1	C.6515C>T	p.Pro2153Leu	Severe	Positive	Yes/yes/—	Probably damaging	Disrupts protein core
25*	C2	C.6857A>G	p.Asp2267Gly	Mild	Sporadic	Yes/no/—	Possibly damaging	Impaired FX- and/or VWF-binding
26	C2	C.7006A>T	p.Ile2317Phe	Moderate	Positive	Yes/yes/—	Benign	Disrupts protein core

Exon	Domain	Mutation		Clinical severity	Family history	Conservation in FVIII/FV/Cp	PolyPhen prediction	Predicted structural and/or functional implication
Exon	Domain	Nucleotide	Protein	Clinical severity	Family history	Conservation in FVIII/FV/Cp	PolyPhen prediction	Predicted structural and/or functional implication
2*	A1	c.248C>G	p.Pro64Arg	Mild	Positive	Yes/yes/no	Probably damaging	Impaired FX binding
4	A1	c.556G>A	p.Asp167Asn	Severe	Positive	Yes/yes/yes	Benign	Eliminates H-bond network/Disrupts domain structure
4	A1	c.584T>C	p.Leu176Pro	Severe	Sporadic	Yes/yes/yes	Possibly damaging	Creates cavity in protein core/disrupts secondary structure
6	A1	c.762A>G	p.Asn235Ser	Severe	Sporadic	Yes/yes/yes	Benign	Eliminates H-bond network/disrupts domain structure
6	A1	c.782T>C	p.Leu242Pro	Moderate	Sporadic	Yes/cons/yes	Possibly damaging	Creates cavity in protein core
7	A1	c.839G>A	p.Gly261Asp	Mild	Sporadic	Yes/no/yes	Possibly damaging	Introduces acidic side chain in unfavorable environment
8*	A2	c.1180G>T	p.Ala375Ser	Mild	Positive	Yes/no/no	Benign	Change at P_3′ position/delayed factor VIII activation
9	A2	c.1421G>T	p.Gly455Val	Mild	NA	Yes/no/no	Probably damaging	Steric clashes with mostly aliphatic residues
10	A2	c.1487C>G	p.Pro477Arg	Severe	Sporadic	Yes/yes/yes	Probably damaging	Major disruption of protein core
11*	A2	c.1538G>T	p.Gly494Val	Moderate	Positive	Yes/no/no	Probably damaging	Impaired FX binding/enhanced binding to LRP
11	A2	c.1706C>G	p.Pro550Arg	Severe	Sporadic	Yes/no/yes	Probably damaging	Major disruption of protein core
13	A2	c.1910A>T	p.Asn618Ile	Moderate	Sporadic	Yes/yes/yes	Probably damaging	Eliminates stabilizing H-bond interactions
14	A3	c.5159C>T	p.Ala1701Val	Mild	Positive	Yes/yes/yes	Benign	Steric clashes with mostly aromatic or polar residues
15	A3	c.5286T>A	p.Phe1743Leu	Moderate	Sporadic	Yes/yes/yes	Possibly damaging	Creates small cavity in domain core/Disrupts loop conformation
22	C1	C.6301C>G	p.His2082Asp	Mild	Positive	Yes/no/—	Probably damaging	Disrupts interactions between domains A3 and C1
22	C1	C.6317A>C	p.Gln2087Pro	Severe	Positive	Yes/yes/—	Possibly damaging	Eliminates H-bond network/disrupts domain structure
22	C1	C.6427A>G	p.Met2124Val	Mild	Sporadic	Yes/yes/—	Possibly damaging	Creates small cavity in protein core
23	C1	C.6515C>T	p.Pro2153Leu	Severe	Positive	Yes/yes/—	Probably damaging	Disrupts protein core
25*	C2	C.6857A>G	p.Asp2267Gly	Mild	Sporadic	Yes/no/—	Possibly damaging	Impaired FX- and/or VWF-binding
26	C2	C.7006A>T	p.Ile2317Phe	Moderate	Positive	Yes/yes/—	Benign	Disrupts protein core

Cp indicates ceruloplasmin; H-bond, hydrogen bond; NA, not available; and —, not applicable.

Type II mutations (further explanation in “Type II mutations”).

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