50 12 M 19 c.2443-1G.C Hmz 2 1 6 - -
Case: 50, M, 12 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: no family history of disease, Consanguinity: no
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): 2, VWF:Ag (U/dl): 1, Bleeding Score: 6
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.2443-1G>C, Exon 19
Homozygous
48 2.5 M 18 c.2303G.A p.R768Q Hmz 2.5 ,1 6 - -
Case: 48, M, 2.5 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: no family history of disease, Consanguinity: no
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): 2.5, VWF:Ag (U/dl): <1, Bleeding Score: 6
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.2303G>A (p.Arg768Gln), Exon 18
Homozygous
13 3 M 31 c.5335C.T p.R1779* Hmz 5.4 ,1 3 - -
Case: 13, M, 3 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: no, no family history of disease
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): 5.4, VWF:Ag (U/dl): <1, Bleeding Score: 3
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.5335C>T (p.Arg1779*), Exon 31, Homozygous
29 0.8 F 28 c.3835G.A p.V1279I Hmz 1.6 1.8 3 + +
Case: 29, F, 0.8 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: family history of disease, Consanguinity: yes
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): 1.6, VWF:Ag (U/dl): 1.8, Bleeding Score: 3
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.3835G>A (p.Val1279Ile), Exon 28
Homozygous
9 2.5 M 28 c.4975C.T p.R1659* Hmz 7 1.5 9 - -
Case: 9, M, 2.5 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: no, no family history of disease
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): 7, VWF:Ag (U/dl): 1.5, Bleeding Score: 9
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.4975C>T (p.Arg1659*), Exon 28, Homozygous
3 22 F 8 c.970C.T p.R324* Hmz ,1 ,1 4 - -
Case: 3, F, 22 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: no, no family history of disease
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): <1, VWF:Ag (U/dl): <1, Bleeding Score: 4
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.970C>T (p.Arg324*), Exon 8, Homozygous
55 9 F 18 c.2303G.A p.R768Q Htz 3.2 ,1 9 + -
Case: 55, F, 9 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: family history of disease, Consanguinity: no
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): 3.2, VWF:Ag (U/dl): <1, Bleeding Score: 9
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.2303G>A (p.Arg768Gln), Exon 18
Heterozygous
66 5 F 28 c.3862C.G p.L1288V Htz 1.4 2.3 6 - -c.3931C.T p.Q1311*c.3951C.T p.A1317Ac.4027A.G p.I1343V
Case: 66, F, 5 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: no family history of disease, Consanguinity: no
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): 1.4, VWF:Ag (U/dl): 2.3, Bleeding Score: 6
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.3862C>G (p.Leu1288Val), Exon 28
c.3931C>T (p.Gln1311*), Exon 28
c.3951C>T (p.Ala1317Ala), Exon 28
c.4027A>G (p.Ile1343Val), Exon 28
Heterozygous
82 2 M 15 c.1830C.A p.Y610* Hmz 1.4 ,1 6 - -
Case: 82, M, 2 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: no, no family history of disease
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): 1.4, VWF:Ag (U/dl): <1, Bleeding Score: 6
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.1830C>A (p.Tyr610*), Exon 15, Homozygous
72 6 F 17 c.2208G.Tp.M736I Htz 2.5 4 4 - -
Case: 72, F, 6 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: no family history of disease, Consanguinity: no
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): 2.5, VWF:Ag (U/dl): 4, Bleeding Score: 4
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.2208G>T (p.Met736Ile), Exon 17
Heterozygous
6 24 F 9 c.1093C.T p.R365* Hmz 1 ,1 22 - +
Case: 6, F, 24 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: yes, no family history of disease
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): 1, VWF:Ag (U/dl): <1, Bleeding Score: 22
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.1093C>T (p.Arg365*), Exon 9, Homozygous
1 10 M 3 c.100C.T p.R34* Hmz ,1 ,1 11 - +
Case: 1, M, 10 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: yes, no family history of disease
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): <1, VWF:Ag (U/dl): <1, Bleeding Score: 11
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.100C>T (p.Arg34*), Exon 3, Homozygous
49 1.1 F 19 c.2443-1G.C Hmz 4 2.6 3 - -
Case: 49, F, 1.1 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: no family history of disease, Consanguinity: no
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): 4, VWF:Ag (U/dl): 2.6, Bleeding Score: 3
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.2443-1G>C, Exon 19
Homozygous
65 10 M 28 c.3789G.A p.S1263S Hmz 2.1 1.4 5 - -c.3797C.T p.P1266Lc.3835G.A p.V1279Ic.3931C.T p.Q1311*c.3951C.T p.A1317A
Case: 65, M, 10 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: no family history of disease, Consanguinity: no
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): 2.1, VWF:Ag (U/dl): 1.4, Bleeding Score: 5
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.3789G>A (p.Ser1263Ser), Exon 28
c.3797C>T (p.Pro1266Leu), Exon 28
c.3835G>A (p.Val1279Ile), Exon 28
c.3931C>T (p.Gln1311*), Exon 28
c.3951C>T (p.Ala1317Ala), Exon 28
Homozygous
25 26 M 14 c.1693C.Tp.Q565* Hmz 2.5 ,1 6 - -
Case: 25, M, 26 years, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: no, no family history of disease
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: FVIII:C: (U/dl): 2.5, VWF:Ag (U/dl): <1, Bleeding Score: 6
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.1693C>T (p.Gln565*), Exon 14, Homozygous
Case: P57, Chinese, male, 28yo
DiseaseAssertion: VWD2B
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type AB blood, bleeding score = 5; VWF:Ag (%) = 33.4, VWF:RCo (%) = 3.2, FVIII:C (%) = 49.2, VWF:CB (%) = 4.8, VWFpp (%) = 67.3, VWF:RCo/VWF:Ag = 0.1, VWF:CB/VWF:Ag = 0.1, VWFpp/VWF:Ag = 2.0, FVIII:C/VWF:Ag = 1.5, RIPA (0.5 mg/ml, %) = 18.2, PLT(×109/l) = 146
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant 1: c.2089G>C (p.Glu697Gln)
HGVS: NM_000552.5:c.2089G>C (p.Glu697Gln)
ClinVarID: NA
CAID: CA383494704; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383494704
gnomAD: absent
Variant 2: c.3922C>T (p.Arg1308Cys)
HGVS: NM_000552.4(VWF):c.3922C>T (p.Arg1308Cys)
ClinVarID: 289; https://www.ncbi.nlm.nih.gov/clinvar/variation/289/
CAID: NA
gnomAD: absent
Variant 3: c.8113G>A (p.Gly2705Arg)
HGVS: NM_000552.4(VWF):c.8113G>A (p.Gly2705Arg)
ClinVarID: 256702; https://www.ncbi.nlm.nih.gov/clinvar/variation/256702/
CAID: NA
gnomAD: MAF = 0.1254 (3839/30614 alleles; 279 homozygotes)
Case: P26, Chinese, female, 30yo
DiseaseAssertion: VWD2A
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type AB blood, bleeding score = 14; VWF:Ag (%) = 11.3, VWF:RCo (%) = 3.7, FVIII:C (%) = 45.0, VWF:CB (%) = 4.0, VWFpp (%) = 41.7, VWF:RCo/VWF:Ag = 0.3, VWF:CB/VWF:Ag = 0.4, VWFpp/VWF:Ag = 3.7, FVIII:C/VWF:Ag = 4.0
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: c.4517C>T (p.Ser1506Leu)
HGVS: NM_000552.4(VWF):c.4517C>T (p.Ser1506Leu)
ClinVarID: 100369; https://www.ncbi.nlm.nih.gov/clinvar/variation/100369/
CAID: NA
gnomAD: absent
Case: P39,Chinese, female, 21yo
DiseaseAssertion: VWD1
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type O blood, bleeding score = 10; VWF:Ag (%) = 13.0, VWF:RCo (%) = 14.3, FVIII:C (%) = 32.1, VWF:CB (%) = 12.9, VWFpp (%) = 12.1, VWF:RCo/VWF:Ag = 1.1, VWF:CB/VWF:Ag = 1.0, VWFpp/VWF:Ag = 0.9, FVIII:C/VWF:Ag = 2.5
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: c.8116-2delA
HGVS: NA
ClinVarID: NA
CAID: NA
gnomAD: NA
Case: P50, Chinese, male, 51yo
DiseaseAssertion: VWD1
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type AB blood, bleeding score = 6; VWF:Ag (%) = 4.1, VWF:RCo (%) = 3.0, FVIII:C (%) = 7.8, VWF:CB (%) = 1.9, VWFpp (%) = 51.0, VWF:RCo/VWF:Ag = 0.7, VWF:CB/VWF:Ag = 0.5, VWFpp/VWF:Ag = 12.4, FVIII:C/VWF:Ag = 1.9, RIPA (1.2 mg/ml, %) = 97.1
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: c.971G>C (p.Arg324Pro)
HGVS: NM_000552.5:c.971G>C (p.Arg324Pro)
ClinVarID: NA
CAID: CA383506405; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383506405
gnomAD: absent
Case: P20, Chinese, female, 15yo
DiseaseAssertion: VWD3
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type A blood, bleeding score = 12; VWF:Ag (%) = 0.7, VWF:RCo (%) = 0.6, FVIII:C (%) = 3.9, VWF:CB (%) = 0.5, VWFpp (%) = 0.6, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 0.7, VWFpp/VWF:Ag = 0.9, FVIII:C/VWF:Ag = 5.6
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: c.2217_2220dup - Unregistered Variant
HGVS: NA
ClinVarID: NA
CAID: NA
gnomAD: NA
Case: P88, Chinese, female, 4yo
DiseaseAssertion: VWD3
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type O blood, bleeding score = 11; VWF:Ag (%) = 0.5, VWF:RCo (%) = <0.5, FVIII:C (%) = 3.0, VWF:CB (%) = <0.5, VWFpp (%) = <0.5, VWF:RCo/VWF:Ag = NA, VWF:CB/VWF:Ag = NA, VWFpp/VWF:Ag = NA, FVIII:C/VWF:Ag = 6.0
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: 1 c.1591C>T (p.Gln531Ter)
HGVS: NM_000552.5:c.1591C>T (p.Gln531Ter)
ClinVarID: NA
CAID: CA383498290; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383498290
gnomAD: absent
Variant 2: c.6678dupC - Unregistered Variant
HGVS: NA
ClinVarID: NA
CAID: NA
gnomAD: NA
Case: P3, Chinese, male, 7yo
DiseaseAssertion: VWD2A
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type B blood, bleeding score = 5; VWF:Ag (%) = 13.0, VWF:RCo (%) = 5.0, FVIII:C (%) = 39.1, VWF:CB (%) = 3.5, VWFpp (%) = 46.8, VWF:RCo/VWF:Ag = 0.4, VWF:CB/VWF:Ag = 0.3, VWFpp/VWF:Ag = 3.6, FVIII:C/VWF:Ag = 3.0
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: c.4517C>T (p.Ser1506Leu)
HGVS: NM_000552.4(VWF):c.4517C>T (p.Ser1506Leu)
ClinVarID: 100369; https://www.ncbi.nlm.nih.gov/clinvar/variation/100369/
CAID: NA
gnomAD: absent
Case: P54, Chinese, female, 30yo
DiseaseAssertion: VWD2A
FamilyInfo: both parents had mild type 1 VWD, a second undetected variant may exist in patient
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type A blood, bleeding score = 4; VWF:Ag (%) = 27.0, VWF:RCo (%) = 1.8, FVIII:C (%) = 44.6, VWF:CB (%) = 1.1, VWFpp (%) = 11.2, VWF:RCo/VWF:Ag = 0.1, VWF:CB/VWF:Ag = 0.0, VWFpp/VWF:Ag = 0.4, FVIII:C/VWF:Ag = 1.7
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: c.875–5T>G - Unregistered Variant
HGVS: NA
ClinVarID: NA
CAID: NA
gnomAD: NA
Case: P43, Chinese, male, 7yo
DiseaseAssertion: VWD2N
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type B blood, bleeding score = 3; VWF:Ag (%) = 48.8, VWF:RCo (%) = 49.9, FVIII:C (%) = 6.4, VWF:CB (%) = 63.9, VWFpp (%) = 52.4, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 1.3, VWFpp/VWF:Ag = 1.1, FVIII:C/VWF:Ag = 0.1, VWF: FVIIIB (%) = 0.0
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant 1: c.2372C>T (p.Thr791Met)
HGVS: NM_000552.4(VWF):c.2372C>T (p.Thr791Met)
ClinVarID: 294; https://www.ncbi.nlm.nih.gov/clinvar/variation/294/
CAID: NA
gnomAD: MAF = 0.00003984 (1/25100 alleles) in European (Finnish) population; https://gnomad.broadinstitute.org/variant/12-6153527-G-A?dataset=gnomad_r2_1
Variant 2: c.2574C>G (p.Cys858Trp)
HGVS: NM_000552.5:c.2574C>G (p.Cys858Trp)
ClinVarID: NA
CAID: CA232299278; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA232299278
gnomAD: MAF = 0.0001002 (2/19954 alleles) in the East Asian population; https://gnomad.broadinstitute.org/variant/12-6143965-G-C
Case: P73, Chinese, female, 16yo
DiseaseAssertion: VWD1
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type O blood, bleeding score = 2; VWF:Ag (%) = 29.6, VWF:RCo (%) = 35.4, FVIII:C (%) = 63.1, VWF:CB (%) = 35.0, VWFpp (%) = 78.3, VWF:RCo/VWF:Ag = 1.2, VWF:CB/VWF:Ag = 1.2, VWFpp/VWF:Ag = 2.6, FVIII:C/VWF:Ag = 2.1
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: c.2279G>A (p.Arg760His)
HGVS: NM_000552.4(VWF):c.2279G>A (p.Arg760His)
ClinVarID: 31011; https://www.ncbi.nlm.nih.gov/clinvar/variation/31011/
CAID: NA
gnomAD: MAF = 0.00008009 (2/24972 alleles) in African/African-American population; https://gnomad.broadinstitute.org/variant/12-6155891-C-T?dataset=gnomad_r2_1
Case: P58, Chinese, female, 27yo
DiseaseAssertion: VWD2A
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs:
CaseHPOFreeText: HP:0012147
(Reduced quantity of VWF)
CaseNOTHPOs: type O blood, bleeding score = 8; VWF:Ag (%) = 17.1, VWF:RCo (%) = 2.3, FVIII:C (%) = 44.3, VWF:CB (%) = 3.7, VWFpp (%) = 41.1, VWF:RCo/VWF:Ag = 0.1, VWF:CB/VWF:Ag = 0.2, VWFpp/VWF:Ag = 2.4, FVIII:C/VWF:Ag = 2.6
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: c.4790G>T (p.Arg1597Leu)
HGVS: NM_000552.4(VWF):c.4790G>T (p.Arg1597Leu)
ClinVarID: 100392; https://www.ncbi.nlm.nih.gov/clinvar/variation/100392/
CAID: NA
gnomAD: absent
Case: P18, Chinese, male, 23yo
DiseaseAssertion: VWD2A
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type O blood, bleeding score = 7; VWF:Ag (%) = 25.0, VWF:RCo (%) = 5.2, FVIII:C (%) = 39.0, VWF:CB (%) = 6.7, VWFpp (%) = 49.6, VWF:RCo/VWF:Ag = 0.2, VWF:CB/VWF:Ag = 0.3, VWFpp/VWF:Ag = 2.0, FVIII:C/VWF:Ag = 1.6
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: c.4735G>A (p.Gly1579Arg)
HGVS: NM_000552.4(VWF):c.4735G>A (p.Gly1579Arg)
ClinVarID: 100385; https://www.ncbi.nlm.nih.gov/clinvar/variation/100385/
CAID: NA
gnomAD: absent
Case: P17, Chinese, female, 20yo
DiseaseAssertion: VWD2M
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type B blood, bleeding score = 10; VWF:Ag (%) = 17.6, VWF:RCo (%) = 7.3, FVIII:C (%) = 35.8, VWF:CB (%) = 15.8, VWFpp (%) = 51.9, VWF:RCo/VWF:Ag = 0.4, VWF:CB/VWF:Ag = 0.9, VWFpp/VWF:Ag = 2.9, FVIII:C/VWF:Ag = 2.0
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: c.3389G>T (p.Cys1130Phe)
HGVS: NM_000552.4(VWF):c.3389G>T (p.Cys1130Phe)
ClinVarID: 100261; https://www.ncbi.nlm.nih.gov/clinvar/variation/100261/
CAID: NA
gnomAD: absent
Case: P74, Chinese, female, 26yo
DiseaseAssertion: VWD1
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type A blood, bleeding score = 10; VWF:Ag (%) = 4.7, VWF:RCo (%) = 4.1, FVIII:C (%) = 31.0, VWF:CB (%) = 3.6, VWFpp (%) = 5.2, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 0.8, VWFpp/VWF:Ag = 1.1, FVIII:C/VWF:Ag = 6.6, RIPA (1.2 mg/ml, %) = 93.4
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant 1: c.-1+3A>C
HGVS: NA
ClinVarID: NA
CAID: NA
gnomAD: NA
Variant 2: c.3322G>C (p.Ala1108Pro)
HGVS: NM_000552.3:c.3322G>C (p.Ala1108Pro)
ClinVarID: NA
CAID: CA383512138; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383512138
gnomAD: absent
Case: P23, Chinese, female 23
DiseaseAssertion: VWD3
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type O blood, bleeding score = 14; VWF:Ag (%) = 1.0, VWF:RCo (%) = 0.9, FVIII:C (%) = 4.7, VWF:CB (%) = 0.8, VWFpp (%) = 0.7, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 0.8, VWFpp/VWF:Ag = 0.8, FVIII:C/VWF:Ag = 5.6
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: c.7361C>A (p.Thr2454Asn)
HGVS: NM_000552.5:c.7361C>A (p.Thr2454Asn)
ClinVarID: NA
CAID: CA6401695; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA6401695
gnomAD: MAF = 0.0003263 (6/18390 alleles) in the East Asian population; https://gnomad.broadinstitute.org/variant/12-6085353-G-T
Case: P31, Chinese, female, 21yo
DiseaseAssertion: VWD3
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type O blood, bleeding score = 15; VWF:Ag (%) = 1.0, VWF:RCo (%) = 0.7, FVIII:C (%) = 4.1, VWF:CB (%) = 0.8, VWFpp (%) = 0.8, VWF:RCo/VWF:Ag = 0.7, VWF:CB/VWF:Ag = 0.8, VWFpp/VWF:Ag = 0.8, FVIII:C/VWF:Ag = 4.1
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant 1: c.953_954insG - Unregistered Variant
HGVS: NA
ClinVarID: NA
CAID: NA
gnomAD: NA
Variant 2: c.4368C>G (p.Tyr1456Ter)
HGVS: NM_000552.4(VWF):c.4368C>G (p.Tyr1456Ter)
ClinVarID: 100350; https://www.ncbi.nlm.nih.gov/clinvar/variation/100350/
CAID: NA
gnomAD: absent
Case: P90, Chinese, female, 30yo
DiseaseAssertion: VWD2A
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type O blood, bleeding score = 12; VWF:Ag (%) = 10.1, VWF:RCo (%) = 3.3, FVIII:C (%) = 10.7, VWF:CB (%) = 2.6, VWFpp (%) = 151.7, VWF:RCo/VWF:Ag = 0.3, VWF:CB/VWF:Ag = 0.3, VWFpp/VWF:Ag = 15.0, FVIII:C/VWF:Ag = 1.1
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant 1: c.1730-2A>G
HGVS: NM_000552.4(VWF):c.1730-2A>G
ClinVarID: 100189; https://www.ncbi.nlm.nih.gov/clinvar/variation/100189/
CAID: NA
gnomAD: absent
Variant 2: c.6979T>A (p.Cys2327Ser)
HGVS: NM_000552.3:c.6979T>A (p.Cys2327Ser)
ClinVarID: NA
CAID: CA383492042; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383492042
gnomAD: absent
Case: P38, Chinese, female, 14yo
DiseaseAssertion: VWD3
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type O blood, bleeding score = 9; VWF:Ag (%) = 1.3, VWF:RCo (%) = 1.0, FVIII:C (%) = 4.5, VWF:CB (%) = 0.7, VWFpp (%) = 0.8, VWF:RCo/VWF:Ag = 0.8, VWF:CB/VWF:Ag = 0.5, VWFpp/VWF:Ag = 0.6, FVIII:C/VWF:Ag = 3.5
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant 1: c.2684A>G (p.Gln895Arg)
HGVS: NM_000552.5:c.2684A>G (p.Gln895Arg)
ClinVarID: NA
CAID: CA383519914; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383519914
gnomAD: NA
Variant 2: c.3043G>T (p.Glu1015Ter)
HGVS: NM_000552.5:c.3043G>T (p.Glu1015Ter)
ClinVarID: NA
CAID: CA383514739; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383514739
gnomAD: absent
Case: P66, Chinese, male, 27yo
DiseaseAssertion: VWD1
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147
(Reduced quantity of VWF)
CaseHPOFreeText: type O blood, bleeding score = 1; VWF:Ag (%) = 56.0, VWF:RCo (%) = 43.4, FVIII:C (%) = 70.0, VWF:CB (%) = 58.9, VWFpp (%) = 53.6, VWF:RCo/VWF:Ag = 0.8, VWF:CB/VWF:Ag = 1.1, VWFpp/VWF:Ag = 1.0, FVIII:C/VWF:Ag = 1.3
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NGS
PreviouslyPublished: NA
Gene: VWF
Variant: c.4414G>C (p.Asp1472His)
HGVS: NM_000552.4(VWF):c.4414G>C (p.Asp1472His)
ClinVarID: 256679; https://www.ncbi.nlm.nih.gov/clinvar/variation/256679/
CAID: NA
gnomAD: MAF = 0.5077 (12039/23712 alleles; 3078 homozygotes) in African/African-American population; https://gnomad.broadinstitute.org/variant/12-6128170-C-G?dataset=gnomad_r2_1
4 C
Case: Patient 4, Family C (Table 1.), F/38, Afro-Caribbean
DiseaseAssertion: VWD1
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs:
CaseHPOFreeRext: BAT = 16, FVIII:C (IU/dL) = NA, VWF:Ag (IU/dL) = 40, VWF:Act (IU/dL) = 36
CaseNOTHPOs:
CaseNOTHPOFreeText: Blood group A
CasePreviousTesting:
GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).
PreviouslyPublished: NA
Gene: VWF
Variant: c.2365A > G p.(Thr789Ala)
HGVS: NM_000552.5:c.2365A>G (p.Thr789Ala)
ClinVarID: 256659
CAID: CA6403090
gnomAD: MAF of 0.5793 (43409/74928 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/12-6044368-T-C?dataset=gnomad_r4
Variant: c.2385T > C p.(Tyr795 =)
HGVS: NM_000552.5:c.2385T>C (p.Tyr795=)
ClinVarID: 256660
CAID: CA6403087
gnomAD: MAF of 0.5788 (43385/74952 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/12-6044348-A-G?dataset=gnomad_r4
Variant: c.4019T > C p.(Leu1340Arg)
the paper incorrectly lists the amino acid change as Leu1340Arg but it should be Leu1340Pro
HGVS: NM_000552.5:c.4019T>C
ClinVarID: 3061402
CAID: CA383505745
gnomAD:
Variant: c.4457C > T p.(Ser1486Leu)
HGVS: NM_000552.5:c.4457C>T (p.Ser1486Leu)
ClinVarID: 560630
CAID: CA6402527
gnomAD: MAF of 0.009120 (684/74998 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/12-6018961-G-A?dataset=gnomad_r4
Variant: c.6187C > T p.(Pro2063Ser)
HGVS: NM_000552.5:c.6187C>T (p.Pro2063Ser)
ClinVarID: 100436
CAID: CA202650
gnomAD: MAF of 0.04780 (4353/91066 alleles) in Africa/African American population https://gnomad.broadinstitute.org/variant/12-5994484-G-A?dataset=gnomad_r4
Variant: c.7059G > C p.(Glu2353Ser)
paper incorrectly lists amino acid change as Glu2353Ser but it should be Glu2353Asp
HGVS: NM_000552.5:c.7059G>C
ClinVarID: 993253
CAID: CA6401794
gnomAD: MAF of 0.006101 (458/75068 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-5983172-C-G?dataset=gnomad_r4
1 A
Case: Patient 1, Family A (Table 1.), F/49, Afro-Caribbean
DiseaseAssertion: VWD2B
FamilyInfo: Patient 2 (F/15, Afro-Caribbean) from same family A (Table 1.)
ParentalGenotype(s): NA
CasePresentingHPOs:
CaseHPOFreeRext: BAT = 7, FVIII:C (IU/dL) = 28, VWF:Ag (IU/dL) = 35, VWF:Act (IU/dL) = 10
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).
PreviouslyPublished: NA
Gene: VWF
Variant: c.3946G > A p.(Val1316Met)
HGVS: NM_000552.5:c.3946G>A (p.Val1316Met)
ClinVarID: 290
CAID: CA114127
gnomAD:
26 N
Case: Patient 26, Family N (Table 1.), F/58, Afro-Caribbean
DiseaseAssertion: VWD2A (IIE)
FamilyInfo: Patient 27 (M/20, Afro-Caribbean) also in Family N. (Table 1.)
ParentalGenotype(s): NA
CasePresentingHPOs:
CaseHPOFreeRext: BAT =12, FVIII:C (IU/dL) = NA, VWF:Ag (IU/dL) = 15, VWF:Act (IU/dL) = 10
CaseNOTHPOs:
CaseNOTHPOFreeText: Blood group B+
CasePreviousTesting:
GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).
PreviouslyPublished: NA
Gene: VWF
Variant: c.1530G > A, p.(Val510 =)
HGVS: NM_000552.5:c.1530G>A (p.Val510=)
ClinVarID:
CAID: CA6403368
gnomAD: MAF of 0.00002198 (2/91004 alleles) in South Asian population https://gnomad.broadinstitute.org/variant/chr12-6062957-C-T?dataset=gnomad_r4
Variant: c.1892C > T, p.(Ala631Val)
HGVS: NM_000552.5:c.1892C>T (p.Ala631Val)
ClinVarID: 422844
CAID: CA6403245
gnomAD: MAF of 0.001908 (137/71810 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6056910-G-A?dataset=gnomad_r4
Variant: c.2220G > A, p.(Met740Ile)
HGVS: NM_000552.5:c.2220G>A (p.Met740Ile)
ClinVarID: 100206
CAID: CA201316
gnomAD: MAF of 0.1816 (13626/75022 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6046784-C-T?dataset=gnomad_r4
Variant: c.2451T > A, p.(His817Gln)
HGVS: NM_000552.5:c.2451T>A (p.His817Gln)
ClinVarID: 100224
CAID: CA228345
gnomAD: MAF of 0.1150 (8626/75016 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6036483-A-T?dataset=gnomad_r4
Variant: c.3445T > C, p.(Cys1149Arg)
HGVS: NM_000552.5:c.3445T>C (p.Cys1149Arg)
ClinVarID: 309
CAID: CA228410
gnomAD: MAF of 0.000003160 (1/316464 alleles) in European (non-Finnish) population https://gnomad.broadinstitute.org/variant/chr12-6022833-A-G?dataset=gnomad_r4
Variant: c.4414G > C p.(Asp1472His)
HGVS: NM_000552.5:c.4414G>C (p.Asp1472His)
ClinVarID: 256679
CAID: CA6402534
gnomAD: MAF of 0.5076 (38011/74882 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019004-C-G?dataset=gnomad_r4
Variant: c.6554G > A, p.(Arg2185Gln)
HGVS: NM_000552.5:c.6554G>A (p.Arg2185Gln)
ClinVarID: 100443
CAID: CA228748
gnomAD: MAF of 0.1927 (14427/74878 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-5993906-C-T?dataset=gnomad_r4
17 G
Case: Patient 17, Family G (Table 1.), F/79, Afro-Caribbean
DiseaseAssertion: VWD2A (IIE)
FamilyInfo: Patient 10 (M/22, Afro-Caribbean) and Patient 17 (F/58, Afro-Caribbean) also from Family G. (Table 1.)
ParentalGenotype(s): NA
CasePresentingHPOs:
CaseHPOFreeRext: BAT =4, FVIII:C (IU/dL) = 29, VWF:Ag (IU/dL) = 17, VWF:Act (IU/dL) = 5
CaseNOTHPOs:
CaseNOTHPOFreeText: Blood group A+
CasePreviousTesting:
GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).
PreviouslyPublished: NA
Gene: VWF
Variant: c.1530G > A, p.(Val510 =) p.
HGVS: NM_000552.5:c.1530G>A (p.Val510=)
ClinVarID:
CAID: CA6403368
gnomAD: MAF of 0.00002198 (2/91004 alleles) in South Asian population https://gnomad.broadinstitute.org/variant/chr12-6062957-C-T?dataset=gnomad_r4
Variant: c.1892C > T, p.(Ala631Val)
HGVS: NM_000552.5:c.1892C>T (p.Ala631Val)
ClinVarID: 422844
CAID: CA6403245
gnomAD: MAF of 0.001908 (137/71810 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6056910-G-A?dataset=gnomad_r4
Variant: c.2220G > A, p.(Met740Ile)
HGVS: NM_000552.5:c.2220G>A (p.Met740Ile)
ClinVarID: 100206
CAID: CA201316
gnomAD: MAF of 0.1816 (13626/75022 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6046784-C-T?dataset=gnomad_r4
Variant: c.2451T > A, p.(His817Gln)
HGVS: NM_000552.5:c.2451T>A (p.His817Gln)
ClinVarID: 100224
CAID: CA228345
gnomAD: MAF of 0.1150 (8626/75016 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6036483-A-T?dataset=gnomad_r4
Variant: c.3445T > C, p.(Cys1149Arg)
HGVS: NM_000552.5:c.3445T>C (p.Cys1149Arg)
ClinVarID: 309
CAID: CA228410
gnomAD: MAF of 0.000003160 (1/316464 alleles) in European (non-Finnish) population https://gnomad.broadinstitute.org/variant/chr12-6022833-A-G?dataset=gnomad_r4
Variant: c.4414G > C p.(Asp1472His)
HGVS: NM_000552.5:c.4414G>C (p.Asp1472His)
ClinVarID: 256679
CAID: CA6402534
gnomAD: MAF of 0.5076 (38011/74882 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019004-C-G?dataset=gnomad_r4
Variant: c.6554G > A, p.(Arg2185Gln)
HGVS: NM_000552.5:c.6554G>A (p.Arg2185Gln)
ClinVarID: 100443
CAID: CA228748
gnomAD: MAF of 0.1927 (14427/74878 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-5993906-C-T?dataset=gnomad_r4
16 G
Case: Patient 16, Family G (Table 1.), F/58, Afro-Caribbean
DiseaseAssertion: VWD2A (IIE)
FamilyInfo: Patient 10 (M/22, Afro-Caribbean) and Patient 17 (F/79, Afro-Caribbean) also from Family G. (Table 1.)
ParentalGenotype(s): NA
CasePresentingHPOs:
CaseHPOFreeRext: BAT =23, FVIII:C (IU/dL) = 44, VWF:Ag (IU/dL) = 20, VWF:Act (IU/dL) = 14
CaseNOTHPOs:
CaseNOTHPOFreeText: Blood group A+
CasePreviousTesting:
GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).
PreviouslyPublished: NA
Gene: VWF
Variant: c.1530G > A, p.(Val510 =) p.
HGVS: NM_000552.5:c.1530G>A (p.Val510=)
ClinVarID:
CAID: CA6403368
gnomAD: MAF of 0.00002198 (2/91004 alleles) in South Asian population https://gnomad.broadinstitute.org/variant/chr12-6062957-C-T?dataset=gnomad_r4
Variant: c.1892C > T, p.(Ala631Val)
HGVS: NM_000552.5:c.1892C>T (p.Ala631Val)
ClinVarID: 422844
CAID: CA6403245
gnomAD: MAF of 0.001908 (137/71810 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6056910-G-A?dataset=gnomad_r4
Variant: c.2220G > A, p.(Met740Ile)
HGVS: NM_000552.5:c.2220G>A (p.Met740Ile)
ClinVarID: 100206
CAID: CA201316
gnomAD: MAF of 0.1816 (13626/75022 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6046784-C-T?dataset=gnomad_r4
Variant: c.2451T > A, p.(His817Gln)
HGVS: NM_000552.5:c.2451T>A (p.His817Gln)
ClinVarID: 100224
CAID: CA228345
gnomAD: MAF of 0.1150 (8626/75016 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6036483-A-T?dataset=gnomad_r4
Variant: c.3445T > C, p.(Cys1149Arg)
HGVS: NM_000552.5:c.3445T>C (p.Cys1149Arg)
ClinVarID: 309
CAID: CA228410
gnomAD: MAF of 0.000003160 (1/316464 alleles) in European (non-Finnish) population https://gnomad.broadinstitute.org/variant/chr12-6022833-A-G?dataset=gnomad_r4
Variant: c.4414G > C p.(Asp1472His)
HGVS: NM_000552.5:c.4414G>C (p.Asp1472His)
ClinVarID: 256679
CAID: CA6402534
gnomAD: MAF of 0.5076 (38011/74882 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019004-C-G?dataset=gnomad_r4
Variant: c.6554G > A, p.(Arg2185Gln)
HGVS: NM_000552.5:c.6554G>A (p.Arg2185Gln)
ClinVarID: 100443
CAID: CA228748
gnomAD: MAF of 0.1927 (14427/74878 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-5993906-C-T?dataset=gnomad_r4
2 A
Case: Patient 2, Family A (Table 1.), F/15, Afro-Caribbean
DiseaseAssertion: VWD2B
FamilyInfo: Patient 1 (F/49, Afro-Caribbean) from same family G. (Table 1.)
ParentalGenotype(s): NA
CasePresentingHPOs:
CaseHPOFreeRext: BAT = 3, FVIII:C (IU/dL) = 50, VWF:Ag (IU/dL) = 57, VWF:Act (IU/dL) = 14
CaseNOTHPOs:
CaseNOTHPOFreeText: Blood group O+
CasePreviousTesting:
GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).
PreviouslyPublished: NA
Gene: VWF
Variant: c.3946G > A p.(Val1316Met)
HGVS: NM_000552.5:c.3946G>A (p.Val1316Met)
ClinVarID: 290
CAID: CA114127
gnomAD:
54 A1
Case: Patient 54, Family A1 (Table 1.), M/33, Afro-Caribbean
DiseaseAssertion: VWD1
FamilyInfo: Patient 55 (F/54, Afro-Caribbean), Patient 56 (M/64, Afro-Caribbean), Patient 57 (F/26, Afro-Caribbean), Patient 63 (F/59, Afro-Caribbean) also from Family A1. (Table 1.)
ParentalGenotype(s): NA
CasePresentingHPOs:
CaseHPOFreeRext: BAT = 1, FVIII:C (IU/dL) = 58.1, VWF:Ag (IU/dL) = 35, VWF:Act (IU/dL) = 38
CaseNOTHPOs:
CaseNOTHPOFreeText: Blood group A+
CasePreviousTesting:
GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).
PreviouslyPublished: NA
Gene: VWF
Variant: c.7472G > A, p.(Cys2491Tyr)
HGVS: NM_000552.5:c.7472G>A (p.Cys2491Tyr)
ClinVarID:
CAID: CA383489765
gnomAD:
19 L
Case: Patient 19, Family L (Table 1.), M/76, Afro-Caribbean
DiseaseAssertion: VWD2A (IIE)
FamilyInfo:
ParentalGenotype(s): NA
CasePresentingHPOs:
CaseHPOFreeRext: BAT =4, FVIII:C (IU/dL) = NA, VWF:Ag (IU/dL) = 70, VWF:Act (IU/dL) = 28
CaseNOTHPOs:
CaseNOTHPOFreeText: Blood group A+
CasePreviousTesting:
GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).
PreviouslyPublished: NA
Gene: VWF
Variant: c.1530G > A, p.(Val510 =) p.
HGVS: NM_000552.5:c.1530G>A (p.Val510=)
ClinVarID:
CAID: CA6403368
gnomAD: MAF of 0.00002198 (2/91004 alleles) in South Asian population https://gnomad.broadinstitute.org/variant/chr12-6062957-C-T?dataset=gnomad_r4
Variant: c.1892C > T, p.(Ala631Val)
HGVS: NM_000552.5:c.1892C>T (p.Ala631Val)
ClinVarID: 422844
CAID: CA6403245
gnomAD: MAF of 0.001908 (137/71810 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6056910-G-A?dataset=gnomad_r4
Variant: c.2220G > A, p.(Met740Ile)
HGVS: NM_000552.5:c.2220G>A (p.Met740Ile)
ClinVarID: 100206
CAID: CA201316
gnomAD: MAF of 0.1816 (13626/75022 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6046784-C-T?dataset=gnomad_r4
Variant: c.2451T > A, p.(His817Gln)
HGVS: NM_000552.5:c.2451T>A (p.His817Gln)
ClinVarID: 100224
CAID: CA228345
gnomAD: MAF of 0.1150 (8626/75016 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6036483-A-T?dataset=gnomad_r4
Variant: c.3445T > C, p.(Cys1149Arg)
HGVS: NM_000552.5:c.3445T>C (p.Cys1149Arg)
ClinVarID: 309
CAID: CA228410
gnomAD: MAF of 0.000003160 (1/316464 alleles) in European (non-Finnish) population https://gnomad.broadinstitute.org/variant/chr12-6022833-A-G?dataset=gnomad_r4
Variant: c.4414G > C p.(Asp1472His)
HGVS: NM_000552.5:c.4414G>C (p.Asp1472His)
ClinVarID: 256679
CAID: CA6402534
gnomAD: MAF of 0.5076 (38011/74882 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019004-C-G?dataset=gnomad_r4
Variant: c.6554G > A, p.(Arg2185Gln
HGVS: NM_000552.5:c.6554G>A (p.Arg2185Gln)
ClinVarID: 100443
CAID: CA228748
gnomAD: MAF of 0.1927 (14427/74878 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-5993906-C-T?dataset=gnomad_r4
13 I
Case: Patient 13, Family I (Table 1.), F/65, Afro-Caribbean
DiseaseAssertion: VWD2A (IIE)
FamilyInfo: Patient 21 (F/97, Afro-Caribbean), Patient 22 (F/67, Afro-Caribbean), Patient 23 (F/86, Afro-Caribbean), Patient 24 (F/92, Afro-Caribbean), Patient 25 (F/62, Afro-Carribean) also from Family I. (Table 1.)
ParentalGenotype(s): NA
CasePresentingHPOs:
CaseHPOFreeRext: BAT =12, FVIII:C (IU/dL) = 18, VWF:Ag (IU/dL) = 18, VWF:Act (IU/dL) = 7
CaseNOTHPOs:
CaseNOTHPOFreeText: Blood group O+
CasePreviousTesting:
GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).
PreviouslyPublished: NA
Gene: VWF
Variant: c.1530G > A, p.(Val510 =) p.
HGVS: NM_000552.5:c.1530G>A (p.Val510=)
ClinVarID:
CAID: CA6403368
gnomAD: MAF of 0.00002198 (2/91004 alleles) in South Asian population https://gnomad.broadinstitute.org/variant/chr12-6062957-C-T?dataset=gnomad_r4
Variant: c.1892C > T, p.(Ala631Val)
HGVS: NM_000552.5:c.1892C>T (p.Ala631Val)
ClinVarID: 422844
CAID: CA6403245
gnomAD: MAF of 0.001908 (137/71810 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6056910-G-A?dataset=gnomad_r4
Variant: c.2220G > A, p.(Met740Ile)
HGVS: NM_000552.5:c.2220G>A (p.Met740Ile)
ClinVarID: 100206
CAID: CA201316
gnomAD: MAF of 0.1816 (13626/75022 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6046784-C-T?dataset=gnomad_r4
Variant: c.2451T > A, p.(His817Gln)
HGVS: NM_000552.5:c.2451T>A (p.His817Gln)
ClinVarID: 100224
CAID: CA228345
gnomAD: MAF of 0.1150 (8626/75016 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6036483-A-T?dataset=gnomad_r4
Variant: c.3258C > T, p.(Tyr1086 =)
HGVS: NM_000552.5:c.3258C>T (p.Tyr1086=)
ClinVarID: 256664
CAID: CA6402788
gnomAD: MAF of 0.1284 (9131/71128 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6023752-G-A?dataset=gnomad_r4
Variant: c.3445T > C, p.(Cys1149Arg)
HGVS: NM_000552.5:c.3445T>C (p.Cys1149Arg)
ClinVarID: 309
CAID: CA228410
gnomAD: MAF of 0.000003160 (1/316464 alleles) in European (non-Finnish) population https://gnomad.broadinstitute.org/variant/chr12-6022833-A-G?dataset=gnomad_r4
Variant: c.4414G > C p.(Asp1472His)
HGVS: NM_000552.5:c.4414G>C (p.Asp1472His) ClinVarID: 256679
CAID: CA6402534
gnomAD: MAF of 0.5076 (38011/74882 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019004-C-G?dataset=gnomad_r4
Variant: c.6554G > A, p.(Arg2185Gln)
HGVS: NM_000552.5:c.6554G>A (p.Arg2185Gln)
ClinVarID: 100443
CAID: CA228748
gnomAD: MAF of 0.1927 (14427/74878 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-5993906-C-T?dataset=gnomad_r4
8 F
Case: Patient 8, Family F (Table 1.), M/86, Afro-Caribbean
DiseaseAssertion: VWD2A (IIE)
FamilyInfo: Patient 9 (F/76, Afro-Caribbean) and Patient 28 (F/55, Afro-Caribbean) also from Family F. (Table 1.)
ParentalGenotype(s): NA
CasePresentingHPOs:
CaseHPOFreeRext: BAT = 5, FVIII:C (IU/dL) = 17, VWF:Ag (IU/dL) = 20, VWF:Act (IU/dL) = 10
CaseNOTHPOs:
CaseNOTHPOFreeText: Blood group O+
CasePreviousTesting:
GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).
PreviouslyPublished: NA
Gene: VWF
Variant: c.1530G > A, p.(Val510 =) p.
HGVS: NM_000552.5:c.1530G>A (p.Val510=)
ClinVarID:
CAID: CA6403368
gnomAD: MAF of 0.00002198 (2/91004 alleles) in South Asian population https://gnomad.broadinstitute.org/variant/chr12-6062957-C-T?dataset=gnomad_r4
Variant: c.1892C > T, p.(Ala631Val)
HGVS: NM_000552.5:c.1892C>T (p.Ala631Val)
ClinVarID: 422844
CAID: CA6403245
gnomAD: MAF of 0.001908 (137/71810 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6056910-G-A?dataset=gnomad_r4
Variant: c.2220G > A, p.(Met740Ile)
HGVS: NM_000552.5:c.2220G>A (p.Met740Ile)
ClinVarID: 100206
CAID: CA201316
gnomAD: MAF of 0.1816 (13626/75022 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6046784-C-T?dataset=gnomad_r4
Variant: c.2451T > A, p.(His817Gln)
HGVS: NM_000552.5:c.2451T>A (p.His817Gln)
ClinVarID: 100224
CAID: CA228345
gnomAD: MAF of 0.1150 (8626/75016 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6036483-A-T?dataset=gnomad_r4
Variant: c.3426T > C, p.(Cys1142 =)
HGVS: NM_000552.5:c.3426T>C (p.Cys1142=)
ClinVarID: 256668
CAID: CA6402757
gnomAD: MAF of 0.2077 (7935/38206 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6022852-A-G?dataset=gnomad_r4
Variant: c.3445T > C, p.(Cys1149Arg)
HGVS: NM_000552.5:c.3445T>C (p.Cys1149Arg)
ClinVarID: 309
CAID: CA228410
gnomAD: MAF of 0.000003160 (1/316464 alleles) in European (non-Finnish) population https://gnomad.broadinstitute.org/variant/chr12-6022833-A-G?dataset=gnomad_r4
Variant: c.3485C > T, p.(Pro1162Leu)
HGVS: NM_000552.5(VWF):c.3485C>T (p.Pro1162Leu)
ClinVarID: 256669
CAID: CA6402756
gnomAD: MAF of 0.2076 (7087/34136 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6022793-G-A?dataset=gnomad_r4
Variant: c.3486A > G, p.(Pro1162 =)
HGVS: NM_000552.5:c.3486A>G (p.Pro1162=)
ClinVarID: 256670
CAID: CA6402755
gnomAD: MAF of 0.2083 (7074/33968 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6022792-T-C?dataset=gnomad_r4
Variant: c.4414G > C p.(Asp1472His)
HGVS: NM_000552.5:c.4414G>C (p.Asp1472His)
ClinVarID: 256679
CAID: CA6402534
gnomAD: MAF of 0.5076 (38011/74882 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019004-C-G?dataset=gnomad_r4
Variant: c.6554G > A, p.(Arg2185Gln)
HGVS: NM_000552.5:c.6554G>A (p.Arg2185Gln)
ClinVarID: 100443
CAID: CA228748
gnomAD: MAF of 0.1927 (14427/74878 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-5993906-C-T?dataset=gnomad_r4
53 Z
Case: Patient 53, Family Z (Table 1.), F/92, Afro-Caribbean
DiseaseAssertion: VWD1
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs:
CaseHPOFreeRext: BAT = 0, FVIII:C (IU/dL) = 33, VWF:Ag (IU/dL) = 35, VWF:Act (IU/dL) = 30
CaseNOTHPOs:
CaseNOTHPOFreeText: Blood group O+
CasePreviousTesting:
GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).
PreviouslyPublished: NA
Variant: c.2220G > A, p.(Met740Ile)
HGVS: NM_000552.5:c.2220G>A (p.Met740Ile)
ClinVarID: 100206
CAID: CA201316
gnomAD: MAF of 0.1816 (13626/75022 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6046784-C-T?dataset=gnomad_r4
Variant: c.2451T > A, p.(His817Gln)
HGVS: NM_000552.5:c.2451T>A (p.His817Gln)
ClinVarID: 100224
CAID: CA228345
gnomAD: MAF of 0.1150 (8626/75016 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6036483-A-T?dataset=gnomad_r4
Variant: c.3258C > T, p.(Tyr1086 =)
HGVS: NM_000552.5:c.3258C>T (p.Tyr1086=)
ClinVarID: 256664
CAID: CA6402788
gnomAD: MAF of 0.1284 (9131/71128 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6023752-G-A?dataset=gnomad_r4
Variant: c.4414G > C p.(Asp1472His)
HGVS: NM_000552.5:c.4414G>C (p.Asp1472His)
ClinVarID: 256679
CAID: CA6402534
gnomAD: MAF of 0.5076 (38011/74882 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019004-C-G?dataset=gnomad_r4
Variant: c.6554G > A, p.(Arg2185Gln)
HGVS: NM_000552.5:c.6554G>A (p.Arg2185Gln)
ClinVarID: 100443
CAID: CA228748
gnomAD: MAF of 0.1927 (14427/74878 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-5993906-C-T?dataset=gnomad_r4
Variant: c.6647del, (Cys2216Phefs*9)
HGVS: NM_000552.5:c.6647del (p.Cys2216Phefs*9)
ClinVarID:
CAID: CA2695216024
gnomAD:
Variant: c.6859C > T, p.(Arg2287Trp)
HGVS: NM_000552.5:c.6859C>T (p.Arg2287Trp)
ClinVarID: 100450
CAID: CA228760
gnomAD: MAF of 0.008928 (670/75044 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-5985605-G-A?dataset=gnomad_r4
21 I
Case: Patient 21, Family I (Table 1.), F/97, Afro-Caribbean
DiseaseAssertion: VWD2A (IIE)
FamilyInfo: Patient 13 (F/65, Afro-Caribbean), Patient 22 (F/67, Afro-Caribbean), Patient 23 (F/86, Afro-Caribbean), Patient 24 (F/92, Afro-Caribbean), Patient 25 (F/62, Afro-Carribean) also from Family I. (Table 1.)
ParentalGenotype(s): NA
CasePresentingHPOs:
CaseHPOFreeRext: BAT =0, FVIII:C (IU/dL) = 35, VWF:Ag (IU/dL) = 25, VWF:Act (IU/dL) = 8
CaseNOTHPOs:
CaseNOTHPOFreeText: Blood group B+
CasePreviousTesting:
GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).
PreviouslyPublished: NA
Gene: VWF
Variant: c.1530G > A, p.(Val510 =) p.
HGVS: NM_000552.5:c.1530G>A (p.Val510=)
ClinVarID:
CAID: CA6403368
gnomAD: MAF of 0.00002198 (2/91004 alleles) in South Asian population https://gnomad.broadinstitute.org/variant/chr12-6062957-C-T?dataset=gnomad_r4
Variant: c.1892C > T, p.(Ala631Val)
HGVS: NM_000552.5:c.1892C>T (p.Ala631Val)
ClinVarID: 422844
CAID: CA6403245
gnomAD: MAF of 0.001908 (137/71810 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6056910-G-A?dataset=gnomad_r4
Variant: c.2220G > A, p.(Met740Ile)
HGVS: NM_000552.5:c.2220G>A (p.Met740Ile)
ClinVarID: 100206
CAID: CA201316
gnomAD: MAF of 0.1816 (13626/75022 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6046784-C-T?dataset=gnomad_r4
Variant: c.2451T > A, p.(His817Gln)
HGVS: NM_000552.5:c.2451T>A (p.His817Gln)
ClinVarID: 100224
CAID: CA228345
gnomAD: MAF of 0.1150 (8626/75016 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6036483-A-T?dataset=gnomad_r4
Variant: c.3258C > T, p.(Tyr1086 =)
HGVS: NM_000552.5:c.3258C>T (p.Tyr1086=)
ClinVarID: 256664
CAID: CA6402788
gnomAD: MAF of 0.1284 (9131/71128 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6023752-G-A?dataset=gnomad_r4
Variant: c.3445T > C, p.(Cys1149Arg)
HGVS: NM_000552.5:c.3445T>C (p.Cys1149Arg)
ClinVarID: 309
CAID: CA228410
gnomAD: MAF of 0.000003160 (1/316464 alleles) in European (non-Finnish) population https://gnomad.broadinstitute.org/variant/chr12-6022833-A-G?dataset=gnomad_r4
Variant: c.4414G > C p.(Asp1472His)
HGVS: NM_000552.5:c.4414G>C (p.Asp1472His)
ClinVarID: 256679
CAID: CA6402534
gnomAD: MAF of 0.5076 (38011/74882 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019004-C-G?dataset=gnomad_r4
Variant: c.6554G > A, p.(Arg2185Gln)
HGVS: NM_000552.5:c.6554G>A (p.Arg2185Gln)
ClinVarID: 100443
CAID: CA228748
gnomAD: MAF of 0.1927 (14427/74878 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-5993906-C-T?dataset=gnomad_r4
14 J
Case: Patient 14, Family J (Table 1.), M/36, Afro-Caribbean
DiseaseAssertion: VWD2A (IIE)
FamilyInfo: Patient 15 (F/64, Afro-Carribean) also from Family J. (Table 1.)
ParentalGenotype(s): NA
CasePresentingHPOs:
CaseHPOFreeRext: BAT =0, FVIII:C (IU/dL) = 25, VWF:Ag (IU/dL) = 25, VWF:Act (IU/dL) = 8
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).
PreviouslyPublished: NA
Gene: VWF
Variant: c.3505T > A, p.(Cys1169Ser)
HGVS: NM_000552.5:c.3505T>A (p.Cys1169Ser)
ClinVarID:
CAID: CA383511219
gnomAD:
Variant: c.4414G > C p.(Asp1472His)
HGVS: NM_000552.5:c.4414G>C (p.Asp1472His)
ClinVarID: 256679
CAID: CA6402534
gnomAD: MAF of 0.5076 (38011/74882 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019004-C-G?dataset=gnomad_r4
25 I
Case: Patient 25, Family I (Table 1.), F/62, Afro-Caribbean
DiseaseAssertion: VWD2A (IIE)
FamilyInfo: Patient 13 (F/65, Afro-Caribbean), Patient 21 (F/97, Afro-Caribbean), Patient 22 (F/67, Afro-Caribbean), Patient 23 (F/86, Afro-Caribbean), Patient 24 (F/92, Afro-Carribean) also from Family I. (Table 1.)
ParentalGenotype(s): NA
CasePresentingHPOs:
CaseHPOFreeRext: BAT =6, FVIII:C (IU/dL) = 16, VWF:Ag (IU/dL) = 25, VWF:Act (IU/dL) = 14
CaseNOTHPOs:
CaseNOTHPOFreeText: Blood group B+
CasePreviousTesting:
GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).
PreviouslyPublished: NA
Gene: VWF
Variant: c.1530G > A, p.(Val510 =) p.
HGVS: NM_000552.5:c.1530G>A (p.Val510=)
ClinVarID:
CAID: CA6403368
gnomAD: MAF of 0.00002198 (2/91004 alleles) in South Asian population https://gnomad.broadinstitute.org/variant/chr12-6062957-C-T?dataset=gnomad_r4
Variant: c.1892C > T, p.(Ala631Val)
HGVS: NM_000552.5:c.1892C>T (p.Ala631Val)
ClinVarID: 422844
CAID: CA6403245
gnomAD: MAF of 0.001908 (137/71810 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6056910-G-A?dataset=gnomad_r4
Variant: c.2220G > A, p.(Met740Ile)
HGVS: NM_000552.5:c.2220G>A (p.Met740Ile)
ClinVarID: 100206
CAID: CA201316
gnomAD: MAF of 0.1816 (13626/75022 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6046784-C-T?dataset=gnomad_r4
Variant: c.2451T > A, p.(His817Gln)
HGVS: NM_000552.5:c.2451T>A (p.His817Gln)
ClinVarID: 100224
CAID: CA228345
gnomAD: MAF of 0.1150 (8626/75016 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6036483-A-T?dataset=gnomad_r4
Variant: c.3258C > T, p.(Tyr1086 =)
HGVS: NM_000552.5:c.3258C>T (p.Tyr1086=)
ClinVarID: 256664
CAID: CA6402788
gnomAD: MAF of 0.1284 (9131/71128 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6023752-G-A?dataset=gnomad_r4
Variant: c.3445T > C, p.(Cys1149Arg)
HGVS: NM_000552.5:c.3445T>C (p.Cys1149Arg)
ClinVarID: 309
CAID: CA228410
gnomAD: MAF of 0.000003160 (1/316464 alleles) in European (non-Finnish) population https://gnomad.broadinstitute.org/variant/chr12-6022833-A-G?dataset=gnomad_r4
Variant: c.4138A > G, p.(Ile1380Val)
HGVS: NM_000552.5:c.4138A>G (p.Ile1380Val)
ClinVarID: 310063
CAID: CA6402595
gnomAD: MAF of 0.1184 (8878/74958 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019280-T-C?dataset=gnomad_r4
Variant: c.4304A > G, p.(Asn1435Ser)
HGVS: NM_000552.5:c.4304A>G (p.Asn1435Ser)
ClinVarID: 310062
CAID: CA6402552
gnomAD: MAF of 0.1124 (8427/74964 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019114-T-C?dataset=gnomad_r4
Variant: c.4414G > C p.(Asp1472His)
HGVS: NM_000552.5:c.4414G>C (p.Asp1472His)
ClinVarID: 256679
CAID: CA6402534
gnomAD: MAF of 0.5076 (38011/74882 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019004-C-G?dataset=gnomad_r4
Variant: c.6554G > A, p.(Arg2185Gln)
HGVS: NM_000552.5:c.6554G>A (p.Arg2185Gln)
ClinVarID: 100443
CAID: CA228748
gnomAD: MAF of 0.1927 (14427/74878 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-5993906-C-T?dataset=gnomad_r4
12 H
Case: Patient 12, Family H (Table 1.), F/99, Afro-Caribbean
DiseaseAssertion: VWD2A (IIE)
FamilyInfo: Patient 11 (M/71, Afro-Caribbean) also from Family H. (Table 1.)
ParentalGenotype(s): NA
CasePresentingHPOs:
CaseHPOFreeRext: BAT =8, FVIII:C (IU/dL) = 56, VWF:Ag (IU/dL) = 15, VWF:Act (IU/dL) = 24
CaseNOTHPOs:
CaseNOTHPOFreeText: Blood group O+
CasePreviousTesting:
GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).
PreviouslyPublished: NA
Gene: VWF
Variant: c.1530G > A, p.(Val510 =) p.
HGVS: NM_000552.5:c.1530G>A (p.Val510=)
ClinVarID:
CAID: CA6403368
gnomAD: MAF of 0.00002198 (2/91004 alleles) in South Asian population https://gnomad.broadinstitute.org/variant/chr12-6062957-C-T?dataset=gnomad_r4
Variant: c.1892C > T, p.(Ala631Val)
HGVS: NM_000552.5:c.1892C>T (p.Ala631Val)
ClinVarID: 422844
CAID: CA6403245
gnomAD: MAF of 0.001908 (137/71810 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6056910-G-A?dataset=gnomad_r4
Variant: c.2220G > A, p.(Met740Ile)
HGVS: NM_000552.5:c.2220G>A (p.Met740Ile)
ClinVarID: 100206
CAID: CA201316
gnomAD: MAF of 0.1816 (13626/75022 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6046784-C-T?dataset=gnomad_r4
Variant: c.2451T > A, p.(His817Gln)
HGVS: NM_000552.5:c.2451T>A (p.His817Gln)
ClinVarID: 100224
CAID: CA228345
gnomAD: MAF of 0.1150 (8626/75016 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6036483-A-T?dataset=gnomad_r4
Variant: c.3445T > C, p.(Cys1149Arg)
HGVS: NM_000552.5:c.3445T>C (p.Cys1149Arg)
ClinVarID: 309
CAID: CA228410
gnomAD: MAF of 0.000003160 (1/316464 alleles) in European (non-Finnish) population https://gnomad.broadinstitute.org/variant/chr12-6022833-A-G?dataset=gnomad_r4
Variant: c.4414G > C p.(Asp1472His)
HGVS: NM_000552.5:c.4414G>C (p.Asp1472His)
ClinVarID: 256679
CAID: CA6402534
gnomAD: MAF of 0.5076 (38011/74882 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019004-C-G?dataset=gnomad_r4
Variant: c.6554G > A, p.(Arg2185Gln)
HGVS: NM_000552.5:c.6554G>A (p.Arg2185Gln)
ClinVarID: 100443
CAID: CA228748
gnomAD: MAF of 0.1927 (14427/74878 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-5993906-C-T?dataset=gnomad_r4
3 B
Case: Patient 3, Family B (Table 1.), M/30, Afro-Caribbean
DiseaseAssertion: VWD2A (IIE)
FamilyInfo: Patient 5 (F/47, Afro-Caribbean) from same family B (Table 1.).
ParentalGenotype(s): NA
CasePresentingHPOs:
CaseHPOFreeRext: BAT = 4, FVIII:C (IU/dL) = 14, VWF:Ag (IU/dL) = 10, VWF:Act (IU/dL) = 4.9
CaseNOTHPOs:
CaseNOTHPOFreeText: Blood group O+
CasePreviousTesting:
GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).
PreviouslyPublished: NA
Gene: VWF
Variant: c.2739A > C, p.(Gly913 =)
HGVS: NM_000552.5:c.2739A>C p.(Gly913=)
ClinVarID: 1336650
CAID: CA6402959
gnomAD: MAF of 0.003374 (253/74996 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/12-6031525-T-G?dataset=gnomad_r4
Variant: c.2815G > A, p.(Gly939Arg)
HGVS: NM_000552.5:c.2815G>A (p.Gly939Arg)
ClinVarID: 2500546
CAID: CA6402950
gnomAD: MAF of 0.0009595 (72/75038 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/12-6031449-C-T?dataset=gnomad_r4
Variant: c.3101_3103delCCA (p.Thr1034del)
HGVS: NM_000552.5:c.3101_3103delCCA (p.Thr1034del)
ClinVarID: 802812
CAID: CA6402852
gnomAD: MAF of 0.01532 (1150/7504 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6025910-CTGG-C?dataset=gnomad_r4
Variant: c.4138A > G, p.(Ile1380Val)
HGVS: NM_000552.5:c.4138A>G (p.Ile1380Val)
ClinVarID: 310063
CAID: CA6402595
gnomAD: MAF of 0.1184 (8878/74958 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019280-T-C?dataset=gnomad_r4
Variant: c.4304A > G p.(Asn1435Ser)
HGVS: NM_000552.5:c.4304A>G (p.Asn1435Ser)
ClinVarID: 310062
CAID: CA6402552
gnomAD: MAF of 0.1124 (8427/74964 alleles) in Africa/African American population https://gnomad.broadinstitute.org/variant/chr12-6019114-T-C?dataset=gnomad_r4
Variant: c.4414G > C p.(Asp1472His)
HGVS: NM_000552.5:c.4414G>C (p.Asp1472His)
ClinVarID: 256679
CAID: CA6402534
gnomAD: MAF of 0.5076 (38011/74882 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019004-C-G?dataset=gnomad_r4
7 E
Case: Patient 7, Family E (Table 1.), M/47, Afro-Caribbean
DiseaseAssertion: VWD2A (IIE)
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs:
CaseHPOFreeRext: BAT = 1, FVIII:C (IU/dL) = 15, VWF:Ag (IU/dL) = 15, VWF:Act (IU/dL) = 11
CaseNOTHPOs:
CaseNOTHPOFreeText: Blood group O+
CasePreviousTesting:
GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).
PreviouslyPublished: NA
Gene: VWF
Variant: c.1530G > A, p.(Val510 =) p.
HGVS: NM_000552.5:c.1530G>A (p.Val510=)
ClinVarID:
CAID: CA6403368
gnomAD: MAF of 0.00002198 (2/91004 alleles) in South Asian population https://gnomad.broadinstitute.org/variant/chr12-6062957-C-T?dataset=gnomad_r4
Variant: c.1892C > T, p.(Ala631Val)
HGVS: NM_000552.5:c.1892C>T (p.Ala631Val)
ClinVarID: 422844
CAID: CA6403245
gnomAD: MAF of 0.001908 (137/71810 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6056910-G-A?dataset=gnomad_r4
Variant: c.2220G > A, p.(Met740Ile)
HGVS: NM_000552.5:c.2220G>A (p.Met740Ile)
ClinVarID: 100206
CAID: CA201316
gnomAD: MAF of 0.1816 (13626/75022 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6046784-C-T?dataset=gnomad_r4
Variant: c.2451T > A, p.(His817Gln)
HGVS: NM_000552.5:c.2451T>A (p.His817Gln)
ClinVarID: 100224
CAID: CA228345
gnomAD: MAF of 0.1150 (8626/75016 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6036483-A-T?dataset=gnomad_r4
Variant: c.3445T > C, p.(Cys1149Arg)
HGVS: NM_000552.5:c.3445T>C (p.Cys1149Arg)
ClinVarID: 309
CAID: CA228410
gnomAD: MAF of 0.000003160 (1/316464 alleles) in European (non-Finnish) population https://gnomad.broadinstitute.org/variant/chr12-6022833-A-G?dataset=gnomad_r4
Variant: c.4414G > C p.(Asp1472His)
HGVS: NM_000552.5:c.4414G>C (p.Asp1472His)
ClinVarID: 256679
CAID: CA6402534
gnomAD: MAF of 0.5076 (38011/74882 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019004-C-G?dataset=gnomad_r4
Variant: c.6554G > A, p.(Arg2185Gln)
HGVS: NM_000552.5:c.6554G>A (p.Arg2185Gln)
ClinVarID: 100443
CAID: CA228748
gnomAD: MAF of 0.1927 (14427/74878 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-5993906-C-T?dataset=gnomad_r4
6 D
Case: Patient 6, Family D (Table 1.), F/60, Afro-Caribbean
DiseaseAssertion: VWD2A (IIE)
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs:
CaseHPOFreeRext: BAT = 12, FVIII:C (IU/dL) = 13, VWF:Ag (IU/dL) = 10, VWF:Act (IU/dL) = 12
CaseNOTHPOs:
CaseNOTHPOFreeText: Blood group O+
CasePreviousTesting:
GenotypingMethod: All samples were analyzed by captured-based high throughput sequencing which was performed with a custom-design of the VWF gene provided by Twist BioScience (San Francisco, USA). It comprised all 52 exons, intronic flanking regions, promoter and 3’UTR region of the VWF gene. Libraries were prepared by using the Twist NGS target enrichment solution (Twist BioScience) according to the manufacturer protocol. Samples were analyzed on a NovaSeq 6000 sequencer (Illumina) with a median read depth of 2500X by using the 300-cycle S1 NovaSeq 6000seq reagent kit with 150-bp paired-end reads. The raw data were analyzed with Mutect21 and Vardict2 tools. The inhouse NGSreport software (CHU Lille) was used for data visualization, sequences check and conservation of variants with high quality metrics. In some cases, patients genomic DNA was screened for sequence variations (large deletions, insertions and duplications) by Multiplex Ligation-dependent Probe Amplification (MCR Holland).
PreviouslyPublished: NA
Gene: VWF
Variant: c.1530G > A, p.(Val510 =) p.
HGVS: NM_000552.5:c.1530G>A (p.Val510=)
ClinVarID:
CAID: CA6403368
gnomAD: MAF of 0.00002198 (2/91004 alleles) in South Asian population https://gnomad.broadinstitute.org/variant/chr12-6062957-C-T?dataset=gnomad_r4
Variant: c.2451T > A, p.(His817Gln)
HGVS: NM_000552.5:c.2451T>A (p.His817Gln)
ClinVarID: 100224
CAID: CA228345
gnomAD: MAF of 0.1150 (8626/75016 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6036483-A-T?dataset=gnomad_r4
Variant: c.3258C > T, p.(Tyr1086 =)
HGVS: NM_000552.5:c.3258C>T (p.Tyr1086=)
ClinVarID: 256664
CAID: CA6402788
gnomAD: MAF of 0.1284 (9131/71128 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6023752-G-A?dataset=gnomad_r4
Variant: c.3426T > C, p.(Cys1142 =)
HGVS: NM_000552.5:c.3426T>C (p.Cys1142=)
ClinVarID: 256668
CAID: CA6402757
gnomAD: MAF of 0.2077 (7935/38206 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6022852-A-G?dataset=gnomad_r4
Variant: c.3445T > C, p.(Cys1149Arg)
HGVS: NM_000552.5:c.3445T>C (p.Cys1149Arg)
ClinVarID: 309
CAID: CA228410
gnomAD: MAF of 0.000003160 (1/316464 alleles) in European (non-Finnish) population https://gnomad.broadinstitute.org/variant/chr12-6022833-A-G?dataset=gnomad_r4
Variant: c.3485C > T, p.(Pro1162Leu)
HGVS: NM_000552.5:c.3485C>T (p.Pro1162Leu)
ClinVarID: 256669
CAID: CA6402756
gnomAD: MAF of 0.2076 (7087/34136 alleles) African/African American population https://gnomad.broadinstitute.org/variant/chr12-6022793-G-A?dataset=gnomad_r4
Variant: c.3486A > G, p.(Pro1162 =)
HGVS: NM_000552.5:c.3486A>G (p.Pro1162=)
ClinVarID: 256670
CAID: CA6402755
gnomAD: MAF of 0.2083 (7074/33968 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6022792-T-C?dataset=gnomad_r4
Variant: c.4414G > C p.(Asp1472His)
HGVS: NM_000552.5:c.4414G>C (p.Asp1472His)
ClinVarID: 256679
CAID: CA6402534
gnomAD: MAF of 0.5076 (38011/74882 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6019004-C-G?dataset=gnomad_r4
Case#: 37006, Age 45, Female, Blood Type B+ (Table S3)
Disease Assertion: VWD 1
FamilyInfo: The patient is the only member of Family#3706.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: VWF:Ag:7.6, VWF:RCo:5, FVIII:C: 8.9, VWF:CB: 6.9
CaseNotHPOs: N/A
CaseNotHPOFreeText: Bleeding Score 5
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.
Gene: VWF
Variant: NM_000552.4:c.3426T>C (p.Cys1142=), NM_000552.4:c.3614G>A (p.Arg1205His), NM_000552.4:c.7771-49G>A , NM_000552.4:c.3485_3486delinsTG (pPro1162Leu)
ClinVar: 256668 , 308, 619934 ClinVar1 ClinVar2 ClinVar3
CAID: CA6402757, CA114160, CA1139532197, and CA658683073 CAID1 CAID2 CAID3 CAID4
gnomAD: MAF of 0.2228 (2240/ 10052 alleles) in the African population (CA6402757). gnomAD
Case#: 35004, Age 16, Male, Blood Type A+ (Table S3)
Disease Assertion: VWD 1
FamilyInfo: The patient is one of 4 members of Family# 3501. All members have the same variants, and patient 35001 has an additional variant.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding Score 6, VWF:Ag: 5.6, VWF:RCo: 7.9, FVIII:C: 19, VWF:CB: 7.8
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.
Gene: VWF
Variant: NM_000552.3:c.5198T>C (p.Leu1733Pro) and NM_000552.4:c.6187C>T (p.Pro2063Ser)
ClinVar: 100436 ClinVar
CAID: CA383496267 and CA202650 CAID1 CAID2
gnomAD: MAF of 0.04854 (1486/ 30616 alleles) in the South Asian population (CA202650). gnomAD
Case#: 21011, Age 54, Male, Blood Type A+ (Table S3)
Disease Assertion: VWD 1
FamilyInfo: The patient is the only member of Family#2111.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding Score 5, VWF:Ag: 12, VWF:RCo:20.3, FVIII:C 33, VWF:CB:16
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations
Gene: VWF
Variant: NP_000543.2:p.Ser83Ter (c.246_247insT)
ClinVar: N/A
CAID: PA1139532036 CAID
gnomAD: N/A
Case#: 02068, Age 58, Female, Blood Type O+ (Table S3)
Disease Assertion: VWD 1
FamilyInfo: Patient is the only member of family #0225
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding Score 13,VWF:Ag: 11, VWF:RCo: 9.2, FVIII:C: 46, VWF:CB:14
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations
Gene: VWF
Variant:NM_000552.4:c.6352C>T (p.Arg2118Trp) and NM_000552.4:c.8155+3G>C
ClinVar: 100490
CAID: CA6402006 and CA228825
gnomAD: MAF of 0.0001504 (3/19950 alleles) in the East Asian population (CA6402006).
Case#: 32004, Age 65, Female, Blood Type A-
Disease Assertion: VWD 1
FamilyInfo: The patient is the only member of Family#3204.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding Score 19, VWF:Ag: 9.8, VWF:RCo:4, FVIII:C: 6.3, VWF:CB: 5
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.
Gene: VWF
Variant: NM_000552.4:c.2821-123A>C (p.=)
ClinVar: N/A
CAID: CA1139532189 CAID
gnomAD: N/A
Case#: 01028, Age 8, Male, Blood type O+( Table S3)
Disease Assertion: VWD 1
FamilyInfo: Not listed
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding score 7, VWF:Ag: 21, VWF:RCo: 33, FVIII:C: 34, VWF:CB: 30
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.
Gene: VWF
Variant: NM_000552.4:c.4751A>G (p.Tyr1584Cys) and NM_000552.3:c.5312-19A>C
ClinVar: 310 and 806794
CAID: CA114162 and CA6402297 CAID1 CAID2
gnomAD: MAF of 0.004024 (519/128972 alleles) in the European (non-Finnish) population (CA114162). MAF of 0.002507 (26/10370 alleles) in the Ashkenazi Jewish population.
Case#: 23013, Age 46, Female, Blood Type O+ (Table S3)
Disease Assertion: VWD 1
FamilyInfo: The patient is the member of Family #2309.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding Score 0, VWF:Ag: 33, VWF:RCo: 27.5, FVIII:C:56, VWF:CB:26
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations
Gene: VWF
Variant: NM_000552.4:c.6911G>A (p.Cys2304Tyr)
ClinVar: 100451 ClinVar
CAID: CA228762 CAID
gnomAD: N/A
Case#: 36004, Age 69, Female, Blood Type O- (Table S3)
Disease Assertion: VWD 1
FamilyInfo: The patient is the only member of Family#3603.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: VWF:Ag: 22, VWF:RCo:18.5, FVIII:C: 19, VWF:CB: 19
CaseNotHPOs: N/A
CaseNotHPOFreeText: Bleeding Score 3
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.
Gene: VWF
Variant: NM_000552.4:c.2546+55G>T (p.=)
ClinVar: N/A
CAID: N/A
gnomAD: N/A
Case#: 10003, Age 33, Male, Blood Type A+ (Table S3)
Disease Assertion: VWD1
FamilyInfo: The patient and one other patient are members of Family#1002. The second member has the same exonic variant and also has an intronic variant.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding Score 1, VWF:Ag:7.4, VWF:RCo: 7.2, FVIII:C:11, VWF:CB: 6.3
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations
Gene: VWF
Variant: NM_000552.4:c.3614G>A (p.Arg1205His)
ClinVar: 308 ClinVar
CAID: CA114160 CAID
gnomAD: N/A
Molecular and clinical profile of von Willebrand disease in Spain (PCM-EVW-ES): comprehensive genetic analysis by next-generation sequencing of 480 patients
PMID: 28971901
Gene: von Willebrand Disease (VWF)
Case#: 36001, Age 5, Male, Blood Type A+ (Table S3)
Disease Assertion: VWD 1
FamilyInfo: The patient is the only member of Family#3601.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: VWF:Ag: 33, VWF:RCo: 26.4, FVIII:C: 88, VWF:CB: 58
CaseNotHPOs: N/A
CaseNotHPOFreeText: Bleeding Score 2
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.
Gene: VWF
Variant: NM_000552.4(VWF):c.5170+10C>T (p.=) and NM_000552.4(VWF):c.7730-1G>C (p.=)
ClinVar: 100418 and 100485 ClinVar1 ClinVar2
CAID: CA228702 and CA228816 CAID1 CAID2
gnomAD: MAF of 0.01298 (326/ 25116 alleles) in the European (Finnish) population (CA228702). gnomAD
Case#: 22006, Age 58, Male, Blood Type O+ (Table S3)
Disease Assertion: VWD 1
FamilyInfo: The patient is one of 2 patients in Family# 2206. Patient 22007's variant information was not described.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding Score 7, VWF:Ag: 27, VWF:RCo: 20, FVIII:C: 12, VWF:CB:22
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations
Gene: VWF
Variant:NM_000552.4:c.1001G>A (p.Gly334Glu) and NM_000552.4(VWF):c.2561G>A (p.Arg854Gln)
ClinVar: 626947 and 296 ClinVar1 ClinVar2
CAID: CA232322015 and CA114139 CAID1 CAID2
gnomAD: MAF of 0.000008824 (1/11326 alleles) in the European (non-Finnish) population (CA232322015). gnomAD1
MAF of 0.005692 (143/25122 alleles) in the European (Finnish) population (CA114139). gnomAD2
Case#: 13010, Age 37, Female, Blood Type O+ (Table S3)
Disease Assertion: VWD1
FamilyInfo: The patient is one of two members of Family#1308. Patient 13011 has one of the same exonic variant but has one different exonic variant (c.546G>A).
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding Score 18, VWF:Ag:16, VWF:RCo:15.1, FVIII:C:45, VWF:CB14
CaseNotHPOs: N/A
CaseNotHPOFreeText:N/A
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations
Gene: VWF
Variant: NM_000552.4:c.1472G>C(p.Arg491Pro) and NM_000552.4:c.546G>A (p.=)
ClinVar: 256684 ClinVar
CAID: CA383500718 and CA6403759 [CAID1] (http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383500718)
gnomAD: MAF of 0.002398 (85/35440 alleles) in the Latino population (CA6403759).
Case#: 30037, Age 69, Male, Blood Type O+ (Table S3)
Disease Assertion: VWD 1
FamilyInfo: The patient is the only member of Family# 3013
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: VWF:Ag: 20, VWF:RCo: 17, FVIII:C: 25, VWF:CB: 13
CaseNotHPOs: N/A
CaseNotHPOFreeText: Bleeding Score 1
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations.
Gene: VWF
Variant: NM_000552.4:c.5336G>T (p.Arg1779Leu)
ClinVar: N/A
CAID: CA383495656 CAID
gnomAD:MAF of 0.00002891 (1/ 34592 alleles) in the Latino population. gnomAD
Case#: 13012, Age 42, Male, Blood Type A+ (Table S3)
Disease Assertion: VWD 1
FamilyInfo: The patient is the only member of Family#1309.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: Bleeding score 7, VWF:Ag:14, VWF:RCo:9, FVIII:C: 20, VWF:CB:11
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations
Gene: VWF
Variant: NM_000552.4:c.3614G>A (p.Arg1205His) and
ClinVar: 308 ClinVar
CAID: CA114160 and CA6403769 CAID1 CAID2
gnomAD: MAF of 0.0005784 (20/34578 alleles) in the Latino population (CA6403769). gnomAD
Case#: 21023, Age 43, Female, Blood Type O+ (Table S3)
Disease Assertion: VWD 1
FamilyInfo: The patient is the only member of Family #2120.
Parental Genotype: Not listed
CasePresentingHPOs: N/A
CaseHPOFreeText: VWF:Ag:7.6, VWF:RCo:6, FVIII:C: 11, VWF:CB:3.9
CaseNotHPOs: N/A
CaseNotHPOFreeText: Bleeding Score 2
Protein Expression: N/A
CasePreviousTesting: 48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations
Gene: VWF
Variant: NM_000552.4:c.1110-26T>A (p.=) , NM_000552.4:c.2103C>T (p.Cys701=), and NM_000552.4:c.6248G>A (p.Gly2083Asp)
ClinVar: 310076 ClinVar1
CAID: CA6403542 , CA6403175, and CA383492072 CAID1 CAID2 CAID3
gnomAD: MAF of 0.008911 (222/ 24914 alleles) in the African population (CA6403542). MAF of 0.005928 (148/ 24968 alleles) in the African population (CA6403175). gnomAD1
Case#: 23012, Age 32, Female, Blood Type O+ (Table S3)
Disease Assertion: VWD 1
FamilyInfo: The patient is one of two members of Family# 2308. Patient 23011 has an additional exonic variant.
Parental Genotype: Not listed
CasePresentingHPOs:N/A
CaseHPOFreeText: Bleeding score 12, VWF:Ag:7, VWF:RCo:5.3, FVIII:C:6.5, VWF:CB:6
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
Protein Expression: N/A
CasePreviousTesting:48,48 Access-Array amplification. NGS Molecular analysis was performed. Sanger sequencing was used to validate selected mutations
Gene: VWF
Variant:NM_000552.4:c.3614G>A (p.Arg1205His)
ClinVar: 308 ClinVar
CAID:CA114160 CAID
gnomAD: N/A
P16
Case: P16, F/20
DiseaseAssertion: VWD1
FamilyInfo: No family history
ParentalGenotype: NA
CaseHPOFreeText: The bleeding score was 10, aPTT was 35 seconds, FVIII:C was 58%, VWF:RCo was 71 IU/dL, and VWF:Ag was 73 IU/dL, with a VWF:RCo/VWF:Ag ratio of 1.0. The VWF multimer pattern was normal, RIPA was not tested, and the platelet count was 250 × 10⁹/L.
CasePreviousTesting: NA
GenotypingMethod: Direct sequencing of all exons, flanking intronic sequences, and the promoter of VWF was performed.
Gene: VWF
Variant: no mutation detected
HGVS:
ClinVar:
CAID:
gnomAD:
P15
Case: P15, M/45
DiseaseAssertion: VWD1
FamilyInfo: Positive family history, no details provided.
ParentalGenotype: NA
CaseHPOFreeText: The bleeding score was 11, aPTT was 59 seconds, FVIII:C was 3%, VWF:RCo was 11 IU/dL, and VWF:Ag was 6 IU/dL, with a VWF:RCo/VWF:Ag ratio of 1.8. The VWF multimer pattern was normal, RIPA was 2 ohms, and the platelet count was 378 × 10⁹/L.
CasePreviousTesting: NA
GenotypingMethod: Direct sequencing of all exons, flanking intronic sequences, and the promoter of VWF was performed.
Gene: VWF
Variant: c.2574C>G, p.C858W — heterozygous
HGVS: NM_000552.5(VWF):c.2574C>G (p.Cys858Trp)
ClinVar:
CAID: CA232299278
gnomAD: https://gnomad.broadinstitute.org/variant/chr12-6034799-G-C?dataset=gnomad_r4
P14
Case: P14, M/19
DiseaseAssertion: VWD1
FamilyInfo: Positive family history, no details provided.
ParentalGenotype: NA
CaseHPOFreeText: The bleeding score was 1, aPTT was 46 seconds, FVIII:C was 38%, VWF:RCo was 49 IU/dL, and VWF:Ag was 24 IU/dL, with a VWF:RCo/VWF:Ag ratio of 2.0. The VWF multimer pattern was normal, RIPA was not tested, and the platelet count was 240 × 10⁹/L.
CasePreviousTesting: NA
GenotypingMethod: Direct sequencing of all exons, flanking intronic sequences, and the promoter of VWF was performed.
Gene: VWF
Variant: no mutation detected
HGVS:
ClinVar:
CAID:
gnomAD:
P13
Case: P13, M/15
DiseaseAssertion: VWD1
FamilyInfo: No family history
ParentalGenotype: NA
CaseHPOFreeText: The bleeding score was 5, aPTT was 35 seconds, FVIII:C was 64%, VWF:RCo was 62 IU/dL, and VWF:Ag was 57 IU/dL, with a VWF:RCo/VWF:Ag ratio of 1.1. The VWF multimer pattern was normal, RIPA was not tested, and the platelet count was 240 × 10⁹/L.
CasePreviousTesting: NA
GenotypingMethod: Direct sequencing of all exons, flanking intronic sequences, and the promoter of VWF was performed.
Gene: VWF
Variant: no mutation detected
HGVS:
ClinVar:
CAID:
gnomAD:
P12
Case: P12, M/18
DiseaseAssertion: VWD1
FamilyInfo: No family history
ParentalGenotype: NA
CaseHPOFreeText: The bleeding score was 4, aPTT was 37 seconds, FVIII:C was 46%, VWF:RCo was 42 IU/dL, and VWF:Ag was 27 IU/dL, with a VWF:RCo/VWF:Ag ratio of 1.6. The VWF multimer pattern was normal, RIPA was 10 ohms, and the platelet count was 250 × 10⁹/L.
CasePreviousTesting: NA
GenotypingMethod: Direct sequencing of all exons, flanking intronic sequences, and the promoter of VWF was performed.
Gene: VWF
Variant: no mutation detected
HGVS:
ClinVar:
CAID:
gnomAD:
Whole blood ristocetin-activated platelet impedance aggregometry (Multiplate) for the rapid detection of Von Willebrand disease
PMID: 28692107
Gene: VWF
HGNCID: 12726
von Willebrand factor propeptide missense variants affect anterograde transport to Golgi resulting in ER retention
Case: VWD cohort index patients (IPs)
DiseaseAssertion: congenital bleeding disorder
FamilyInfo: Six index patients (IPs), from VWD cohort of patients of Germany and Pakistan
ParentalGenotype(s):
CasePresentingHPOs: HP:0000006
CaseHPOFreeText: IP1 (VWF:Ag (IU/dl)=12), IP2 (WF:Ag (IU/dl)=1), IP3 (VWF:Ag (IU/dl)=29), IP4 (VWF:Ag (IU/dl)= 1), IP5 (VWF:Ag (IU/dl)=35), IP6 (VWF:Ag (IU/dl)= 1)
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Not provided
PreviouslyPublished:
Gene: VWF
Variant: IP1 c.164G>A (p.Gly55Glu), IP2 c.4019T>G, c.257T>A (p.Leu1340Arg , p.Val86Glu), IP3 c.571T>C (p.Trp191Arg), IP4 c.3797C>T, c.631A>G (p.Pro1266Leu, p.Asn211Asp) , IP5 c.3931C>T, c.1001G>A (p.Gln1311X,p.Gly334Glu) , IP6 c.2561G>A, c.1824C>G (p.Arg854Gln , p.Cys608Trp)
HGVS: NM_000552.4 and NP_000543.2
ClinVarID:https://www.ncbi.nlm.nih.gov/clinvar/?term=VWF%5Bgene%5D&redir=gene
CAID: 00311186–00311190
gnomAD:n/a
20
Case: Patient 20 (Family G), male, 58yo
DiseaseAssertion: VWD2B
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0030132, HP:0030129, HP:0030130, HP:0011871, HP:0012147
(Absence of large von Willebrand factor multimers, impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Impaired RIPA, Reduced quantity of VWF)
CaseHPOFreeText: blood group B, Platelet count x103/μl = 213, PFA 100 sec = >300, SPA % = 12.6, MADR mg/mL = 0.3, VWF:Ag U/dL = 48.4, VWF:CB U/dL = 4.6, VWF:CB ratio = 0.10, VWF:RCo U/dL = 13.5, VWF:RCo ratio = 0.28, Platelet VWF U/dL = 175, FVIII U/dL = 56.4, BAT F/M = 17
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: Sequencing of exon 28 of VWF
PreviouslyPublished: NA
Gene: VWF
Variant: c.3922C>T (p.Arg1308Cys)
HGVS: NM_000552.4(VWF):c.3922C>T (p.Arg1308Cys)
ClinVarID: 289; https://www.ncbi.nlm.nih.gov/clinvar/variation/289/
CAID: NA
gnomAD: absent
1
Case: Patient 1 (Family A), female, 3yo
DiseaseAssertion: VWD2B
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0030132, HP:0030129, HP:0030130, HP:0011871, HP:0012147
(Absence of large von Willebrand factor multimers, impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Impaired RIPA, Reduced quantity of VWF)
CaseHPOFreeText: blood group B, Platelet count x103/μl = 290, PFA 100 sec = >264, SPA % = NA, MADR mg/mL = NA, VWF:Ag U/dL = 41.0, VWF:CB U/dL = 4.4, VWF:CB ratio = 0.11, VWF:RCo U/dL = 13.2, VWF:RCo ratio = 0.33, Platelet VWF U/dL = 76.4, FVIII U/dL = 36.1, BAT F/M = NA
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: Sequencing of exon 28 of VWF
PreviouslyPublished: NA
Gene: VWF
Variant: c.3922C>T (p.Arg1308Cys)
HGVS: NM_000552.4(VWF):c.3922C>T (p.Arg1308Cys)
ClinVarID: 289; https://www.ncbi.nlm.nih.gov/clinvar/variation/289/
CAID: NA
gnomAD: absent
8
Case: Patient 8 (Family D), male, 49yo
DiseaseAssertion: VWD2B
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0030129, HP:0030130, HP:0011871, HP:0012147
(impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Impaired RIPA, Reduced quantity of VWF)
CaseHPOFreeText: blood group A, Platelet count x103/μl = 252, PFA 100 sec = 175, SPA % = 0, MADR mg/mL = 0.6, VWF:Ag U/dL = 54.3, VWF:CB U/dL = 55.1, VWF:CB ratio = 1.01, VWF:RCo U/dL = 51.6, VWF:RCo ratio = 0.94, Platelet VWF U/dL = 60.3, FVIII U/dL = 62.2, BAT F/M = NA
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: Sequencing of exon 28 of VWF
PreviouslyPublished: NA
Gene: VWF
Variant 1: c.4135C>T (p.Arg1379Cys)
HGVS: NM_000552.4(VWF):c.4135C>T (p.Arg1379Cys)
ClinVarID: 100333; https://www.ncbi.nlm.nih.gov/clinvar/variation/100333/
CAID: NA
gnomAD: MAF = 0.00003891 (5/128500 alleles) in the European (non-Finnish) population; https://gnomad.broadinstitute.org/variant/12-6128449-G-A?dataset=gnomad_r2_1
Variant 2: c.3797C>A (p.Pro1266Gln)
HGVS: NM_000552.4(VWF):c.3797C>A (p.Pro1266Gln)
ClinVarID: 100279; https://www.ncbi.nlm.nih.gov/clinvar/variation/100279/
CAID: NA
gnomAD: MAF = 0.001346 (41/30468 alleles; 2 homozygotes) in the South Asian population; https://gnomad.broadinstitute.org/variant/12-6128787-G-T?dataset=gnomad_r2_1
14
Case: Patient 14 (Family C), male, 39yo
DiseaseAssertion: VWD2B
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0030132, HP:0030129, HP:0030130, HP:0011871, HP:0012147
(Absence of large von Willebrand factor multimers, impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Impaired RIPA, Reduced quantity of VWF)
CaseHPOFreeText: blood group O, Platelet count x103/μl = 210, PFA 100 sec = >300, SPA % = 0, MADR mg/mL = 0.6, VWF:Ag U/dL = 61.3, VWF:CB U/dL = 10.4, VWF:CB ratio = 0.17, VWF:RCo U/dL = 18.5, VWF:RCo ratio = 0.3, Platelet VWF U/dL = 119, FVIII U/dL = 40.0, BAT F/M = 6
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: Sequencing of exon 28 of VWF
PreviouslyPublished: NA
Gene: VWF
Variant: c.3922C>T (p.Arg1308Cys)
HGVS: NM_000552.4(VWF):c.3922C>T (p.Arg1308Cys)
ClinVarID: 289; https://www.ncbi.nlm.nih.gov/clinvar/variation/289/
CAID: NA
gnomAD: absent
12
Case: Patient 12 (Family F), female, 50yo
DiseaseAssertion: VWD2B
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0030129, HP:0030130, HP:0011871, HP:0012147
(impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Impaired RIPA, Reduced quantity of VWF)
CaseHPOFreeText: blood group A, Platelet count x103/μl = 204, PFA 100 sec = 91, SPA % = 10, MADR mg/mL = 0.45, VWF:Ag U/dL = 108, VWF:CB U/dL = 101.9, VWF:CB ratio = 0.94, VWF:RCo U/dL = 97.7, VWF:RCo ratio = 0.91, Platelet VWF U/dL = 136.4, FVIII U/dL = 107.5, BAT F/M = 16
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: Sequencing of exon 28 of VWF
PreviouslyPublished: NA
Gene: VWF
Variant: c.3797C>A (p.Pro1266Gln)
HGVS: NM_000552.4(VWF):c.3797C>A (p.Pro1266Gln)
ClinVarID: 100279; https://www.ncbi.nlm.nih.gov/clinvar/variation/100279/
CAID: NA
gnomAD: MAF = 0.001346 (41/30468 alleles; 2 homozygotes) in the South Asian population; https://gnomad.broadinstitute.org/variant/12-6128787-G-T?dataset=gnomad_r2_1
2
Case: Patient 2 (Family A), male, 78yo
DiseaseAssertion: VWD2B
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0030132, HP:0030129, HP:0030130, HP:0011871, HP:0012147
(Absence of large von Willebrand factor multimers, impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Impaired RIPA, Reduced quantity of VWF)
CaseHPOFreeText: blood group O, Platelet count x103/μl = 119, PFA 100 sec = >300, SPA % = 7, MADR mg/mL = 0.75, VWF:Ag U/dL = 44.7, VWF:CB U/dL = 11.8, VWF:CB ratio = 0.27, VWF:RCo U/dL = 28.4, VWF:RCo ratio = 0.63, Platelet VWF U/dL = 115, FVIII U/dL = 48.2, BAT F/M = 1
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: Sequencing of exon 28 of VWF
PreviouslyPublished: NA
Gene: VWF
Variant: c.3922C>T (p.Arg1308Cys)
HGVS: NM_000552.4(VWF):c.3922C>T (p.Arg1308Cys)
ClinVarID: 289; https://www.ncbi.nlm.nih.gov/clinvar/variation/289/
CAID: NA
gnomAD: absent
5
Case: Patient 5 (Family C), female, 50yo
DiseaseAssertion: VWD2B
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0030129, HP:0030130, HP:0011871, HP:0012147
(impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Impaired RIPA, Reduced quantity of VWF)
CaseHPOFreeText: blood group O, Platelet count x103/μl = 211, PFA 100 sec = 210, SPA % = 10, MADR mg/mL = 0.6, VWF:Ag U/dL = 40.6, VWF:CB U/dL = 42.8, VWF:CB ratio = 1.1, VWF:RCo U/dL = NA, VWF:RCo ratio = NA, Platelet VWF U/dL = 41.2, FVIII U/dL = 62.8, BAT F/M = 8
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: Sequencing of exon 28 of VWF
PreviouslyPublished: NA
Gene: VWF
Variant: c.4135C>T (p.Arg1379Cys)
HGVS: NM_000552.4(VWF):c.4135C>T (p.Arg1379Cys)
ClinVarID: 100333; https://www.ncbi.nlm.nih.gov/clinvar/variation/100333/
CAID: NA
gnomAD: MAF = 0.00003891 (5/128500 alleles) in the European (non-Finnish) population; https://gnomad.broadinstitute.org/variant/12-6128449-G-A?dataset=gnomad_r2_1
18
Case: Patient 18 (Family E), female, 1yo
DiseaseAssertion: VWD2B
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0030132, HP:0030129, HP:0030130, HP:0011871, HP:0012147
(Absence of large von Willebrand factor multimers, impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Impaired RIPA, Reduced quantity of VWF)
CaseHPOFreeText: blood group O, Platelet count x103/μl = 28, PFA 100 sec = >300, SPA % = NA, MADR mg/mL = NA, VWF:Ag U/dL = 142.9, VWF:CB U/dL = 97.0, VWF:CB ratio = 0.68, VWF:RCo U/dL = 102.7, VWF:RCo ratio = 0.72, Platelet VWF U/dL = 135, FVIII U/dL = 98.1, BAT F/M = NA
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: Sequencing of exon 28 of VWF
PreviouslyPublished: NA
Gene: VWF
Variant: c.3946G>A (p.Val1316Met)
HGVS: NM_000552.4(VWF):c.3946G>A (p.Val1316Met)
ClinVarID: 290; https://www.ncbi.nlm.nih.gov/clinvar/variation/290/
CAID: NA
gnomAD: absent
12
Case: Patient 12 (Family C), female, 60yo
DiseaseAssertion: VWD2B
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0030132, HP:0030129, HP:0030130, HP:0011871, HP:0012147
(Absence of large von Willebrand factor multimers, impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Impaired RIPA, Reduced quantity of VWF)
CaseHPOFreeText: blood group O, Platelet count x103/μl = 154, PFA 100 sec = >300, SPA % = NA, MADR mg/mL = 0.75, VWF:Ag U/dL = 44.6, VWF:CB U/dL = 8.1, VWF:CB ratio = 0.18, VWF:RCo U/dL = 23.0, VWF:RCo ratio = 0.51, Platelet VWF U/dL = 127, FVIII U/dL = 68.0, BAT F/M = 18
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: Sequencing of exon 28 of VWF
PreviouslyPublished: NA
Gene: VWF
Variant: c.3922C>T (p.Arg1308Cys)
HGVS: NM_000552.4(VWF):c.3922C>T (p.Arg1308Cys)
ClinVarID: 289; https://www.ncbi.nlm.nih.gov/clinvar/variation/289/
CAID: NA
gnomAD: absent
7
Case: Patient 7 (Family C), female, 21yo
DiseaseAssertion: VWD2B
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0030129, HP:0030130, HP:0011871, HP:0012147
(impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Impaired RIPA, Reduced quantity of VWF)
CaseHPOFreeText: blood group O, Platelet count x103/μl = 293, PFA 100 sec = >300, SPA % = 6, MADR mg/mL = 0.6, VWF:Ag U/dL = 26.7, VWF:CB U/dL = 27.2, VWF:CB ratio = 1.01, VWF:RCo U/dL = 25.8, VWF:RCo ratio = 0.92, Platelet VWF U/dL = 59.1, FVIII U/dL = 40.9, BAT F/M = 6
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: Sequencing of exon 28 of VWF
PreviouslyPublished: NA
Gene: VWF
Variant: c.4135C>T (p.Arg1379Cys)
HGVS: NM_000552.4(VWF):c.4135C>T (p.Arg1379Cys)
ClinVarID: 100333; https://www.ncbi.nlm.nih.gov/clinvar/variation/100333/
CAID: NA
gnomAD: MAF = 0.00003891 (5/128500 alleles) in the European (non-Finnish) population; https://gnomad.broadinstitute.org/variant/12-6128449-G-A?dataset=gnomad_r2_1
9
Case: Patient 9 (Family D), male, 18yo
DiseaseAssertion: VWD2B
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0030129, HP:0030130, HP:0011871, HP:0012147
(impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Impaired RIPA, Reduced quantity of VWF)
CaseHPOFreeText: blood group A, Platelet count x103/μl = 231, PFA 100 sec = 95, SPA % = 0, MADR mg/mL = 0.75, VWF:Ag U/dL = 151.1, VWF:CB U/dL = 175.5, VWF:CB ratio = 1.16, VWF:RCo U/dL = 153.5, VWF:RCo ratio = 0.87, Platelet VWF U/dL = 95.2, FVIII U/dL = 148.2, BAT F/M = NA
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: Sequencing of exon 28 of VWF
PreviouslyPublished: NA
Gene: VWF
Variant: c.3797C>A (p.Pro1266Gln)
HGVS: NM_000552.4(VWF):c.3797C>A (p.Pro1266Gln)
ClinVarID: 100279; https://www.ncbi.nlm.nih.gov/clinvar/variation/100279/
CAID: NA
gnomAD: MAF = 0.001346 (41/30468 alleles; 2 homozygotes) in the South Asian population; https://gnomad.broadinstitute.org/variant/12-6128787-G-T?dataset=gnomad_r2_1
16
Case: Patient 16 (Family D), male, 67yo
DiseaseAssertion: VWD2B
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0030132, HP:0030129, HP:0030130, HP:0011871, HP:0012147
(Absence of large von Willebrand factor multimers, impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity, Impaired RIPA, Reduced quantity of VWF)
CaseHPOFreeText: blood group O, Platelet count x103/μl = 60, PFA 100 sec = >300, SPA % = 20, MADR mg/mL = 0.15, VWF:Ag U/dL = 34.3, VWF:CB U/dL = 10.5, VWF:CB ratio = 0.31, VWF:RCo U/dL = 14.0, VWF:RCo ratio = 0.41, Platelet VWF U/dL = 142.50, FVIII U/dL = 43.5, BAT F/M = 20
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: Sequencing of exon 28 of VWF
PreviouslyPublished: NA
Gene: VWF
Variant: c.3946G>A (p.Val1316Met)
HGVS: NM_000552.4(VWF):c.3946G>A (p.Val1316Met)
ClinVarID: 290; https://www.ncbi.nlm.nih.gov/clinvar/variation/290/
CAID: NA
gnomAD: absent
von Willebrand Factor (VWF) Inhibitors in Two Brothers with von Willebrand Disease: A Case Report
PMID: 40673043
Gene: VWF
HGNCID: HGNC:12726
T154M/16240.010.030.01c.1656_1657insT, c.8418_8419insTCCCp.Trp552 fs, p.Ser2807 fs14/52Compound heterozygous
Case: T154, M, 16
DiseaseAssertion: VWD type 3
FamilyInfo: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: Bleeding Score: 24 (Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.01, VWF:RCo (IU/ml): 0.03, FVIII:C (IU/ml): 0.01
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.1656_1657insT (p.Trp552 fs), Exon 14
c.8418_8419insTCCC (p.Ser2807 fs), Exon 52
Compound heterozygous
Note: ELISA-based assay for detecting alloantibodies, genomic analysis via sequencing of leukocytes for the VWF gene including exons 1-52 and about 1.5 km of VWF promoter, PCR amplification for variant confirmation, SALSA-MLPAVWF assay evaluation for partial/total gene deletions when sequencing did not reveal pathogenic explanation
T065M/15220.010.020.01c.3303C>Ap.Cys1101*25Homozygous
Case: T065, M, 15
DiseaseAssertion: VWD type 3
FamilyInfo: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: Bleeding Score: 22 (Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.01, VWF:RCo (IU/ml): 0.02, FVIII:C (IU/ml): 0.01
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.3303C>A (p.Cys1101*), Exon 25, Homozygous
Note: ELISA-based assay for detecting alloantibodies, genomic analysis via sequencing of leukocytes for the VWF gene including exons 1-52 and about 1.5 km of VWF promoter, PCR amplification for variant confirmation, SALSA-MLPAVWF assay evaluation for partial/total gene deletions when sequencing did not reveal pathogenic explanation
T099F/3180.040.020.06c.1750_1765delinsCGp.Cys584_Ser589delinsArg15Heterozygous
Case: T099, F, 3
DiseaseAssertion: VWD type 3
FamilyInfo: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: Bleeding Score: 18 (Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.04, VWF:RCo (IU/ml): 0.02, FVIII:C (IU/ml): 0.06
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.1750_1765delinsCG (p.Cys584_Ser589delinsArg), Exon 15, Heterozygous
Note: ELISA-based assay for detecting alloantibodies, genomic analysis via sequencing of leukocytes for the VWF gene including exons 1-52 and about 1.5 km of VWF promoter, PCR amplification for variant confirmation, SALSA-MLPAVWF assay evaluation for partial/total gene deletions when sequencing did not reveal pathogenic explanation
T110F/41230.010.010.02c.8418_8419insTCCCp.Ser2807 fs52Homozygous
Case: T110, F, 41
DiseaseAssertion: VWD type 3
FamilyInfo: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: Bleeding Score: 23 (Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.01, VWF:RCo (IU/ml): 0.01, FVIII:C (IU/ml): 0.02
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.8418_8419insTCCC (p.Ser2807 fs), Exon 52, Homozygous
Note: ELISA-based assay for detecting alloantibodies, genomic analysis via sequencing of leukocytes for the VWF gene including exons 1-52 and about 1.5 km of VWF promoter, PCR amplification for variant confirmation, SALSA-MLPAVWF assay evaluation for partial/total gene deletions when sequencing did not reveal pathogenic explanation
T018F/18120.040.000.03c.7399C>T, c.8418_8419insTCCCp.Gln2467*, p.Ser2807 fs43/52Compound heterozygous
Case: T018, F, 12
DiseaseAssertion: VWD type 3
FamilyInfo: n/a
CasePresentingHPOs: HP:0000421
CaseHPOFreeText: Bleeding Score: 12 (Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.04, VWF:RCo (IU/ml): 0.00, FVIII:C (IU/ml): 0.03, inhibitor positive
CaseNotHPOs: has not developed any anaphylactic reactions and/or become refractory to replacement therapy
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.7399C>T (p.Gln2467*), Exon 43
c.8418_8419insTCCC (p.Ser2807 fs), Exon 52
Compound heterozygous
Note: ELISA-based assay for detecting alloantibodies, genomic analysis via sequencing of leukocytes for the VWF gene including exons 1-52 and about 1.5 km of VWF promoter, PCR amplification for variant confirmation, SALSA-MLPAVWF assay evaluation for partial/total gene deletions when sequencing did not reveal pathogenic explanation
T030M/6670.030.010.09c.-2328T>G, c.2220G>A, c.3379 + 7A>C, c.3539-33G>A, c.3539-49C>T, c.4414dupC, c.5620 + 33-40delA, c.6554G>A, c.6902-5T>A, c.8418_8419insTCCCp.Met740Ile, p.His1472 fs, p.Arg2185Gln, p.Ser2807 fs28/52Compound heterozygous
Case: T030, M, 66
DiseaseAssertion: VWD type 3
FamilyInfo: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: Bleeding Score: 7 (Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.03, VWF:RCo (IU/ml): 0.01, FVIII:C (IU/ml): 0.09
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.-2328T>G
c.2220G>A (p.Met740Ile)
c.3379 + 7A>C
c.3539-33G>A
c.3539-49C>T
c.4414dupC (p.His1472 fs)
c.5620 + 33-40delA
c.6554G>A (p.Arg2185Gln)
c.6902-5T>A
c.8418_8419insTCCC (p.Ser2807 fs)
Exon 28/52
Compound heterozygous
Note: ELISA-based assay for detecting alloantibodies, genomic analysis via sequencing of leukocytes for the VWF gene including exons 1-52 and about 1.5 km of VWF promoter, PCR amplification for variant confirmation, SALSA-MLPAVWF assay evaluation for partial/total gene deletions when sequencing did not reveal pathogenic explanation
T036F/41250.010.010.01c.5180_5181insTTp.Leu1727 fs30Homozygous
Case: T036, F, 41
DiseaseAssertion: VWD type 3
FamilyInfo: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: Bleeding Score: 25 (Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.01, VWF:RCo (IU/ml): 0.01, FVIII:C (IU/ml) : 0.01
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.5180_5181insTT (p.Leu1727 fs), Exon 30, Homozygous
Note: ELISA-based assay for detecting alloantibodies, genomic analysis via sequencing of leukocytes for the VWF gene including exons 1-52 and about 1.5 km of VWF promoter, PCR amplification for variant confirmation, SALSA-MLPAVWF assay evaluation for partial/total gene deletions when sequencing did not reveal pathogenic explanation
T141F/16130.040.040.06c.817T>Cp.Arg273Trp7Homozygous
Case: T141, F, 16
DiseaseAssertion: VWD type 3
FamilyInfo: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: Bleeding Score: 13 (Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.04, VWF:RCo (IU/ml): 0.04, FVIII:C (IU/ml): 0.06
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.817T>C (p.Arg273Trp), Exon 7, Homozygous
Note: ELISA-based assay for detecting alloantibodies, genomic analysis via sequencing of leukocytes for the VWF gene including exons 1-52 and about 1.5 km of VWF promoter, PCR amplification for variant confirmation, SALSA-MLPAVWF assay evaluation for partial/total gene deletions when sequencing did not reveal pathogenic explanation
T093M/8100.020.020.04c.6709T>C, c.220 + 20G>Tp.Cys2237Arg, -38Homozygous
Case: T093, M, 8
DiseaseAssertion: VWD type 3
FamilyInfo: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: Bleeding Score: 10 (Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.02, VWF:RCo (IU/ml): 0.02, FVIII:C (IU/ml): 0.04
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.6709T>C (p.Cys2237Arg), Exon 38
c.220 + 20G>T
Homozygous
Note: ELISA-based assay for detecting alloantibodies, genomic analysis via sequencing of leukocytes for the VWF gene including exons 1-52 and about 1.5 km of VWF promoter, PCR amplification for variant confirmation, SALSA-MLPAVWF assay evaluation for partial/total gene deletions when sequencing did not reveal pathogenic explanation
T118F/3080.020.000.05c.8418_8419insTCCCp.Ser2807 fs52Homozygous
Case: T118, F, 30
DiseaseAssertion: VWD type 3
FamilyInfo: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: Bleeding Score: 8 (Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.02, VWF:RCo (IU/ml): 0.00, FVIII:C (IU/ml): 0.05
CaseNotHPOs: n/a
CaseNotHPOFreeText: n/a
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.8418_8419insTCCC (p.Ser2807 fs), Exon 52, Homozygous
Note: ELISA-based assay for detecting alloantibodies, genomic analysis via sequencing of leukocytes for the VWF gene including exons 1-52 and about 1.5 km of VWF promoter, PCR amplification for variant confirmation, SALSA-MLPAVWF assay evaluation for partial/total gene deletions when sequencing did not reveal pathogenic explanation
Criteria for low von Willebrand factor diagnosis and risk score to predict future bleeding
PMID: 33370487
Gene: VWF
A Novel Case of Compound Heterozygous Type 3Von Willebrand Disease
PMID: unknown
Gene: VWF
HGNCID: 12726
Case: 2 year old female
DiseaseAssertion: type 3 VWD
FamilyInfo: 27 year old parents with no history of abnormal bleeding, non-consanguineous. Older brother (4 years old) with symptoms, younger brother asymptomatic.
ParentalGenotype(s): Mother is heterozygous for c.2345del variant. Father is heterozygous for exon 6 deletion.
CasePresentingHPOs: HP:0001934, HP:0000978, HP:0000225, HP:0001058, HP:0001058, HP:0012147, HP:0030132
CaseHPOFreeRext: reduced VWF activity
CaseNOTHPOs: HP:0001873, HP:0008151
CaseNOTHPOFreeText: reduced factor VIII
CasePreviousTesting: n/a
GenotypingMethod: unknown
PreviouslyPublished: n/a
Gene: VWF
Variant: compound heterozygous c2345delC in exon 18 and deletion in exon 6
HGVS: NM_000552.5:c.2435del p. (Pro812ArgfsTer31)
ClinVarID: 303
CAID:
gnomAD: 0.00007187 (11/1613916 alleles) https://gnomad.broadinstitute.org/variant/12-6044297-CG-C?dataset=gnomad_r4
proband (II-4 in Fig. 1) had melena at 50 years of age,
Case II-4: Male, Japan, Japanese, part of Family<br /> DiseaseAssertion: VWD2M<br /> FamilyInfo: Japanese; Fig.1; epistaxis and bleeding described and highlighted in text<br /> ParentalGenotype: Consanguineous <br /> CasePresentingHPOs: HP:0002249 (melena), HP:0000421 (epistaxis), HP:0004846 (prolonged bleeding after surgery)<br /> CaseHPOFreeText: Melena at 50 years of age, Left putinamal hemorrhaging at 58 years of age, bleeding time was 30 min<br /> CaseNotHPOs:<br /> NotHPOsFreeText: platelet count, prothrombin time were normal<br /> CasePreviousTesting: Proband's VWF gene was analyzed using an enzyme-linked immunosorbent assay kit and PCR was done. Clinical bleeding expression was estimated.<br /> Gene: VWF<br /> Variant: p.Leu1733Pro mutation <br /> ClinVar:<br /> CAID:<br /> gnomAD:
Role of red blood cells in the anemia‐associated bleeding under high shear conditions
PMID: 28470853
Gene: VWF
HGNCID: 12726
A 30‐year‐old male patient
Case#: Patient B, Male, Age 30, Chinese
Disease Assertion: VWD3
FamilyInfo: Consanguineous marriage between parents. Parents had 2 daughters and a son. One daughter died (1 year old) due to bleeding disorder. Mother's VWF:Ag 58% and VWF:RCo 36%. Family pedigree in Figure 2 (a). Both parents were heterozygous carriers of the variant.
Parental Genotype: Both Heterozygous
CasePresentingHPOs: HP:0003645
(Prolonged partial thromboplastin time)
CaseHPOFreeText: Hematoma in the lower extremity, VWF:Ag: 0.5%, VWF:RCo: 0.1%, FVIII:C 1.2%, APTT: 72.0 s
CaseNotHPOs:
CaseNotHPOFreeText: PT: 13.6 s, TT: 14.9s
Protein Expression: N/A
CasePreviousTesting: NGS targeting all exons and covered F8, F9, and VWF genes; and Sanger Sequencing
Gene: VWF
Variant: NM_000552.4:c.6450C>A
ClinVar: N/A
CAID: CA383491381 CAID
gnomAD:N/A
Two cases of von Willebrand disease type 3 in consanguineous Chinese families
PMID: 31793247
Gene: von Willebrand Factor (VWF)
A 23‐year‐old female
Case#: Patient A, Female, Age 23, Chinese
Disease Assertion: VWD3
FamilyInfo: Family pedigree in figure 1(a). Consanguineous marriage between parents. Parents had a boy who died (1 year old) due to heavy nose bleeds. Parents were heterozygous carriers for the variant.
Parental Genotype: Both parents were heterozygous
CasePresentingHPOs: HP:0000132, HP:0003645, HP:0008151
(Menorrhagia, Prolonged partial thromboplastin time, Prolonged prothrombin time)
CaseHPOFreeText: Scalp hematoma, FVIII:C: 1.3%, VWF:Ag: 3.6%, VWF:RCo: <1.0%, PT: 15.9 s, APTT: 62.7 s
CaseNotHPOs: N/A
CaseNotHPOFreeText: TT: 14.9 s
Protein Expression: N/A
CasePreviousTesting: NGS targeting all exons and covered F8,F9, and VWF genes; and Sanger Sequencing
Gene: VWF
Variant: NM_000552.4(VWF):c.4696C>T (p.Arg1566Ter)
ClinVar:100382 ClinVarID
CAID: CA228639
gnomAD: MAF of 0.00001762 (2/113480 alleles) in the European (Non- Finnish) population.
Case: Case 2, male, hispanic, symptom onset at birth
DiseaseAssertion: Platelet-type VWD (PT-VWD)
FamilyInfo: Parents were tested for platelet antigen 5a (HPA5a): mother was negative and father was positive, parents had normal VWD panels including VWF multimer and RIPA test
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0004846, HP:0000978, HP:0001873, HP:0012541, HP:0030132
(Prolonged bleeding after surgery, easy bruising, thrombocytopenia, Cephalohematoma, Absence of large von Willebrand factor multimers)
CaseHPOFreeText: peripheral blood smear showed platelet clumping and large granular platelets, Platelet (×109/L) = 61, Factor VIII (IU/mL) = 0.94, VWF:Ag (IU/mL) = 0.88, VWF:RCo (IU/mL) = 0.34, VWF:CB (IU/mL) = ND, RCo/Ag ratio = 0.39, CB/Ag ratio = NA, VWF: HMW Multimers = absent
CaseNOTHPOs: NA
CaseNOTHPOFreeText: umbilical cord bleeding, bleeding after heel stick
CasePreviousTesting: no mutations in exon 28 of VWF gene
GenotypingMethod: NA
PreviouslyPublished: NA
Gene: GP1BA
Variant: c.763A>G (p.Met255Val)
HGVS: NM_000173.7(GP1BA):c.763A>G (p.Met255Val)
ClinVarID: 4155; https://www.ncbi.nlm.nih.gov/clinvar/variation/4155/
CAID:
gnomAD: absent
Case: Case 3, female
DiseaseAssertion: Platelet-type VWD (PT-VWD)
FamilyInfo: NA
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0000978, HP:0000421, HP:0000132, HP:0004846, HP:0001873, HP:0030129, HP:0030132
(easy bruising, epistaxis, Menorrhagia, Prolonged bleeding after surgery, thrombocytopenia, Impaired ristocetin cofactor assay activity, Absence of large von Willebrand factor multimers)
CaseHPOFreeText: pregnancy complicated by progressive thrombocytopenia; Platelet (×109/L) = 135, Factor VIII (IU/mL) = 0.78, VWF:Ag (IU/mL) = 0.69, VWF:RCo (IU/mL) = 0.22, VWF:CB (IU/mL) = ND, RCo/Ag ratio = 0.32, CB/Ag ratio = ND, VWF: HMW Multimers = absent
CaseNOTHPOs: NA
CaseNOTHPOFreeText: NA
CasePreviousTesting: NA
GenotypingMethod: NA
PreviouslyPublished: NA
Gene: GP1BA
Variant: c.746G>T (p.Gly249Val)
HGVS: NM_000173.7(GP1BA):c.746G>T (p.Gly249Val)
ClinVarID: 4153; https://www.ncbi.nlm.nih.gov/clinvar/variation/4153/
CAID:
gnomAD: absent
Case: Case 1, male, 13yo at assessment, symptom onset at 45 days old
DiseaseAssertion: Platelet-type VWD (PT-VWD)
FamilyInfo: 1 symptomatic sister (menorrhagia, hemorrhagic follicular cyst); 1 asymptomatic sister; 3 brothers: twin died at 45days old due to leukemia, 1 symptomatic with daily epistaxis, 1 asymptomatic; father had bleeding symptoms; mom had severe bleeding with c-section requiring hysterectomy
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0001973, HP:0001892, HP:0000421, HP:0000979, HP:0001873, HP:0002090, HP:0000023, HP:0030132, HP:0011871
(Autoimmune thrombocytopenia, abnormal bleeding, epistaxis, purpura, thrombocytopenia, pneumonia, inguinal hernia, Absence of large von Willebrand factor multimers, impaired RIPA)
CaseHPOFreeText: bleeding treated with intravenous gamma-globulin (IVIg) and corticosteroids, laparoscopic splenectomy complicated by massive intraperitoneal bleeding, multiple bone marrow aspirations performed; born via c-section of twin pregnancy due to placenta previa; mepacrine uptake assay by flow cytometry was normal, Blood smear showed very large platelets with clear signs of activation and pseudopods; Platelet (×109/L) = 95, Factor VIII (IU/mL) = 1.00, VWF:Ag (IU/mL) = 1.29, VWF:RCo (IU/mL) = 0.28, VWF:CB (IU/mL) = 0.70, RCo/Ag ratio = 0.22, CB/Ag ratio = 0.54, VWF: HMW Multimers = partial loss
CaseNOTHPOs: NA
CaseNOTHPOFreeText: NA
CasePreviousTesting: NA
GenotypingMethod: NA
PreviouslyPublished: NA
Gene: GP1BA
Variant: c.763A>G (p.Met255Val)
HGVS: NM_000173.7(GP1BA):c.763A>G (p.Met255Val)
ClinVarID: 4155; https://www.ncbi.nlm.nih.gov/clinvar/variation/4155/
CAID:
gnomAD: absent
Case: Case 4, female, 5yo at onset, 20yo at report
DiseaseAssertion: Platelet-type VWD (PT-VWD)
FamilyInfo: Fhx of VWD; father diagnosed with type 2B VWD
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0000978, HP:0000421, HP:0000132, HP:0001873, HP:0004846
(easy bruising, epistaxis, menorrhagia, thrombocytopenia, Prolonged bleeding after surgery)
CaseHPOFreeText: pregnancy complicated by thrombocytopenia, Platelet aggregation studies were normal to ADP, epinephrine, collagen, and arachidonic; Platelet (×109/L) = 156, Factor VIII (IU/mL) = ND, VWF:Ag (IU/mL) = 0.57, VWF:RCo (IU/mL) = 0.86, VWF:CB (IU/mL) = ND, RCo/Ag ratio = 1.15, CB/Ag ratio = ND, VWF: HMW Multimers = normal
CaseNOTHPOs: NA
CaseNOTHPOFreeText: NA
CasePreviousTesting: no mutations in exon 28 of the VWF gene
GenotypingMethod: NA
PreviouslyPublished: NA
Gene: GP1BA
Variant: c.746G>T (p.Gly249Val)
HGVS: NM_000173.7(GP1BA):c.746G>T (p.Gly249Val)
ClinVarID: 4153; https://www.ncbi.nlm.nih.gov/clinvar/variation/4153/
CAID:
gnomAD: absent
10 Type 2A c.3610C > T Nc.3839T > C Np.Arg1204Trpp.Phe1280Ser2728D3-E3A1htzhtzMissenseMissensena 26 14 34
Case: 10 (also in (also in row 10 table 6)
DiseaseAssertion: type 2A VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeRext: VWF:Ag [IU/dL] = 26; VWF:Ac [IU/dL] = 14; FVIII:C [IU/dL] = 34
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.3610C>T p.Arg1204Trp
HGVS:
ClinVarID: 2682106
CAID:
gnomAD: absent
MultipleGeneVariants:
Gene: VWF
Variant: c.3839T>C p.Phe1280Ser
CAID: CA383506874
gonmAD: absent
8 Type2A (IIC)c.1915C>TN p.Arg639Cys 15 D2-C8-2htz Missense O 68 49 76
Case: IP #8 (also in row 5 table 6)
DiseaseAssertion: type 2A (IIC) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032442 - blood group O
CaseHPOFreeRext: VWF:Ag [IU/dL] = 68; VWF:Ac [IU/dL] = 49; FVIII:C [IU/dL] = 76
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.1915C>T p.Arg639Cys
HGVS:
ClinVarID: not found
CAID: CA232310080
gnomAD: 0.00001592 (24 in 1508000) no homozygotes https://gnomad.broadinstitute.org/variant/12-6056887-G-A?dataset=gnomad_r4
2 Type2A (IIC)c.1309_1326del p.Asp437_Arg442del 12 D2-VWD2htz SmallDel.A 201 124 244
Case: IP #2
DiseaseAssertion: type 2A (IIC) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032370 - blood group A
CaseHPOFreeRext: VWF:Ag [IU/dL] = 201; VWF:Ac [IU/dL] = 124; FVIII:C [IU/dL] = 244
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.1309_1326del p.Asp437_Arg442del
HGVS:
ClinVarID: 100179
CAID:
gnomAD: 0.000001239 (2 in 1614154) no homozygotes https://gnomad.broadinstitute.org/variant/12-6064351-AGCGGGTGCACACAGCGTC-A?dataset=gnomad_r4
31
Case: IP #31
DiseaseAssertion: type 2A VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeRext: VWF:Ag [IU/dL] = 14; VWF:Ac [IU/dL] = 6; FVIII:C [IU/dL] = n/a
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.4151T>G p.Leu1384Arg
HGVS:
ClinVarID: not found
CAID: CA383504381
gnomAD: absent
11 U c.3586T > C p.Cys1196Arg 27 D3-TIL-3 htz Missense A/O 21/18 18/12 RCo 55 OSCA /27
Case: IP #11 in type U VWD sub-cohort
DiseaseAssertion: unclassified VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032442 - blood group O
CaseHPOFreeRext: VWF:Ag [IU/dL] = 18; VWF:Ac [IU/dL] = 12; FVIII:C [IU/dL] = 27
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.3586T>C p.Cys1196Arg
HGVS:
ClinVarID: 100270
CAID:
gnomAD: 0.000001239 (2 in 1614220) no homozygotes https://gnomad.broadinstitute.org/variant/12-6021988-A-G?dataset=gnomad_r4
63 Type2A(IIA)c.4885G>A p.Gly1629Arg 28 A2 htz Missense B 45 8GPIbR 36
Case: IP #63
DiseaseAssertion: type 2A (IIA) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032440 - blood group B
CaseHPOFreeRext: VWF:Ag [IU/dL] = 45; VWF:Ac [IU/dL] = 8; FVIII:C [IU/dL] = 36
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.4885G>A p.Gly1629Arg
HGVS:
ClinVarID: 100398
CAID:
gnomAD: absent
8 c.4105T > A p.Phe1369Ile 28 A1 htz Missense na 30 16 61 CSA 43
Case: IP #8 in type 2M VWD sub-cohort
DiseaseAssertion: type 2M VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeRext: VWF:Ag [IU/dL] = 30; VWF:Ac [IU/dL] = 16; FVIII:C [IU/dL] = 61; VWF:CB (IU/dL) = 43
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.4105T>A p.Phe1369Ile
HGVS:
ClinVarID: 100326
CAID:
gnomAD: 0.000006197 (10 in 1613726) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019313-A-T?dataset=gnomad_r4
6 Type2A (IIC)c.1835T>GN p.Val612Gly 15 D2-C8-2hmz Missense O 63 39RCo 88
Case: IP #6 (also in row 3 table 6)
DiseaseAssertion: type 2A (IIC) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032442 - blood group O
CaseHPOFreeRext: VWF:Ag [IU/dL] = 63; VWF:Ac [IU/dL] = 39; FVIII:C [IU/dL] = 88
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.1835T>G p.Val612Gly
HGVS:
ClinVarID: not found
CAID: CA383497104
gnomAD: 0.000001298 (2 in 1541314) no homozygotes https://gnomad.broadinstitute.org/variant/12-6056967-A-C?dataset=gnomad_r4
38 U (2A/2B) c.4373G > A p.Cys1458Tyr 28 A2 htz Missense 19 1 RCo 27
Case: IP #38 in type U VWD sub-cohort
DiseaseAssertion: unclassified (2A/2B) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeRext: VWF:Ag [IU/dL] = 19; VWF:Ac [IU/dL] = 1; FVIII:C [IU/dL] = 27
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.4373G>A p.Cys1458Tyr
HGVS:
ClinVarID: 100351
CAID:
gnomAD: absent
21 Type2A (IIE)c.3469T>GN p.Cys1157Gly 26 D3-TIL-3htz Missense na 27 22RCo 57
Case: IP #21 (also in row 9 table 6)
DiseaseAssertion: type 2A (IIE) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeRext: VWF:Ag [IU/dL] = 27; VWF:Ac [IU/dL] = 22; FVIII:C [IU/dL] = 57
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.3469T>G p.Cys1157Gly
HGVS:
ClinVarID:
CAID: CA383511299
gnomAD: absent
5 U (2A/1) c.3389G > Ac.3539–10T > G Np.Cys1130Tyr-2626D3-TIL-3D3-TIL-3htzhtzMissenseSplice Sitena 17 16 20
Case: IP #5 in type U VWD sub-cohort (also in row 3 splice variants table 6)
DiseaseAssertion: unclassified (2A/1) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeRext: VWF:Ag [IU/dL] = 17; VWF:Ac [IU/dL] = 16; FVIII:C [IU/dL] = 20
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.3389G>A
HGVS:
ClinVarID: 1684001
CAID:
gnomAD: absent
MultipleGeneVariants:
Gene: VWF
Variant: c.3539–10T>G
ClinVarID: not found
**gnomAD: absent
31 U (2A/2M/1C) c.4120C > T p.Arg1374Cys C 28 A1 htz Missense A/A/A/A/O/na/O/A22/ 22/23 /18/11/21/20/3210/8/6/12/4/9/11/1440 CSA /26 CSA /23 CSA /22 CSA /11 CSA /42 CSA /27 CSA /43
Case: IP #31 in type U VWD sub-cohort
DiseaseAssertion: unclassified (2A/2M/1C) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032370 - blood group A
CaseHPOFreeRext: VWF:Ag [IU/dL] = 32; VWF:Ac [IU/dL] = 14; FVIII:C [IU/dL] = 43
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.4120C>T p.Arg1374Cys
HGVS:
ClinVarID: 100329
CAID:
gnomAD: absent
34 U (2A/2M/1C) c.4121G > A p.Arg1374His 28 A1 htz Missense A 19 6 38
Case: IP #34 in type U VWD sub-cohort
DiseaseAssertion: unclassified (2A/2M/1C) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032370 - blood group A
CaseHPOFreeRext: VWF:Ag [IU/dL] = 19; VWF:Ac [IU/dL] = 6; FVIII:C [IU/dL] = 38
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.4121G>A p.Arg1374His
HGVS:
ClinVarID: 100330
CAID:
gnomAD: 0.000001239 (2 in 1613878) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019297-C-T?dataset=gnomad_r4
3 U (2A/2M/1C) C.2771G > Ac.3943C > Tp.Arg924Glnp.Arg1315Cys2128D3-VWD3A1htzhtzMissenseMissenseA 13 8 22
Case: IP #3 in type U VWD sub-cohort
DiseaseAssertion: unclassified (2A/2M/1C) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032370 - blood group A
CaseHPOFreeRext: VWF:Ag [IU/dL] = 13; VWF:Ac [IU/dL] = 8; FVIII:C [IU/dL] = 22
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.2771G>A p.Arg924Gln
HGVS:
ClinVarID: 100240
CAID:
gnomAD: 0.01774 (28642 in 1614096) 297 homozygotes https://gnomad.broadinstitute.org/variant/12-6031493-C-T?dataset=gnomad_r4
MultipleGeneVariants:
Gene: VWF
Variant: c.3943C>T p.Arg1315Cys
**ClinVarID: 100310
gnomAD: 6.196e-7 (1 in 1613892) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019475-G-A?dataset=gnomad_r4
24–31 U (2A/2M/1C) c.4120C > T p.Arg1374Cys C 28 A1 htz Missense A/A/A/A/O/na/O/A22/ 22/23 /18/11/21/20/3210/8/6/12/4/9/11/1440 CSA /26 CSA /23 CSA /22
Case: IP #27 in type U VWD sub-cohort
DiseaseAssertion: unclassified (2A/2M/1C) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032370 - blood group A
CaseHPOFreeRext: VWF:Ag [IU/dL] = 18; VWF:Ac [IU/dL] = 12; FVIII:C [IU/dL] = 22
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.4120C>T p.Arg1374Cys
HGVS:
ClinVarID: 100329
CAID:
gnomAD: absent
51-54Type2A(IIA)c.4811T>AN p.Val1604Asp 28 A2 htz Missense O/A/O/O27/24/35/328/9/11/755CSA/57CSA/62
Case: IP #53 (also in row 21 table 6)
DiseaseAssertion: type 2A (IIA) VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032442 - blood group O
CaseHPOFreeRext: VWF:Ag [IU/dL] = 35; VWF:Ac [IU/dL] = 11; FVIII:C [IU/dL] = 62
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.4811T>A p.Val1604Asp
HGVS:
ClinVarID: not found
CAID: CA383499144
gnomAD: absent
2 2N/1 c.1117C > Tc.2561G > Ap.Arg373p.Arg854Gln1020D1-E1D’-E’htzhtzNonsenseMissenseB 43 na 10
Case: IP #2 in type 2N VWD sub-cohort
DiseaseAssertion: type 2N VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032440 - blood group B
CaseHPOFreeRext: VWF:Ag [IU/dL] = 43; VWF:Ac [IU/dL] = n/a; FVIII:C [IU/dL] = 10
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.
PreviouslyPublished:
Gene: VWF
Variant: c.1117C>T p.Arg373*
HGVS:
ClinVarID: 100175
CAID:
gnomAD: 0.000008055 (13 in 1614004) no homozygotes https://gnomad.broadinstitute.org/variant/12-6071336-G-A?dataset=gnomad_r4
**MultipleGeneVariants:
Gene: VWF
Variant: c.2561G>A p.Arg854Gln
ClinVarID: 296
gnomAD: 0.004956 (8000 in 1614214) 26 homozygotes https://gnomad.broadinstitute.org/variant/12-6034812-C-T?dataset=gnomad_r4
Revascularization Operation for Moyamoya Disease with Concurrent von Willebrand Disease
PMID: 28866059
Gene: VWF
HGNCID: 12726
Case UZ043: 8 year old male (row 44 supplemental table)
DiseaseAssertion: type 2B VWD
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: HP:0032442
CaseHPOFreeRext: vWF:Ag (%) = 29.3; vWF:GPIbR (%) = 13.6; Act/Ag ratio = 0.46; FVIII:C (%) = 68.1; Platelets (x10^9/L) = 176
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: The Thrombosis-Hemostasis gene panel test used whole exome sequencing and included 99 diagnostic-grade genes (table 1 in PMID:36696193)
GenotypingMethod: WES using the coagulation subpanel of the UZ Leuven Thrombosis-Haemostasis gene panel test. WES was performed on the sequencing platform NovaSeq 6000 (Illumina), and Alissa Interpret software v5.2-5.4 (Agilent) was used for variant interpretation. Assessment of copy number variation was validated within the bioinformatics pipeline. The American College of Medical Genetics and Genomics and the Association of Molecular Pathology guidelines were used to classify variants as pathogenic (P), likely pathogenic (LP), a variant of uncertain significance (VUS), or (likely) benign (LB, B) variants
PreviouslyPublished:
Gene: VWF
Variant: c.4021C>T p.Arg1341Trp
HGVS:
ClinVarID: 100316
CAID:
gnomAD: 0.00001859 (30 in 1613842) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019397-G-A?dataset=gnomad_r4
Common and rare von Willebrand factor (VWF) coding variants, VWF levels, and factor VIII levels in African Americans: the NHLBI Exome Sequencing Project
PMID: 23690449
Gene: VWF
HGNC: 12726
Disease: von Willebrand Disease Type 2N
MONDO: 0015631
InheritancePattern: Autosomal Recessive
Prevalence: Various sources (PMID: 28847738, PMID:19809303, PMID:29115006) can be combined to estimate the prevalence of VWD Type 2N between 1:15,000 and 1:80,000.
Penetrance: VWD type 2 is fully penetrant / nearly fully penetrant for most pathogenic variants.
Case#: Iannuzzi_1991_IV-1, M, age unknown, origin unknown
DiseaseAssertion: VWD type 2A
FamilyInfo: Affected mother, aunt, grandfather, and many other relatives. LOD score 3.61 reported (12 affected and genotype positive, 4 unaffected genotype positive. 4 affected also have HTT with vWD.
ParentalGenotype:
CasePresentingHPOs: As reported elsewhere (Hanna etal1984), the diagnosis of typeII AvWD was based on the following: bleedingtime, FVIII procoagulant activity, vFW:Ag, ristocetincofactoractivity, platelet aggregation studies, and vWF multimer analysis
CaseHPOFreeText:
CaseNotHPOs:
CaseNotHPOFreeText:
CasePreviousTesting:
GenotypingMethod: PCR-RFLP of exon 28 of VWF
Gene: VWF
Variant:
HGVS: NM_000552.5(VWF):c.4883T>C (p.Ile1628Thr)
ClinVarID: 284
CAID:
gnomAD: not reported
MultipleGeneVariants:
III : 3
Case#: F10, III:3
DiseaseAssertion: Type 2 VWD
CaseHPOFreeText: complete loss of high MWM, VWF:Ag = 25; VWF:RCo = 6; VWF:GPIbM = 17; 0.23; 0.67; 2.95
CasePreviousTesting: Not clearly described
Gene: VWF
Variant: p.[R1306W];[=]
HGVS: c.3916C>T (p.Arg1306Trp)
CAID: CA114123
gnomAD: absent from gnomad v4.1.0
I : 3
Case#: F10, I:3
DiseaseAssertion: Type 2 VWD
CaseHPOFreeText: complete loss of high MWM, VWF:Ag = 50; VWF:RCo = 6; VWF:GPIbM = 29; 0.12; 0.58; 4.82
CasePreviousTesting: Not clearly described
Gene: VWF
Variant: p.[R1306W];[=]
HGVS: c.3916C>T (p.Arg1306Trp)
CAID: CA114123
gnomAD: absent from gnomad v4.1.0
I : 1
Case#: F10, I:1
DiseaseAssertion: Type 2 VWD
CaseHPOFreeText: complete loss of high MWM, VWF:Ag = 82; VWF:RCo = 27; VWF:GPIbM = 97; 0.33; 1.19; 3.62
CasePreviousTesting: Not clearly described
Gene: VWF
Variant: p.[R1306W];[=]
HGVS: c.3916C>T (p.Arg1306Trp)
CAID: CA114123
gnomAD: absent from gnomad v4.1.0
I : 1
Case#: F9, I:1
DiseaseAssertion: Type 2 VWD
CaseHPOFreeText: complete loss of high MWM, VWF:Ag = 23; VWF:RCo = 7; VWF:GPIbM = 21; 0.29; 0.93; 3.18
CasePreviousTesting: Not clearly described
Gene: VWF
Variant: p.[R1306W];[=]
HGVS: c.3916C>T (p.Arg1306Trp)
CAID: CA114123
gnomAD: absent from gnomad v4.1.0
183< 1< 13−−20Mc.1992insC/c.5557C>Tp.C665LfsX13/p.R1853X16/3215/16N/PD
Case: Patient 18, M, Hungarian
DiseaseAssertion: VWD type 3
FamilyInfo: compatible with recessive inheritance
ParentalGenotype(s): n/a
CasePresentingHPOs: n/a
CaseHPOFreeRext: Bleeding score: 20, VWF:Ag (IU dL−1): < 1, VWF:CB (IU dL−1): < 1, FVIII:C (IU dL−1): 3, VWF:RCo below detection limit (<10 IU dL−1), not detectable VWF on multimer gels
CaseNOTHPOs: n/a
CaseNOTHPOFreeText: no inhibitor detected, did not become refractory to factor replacement therapy
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.1992insC (p.Cys665LeufsX13), Exon 16
c.5557C>T (p.Arg1853X), Exon 32
Intron 40 VNTR 15/16
Note: multimer electrophoresis, Recombinant VWF antigen concentrations and Collagen binding activity (VWF:CB) measured by ELISA, direct sequencing of the 51 exons and the exon‐intron boundaries, Breakpoint analysis and breakpoint‐specific PCR
143112−+14Mc.3622delT/c.3622delTp.S1208QfsX7/p.S1208QfsX727/2718/18N/N
Case: Patient 14, M, Hungarian
DiseaseAssertion: VWD type 3
FamilyInfo: compatible with recessive inheritance
ParentalGenotype(s): n/a
CasePresentingHPOs: n/a
CaseHPOFreeRext: Bleeding score: 14, VWF:Ag (IU dL−1): 1, VWF:CB (IU dL−1): 1, FVIII:C (IU dL−1): 2, VWF:RCo below detection limit (<10 IU dL−1), not detectable VWF on multimer gels, anaphylactic reaction to the VWF concentrate, inhibitor and alloantibodies detected
CaseNOTHPOs: n/a
CaseNOTHPOFreeText: did not become refractory to factor replacement therapy
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.3622delT (p.S1208QfsX7), Exon 27, Homozygous
Intron 40 VNTR 18/18
Note: multimer electrophoresis, Recombinant VWF antigen concentrations and Collagen binding activity (VWF:CB) measured by ELISA, direct sequencing of the 51 exons and the exon‐intron boundaries, Breakpoint analysis and breakpoint‐specific PCR
203< 1< 16−14Mc.103T>C/c.4975C>Tp.C35R/p.R1659X3/2814/16N/PD
Case: Patient 20, M, Hungarian
DiseaseAssertion: VWD type 3
FamilyInfo: compatible with recessive inheritance
ParentalGenotype(s): n/a
CasePresentingHPOs: n/a
CaseHPOFreeRext: Bleeding score: 14, VWF:Ag (IU dL−1): < 1, VWF:CB (IU dL−1): < 1, FVIII:C (IU dL−1): 6, VWF:RCo below detection limit (<10 IU dL−1), not detectable VWF on multimer gels
CaseNOTHPOs: n/a
CaseNOTHPOFreeText: did not become refractory to factor replacement therapy
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.103T>C (p.Cys35Arg), Exon 3
c.4975C>T (p.Arg1659X), Exon 28
Intron 40 VNTR 14/16
Note: multimer electrophoresis, Recombinant VWF antigen concentrations and Collagen binding activity (VWF:CB) measured by ELISA, direct sequencing of the 51 exons and the exon‐intron boundaries, Breakpoint analysis and breakpoint‐specific PCR
Prevalence and Risk Factors Associated With Hypertension in von Willebrand Disease
PMID: 27655998
Gene: VWF
HGNCID: 12726
Blood volume–based von Willebrand factor to prevent postpartum hemorrhage in von Willebrand disease
PMID: 29296713
Gene: VWF
HGNCID: 12726
60.862.80.977141.9NormalExon 13c.1531A>C‡p.Lys511GlnD2Missense
Case:Croatian adult patient
DiseaseAssertion: VWD1
ParentalGenotype(s): Not specified
CasePresentingHPOs: HP:0001892, HP:0011890, HP:0000132, HP:0002239, HP:0000790, HP:0001342
CaseHPOFreeText: Normal VWF:Ag of 62.8%, VWF:GPIbM of 60.8%, FVIII:C of 71% and VWF:CBA of 41.9%. Normal multimer distribution.
CaseNOTHPOs: Not specified
CaseNOTHPOFreeText: Normal multimer size distribution (tested in Agarose gel).
CasePreviousTesting: Not reported
GenotypingMethod: Illumina NGS, custom designed panel covering all 52 exons as well as intronic flanking regions and promoter region of VWF gene.
PreviouslyPublished: None
Gene: VWF
Variant: c.1531A>C
HGVS: NM_000552.4:c.1531A>C (p.Lys511Gln)
ClinVarID: Not available
CAID: CA383500354
gnomAD: Not available
VWD2-3†10.917.20.632110.1↓HMWM,↓IMWM28c.3829G>T§p.Asp1277TyrA1Missense2A
Case: Croatian adult patient
DiseaseAssertion: VWD2A
FamilyInfo: No variant detected in a family member with VWD2
ParentalGenotype(s): Not specified
CasePresentingHPOs: HP:0001892, HP:0011890, HP:0000132, HP:0002239, HP:0000790, HP:0001342
CaseHPOFreeText: Reduced VWF:Ag of 17.2%, VWF:GPIbM of 10.9%, FVIII:C of 21% and VWF:CBA of 10.1%. Reduced levels of HMWM and IMWM in multimer distribution.
CaseNOTHPOs: Not specified
CaseNOTHPOFreeText: Not reported.
CasePreviousTesting: Not reported
GenotypingMethod: Illumina NGS, custom designed panel covering all 52 exons as well as intronic flanking regions and promoter region of VWF gene.
PreviouslyPublished: None
Gene: VWF
Variant: c.3829G>T
HGVS: NM_000552.4:c.3829G>T (p.Asp1277Tyr)
ClinVarID: Not available
CAID: CA383506920
gnomAD: Not available
Next-generation sequencing of von Willebrand factor and coagulation factor VIII genes: a cross-sectional study in Croatian adult patients diagnosed with von Willebrand disease
PMID:35505650
Gene: VWF
HGNCID: 12726
VWD1-1339.751.50.777428.1NormalIntron 37c.6599-2A>G‡-
Case: Croatian adult patient
DiseaseAssertion: VWD1
FamilyInfo: Not specified
ParentalGenotype(s): Not specified
CasePresentingHPOs: HP:0001892, HP:0011890, HP:0000132, HP:0002239, HP:0000790, HP:0001342
CaseHPOFreeText: Normal VWF:Ag of 51.5%, reduced VWF:GPIbM of 39.7%, normal FVIII:C of 74% and reduced VWF:CBA of 28.1%. Normal multimer distribution.
CaseNOTHPOs: Not specified
CaseNOTHPOFreeText: Normal multimer size distribution (tested in Agarose gel).
CasePreviousTesting: Not reported
GenotypingMethod: Illumina NGS, custom designed panel covering all 52 exons as well as intronic flanking regions and promoter region of VWF gene.
PreviouslyPublished: None
Gene: VWF
Variant: c.6599-2A>G
HGVS: NM_000552.4:c.6599-2A>G
ClinVarID: Not available
CAID: CA383490280
gnomAD: Not available
Management of pregnancy in type 3 von Willebrand disease with alloantibodies
PMID: 28699647
Gene: VWF
HGNCID: 12726
Molecular study of VWF gene from Mexican Mestizo patients with von Willebrand disease, and the finding of three new mutations
PMID: 17681836
Gene: VWF
HGNCID: 12726
Perioperative management of patients with von Willebrand disease
PMID: 31808837 Gene: VWF HGNCID: 12726
Wild type and several naturally occurring type 2N VWF variants (H817Q, R854Q+T789A, R782W, and R782W+H817Q) or a hereditary persistance of propeptide (HPP) variant (Fig. 1A) were constructed and expressed transiently in human embryonic kidney 293T cells.
ExperimentName: Transient expression of VWD type 2N variants in 293T cells
NonPatientCell: human embryonic kidney 293T cells (EFO:0001082)
GeneFunction: GO:0005515 (protein binding, specifically to Factor VIII)
GeneAlteration: A mutation encoding p.His817Gln was introduced into a construct for exogenous expression of the VWF protein.
FunctionalEvidence: The variant protein exhibited a mild defect in FVIII binding relative to the wild-type (less severe than other VWD type 2N variants) (Figure 1C). Because of the defect in FVIII interaction, the variant also exhibits mildly reduced cleavage by ADAMTS13 (Figures 1F, 1G, and 1H).
FAVariants: A construct equivalent to the c.2451T>A (p.His817Gln) variant was used (ClinVar:100224).
.3797C>Tc.3835G>A
Case 1: Southern Spanish, unrelated patient to Case 2
DiseaseAssertion: VWD1
FamilyInfo: Patient unrelated to families of Case 2, but same two VWF variants found on the same allele
CasePresentingHPOs4: Not reported
CaseHPOFreeText4: Bleeding score of 4
CaseNotHPOs: Not reported
CaseNotHPOFreeText: Normal multimeric assay, VWF:Ag level at 66%, VWF:RCo at 60 U/mL, FVIIIC at 84 U/dL, VWF:RCo/VWF:Ag ratio of 0.9, PFA-100:Col-EPI/Col-ADP of 277s/124s
CasePreviousTesting: Sequencing of exon 28 of VWF gene in 11 families.
Gene: VWF
Variant: c.3797C>T, c.3835G>A
ClinVarID:314, 100288
0.45
Case: 2A-2
DiseaseAssertion: VWD2A
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: AcuStar RCo/Ag = 0.45; AcuStar CB/Ag = 0.26; ELISA CB/Ag = 0.30
CaseHPOFreeText:
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: not described
PreviouslyPublished: PMID: 8435341
Gene: VWF
Variant: c.4541T>G (p.Phe1514Cys)
HGVS: NM_000552.5(VWF):c.4541T>G (p.Phe1514Cys)
ClinVarID: 304; https://www.ncbi.nlm.nih.gov/clinvar/variation/304/?new_evidence=false
CAID:
gnomAD: absent
0.70
Case: 2B-11
DiseaseAssertion: VWD2B
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: AcuStar RCo/Ag = 0.70; AcuStar CB/Ag = 0.83; ELISA CB/Ag = 1.07
CaseHPOFreeText:
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: not described
PreviouslyPublished: 11325649
Gene: VWF
Variant: c.4135C>T (p.Arg1379Cys)
HGVS: NM_000552.5(VWF):c.4135C>T (p.Arg1379Cys)
ClinVarID: 100333; https://www.ncbi.nlm.nih.gov/clinvar/variation/100333/?new_evidence=false
CAID:
gnomAD: MAF (European, non-Finnish) = 0.00003891; 0 homozygotes; https://gnomad.broadinstitute.org/variant/12-6128449-G-A
0.66
Case: 2B-6
DiseaseAssertion: VWD2B
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: AcuStar RCo/Ag = 0.66; AcuStar CB/Ag = 0.69; ELISA CB/Ag = 0.71
CaseHPOFreeText:
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: not described
PreviouslyPublished: 1373334
Gene: VWF
Variant: c.4010C>T (p.Pro1337Leu)
HGVS: NM_000552.5(VWF):c.4010C>T (p.Pro1337Leu)
ClinVarID: 100314; https://www.ncbi.nlm.nih.gov/clinvar/variation/100314/?new_evidence=false
CAID:
gnomAD: MAF = 0.00005440 in East Asian population; https://gnomad.broadinstitute.org/variant/12-6128574-G-A
1
Case: 2M-1
DiseaseAssertion: VWD2M
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs: AcuStar RCo/Ag = 0.60; AcuStar CB/Ag = 1.16; ELISA CB/Ag = 1.12
CaseHPOFreeText:
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: not described
PreviouslyPublished:
Gene: VWF
Variant: p.Arg1315Gln
HGVS: n/a
ClinVarID: n/a
CAID: n/a
gnomAD: n/a
Gene of the issue: GP1BA gene mutations associated with bleeding
PMID: 28961024
Gene: GP1BA
HGNCID: 12726
A discontinuous autoinhibitory module masks the A1 domain of von Willebrand factor
PMID: 28692141
Gene: VWF
HGNCID: 12726
Differential diagnosis of neonatal alloimmune thrombocytopenia: Type 2B von Willebrand disease.
PMID: 28436749
Gene: VWF
HGNCID: 12726
Misfolding of vWF to Pathologically Disordered Conformations Impacts the Severity of von Willebrand Disease
PMID: 25185554
Gene: VWF
HGNC: 12726
Disease: von Willebrand disease type 2M
MONDO: 0015630
InheritancePattern: Autosomal Dominant
Prevalence: Overall VWD prevalence is estimated to be as high as 1 in 100 in the general population, with 1 in 10,000 pursuing tertiary care referral (PMID: 28847738).
Penetrance: Fully penetrant / nearly fully penetrant for most pathogenic type 2 variants
Abnormal von Willebrand factor secretion, factor VIII stabilization and thrombus dynamics in type 2N von Willebrand disease mice
PMID: 28581694
Gene: VWF
HGCNID: 12726
Upper motor neuron signs and early onset gait abnormalities in young children with bi-allelic VWA1 variants
PMID: 35975723
Gene: VWA1
HGNCID: 12726
A Unique Case of Type 3 Von Willebrand Disease
Gene: VWF
HGNCID: 12726
Outcome of laparoscopic ovariohysterectomy or ovariectomy in dogs with von Willebrand disease or factor VII deficiency: 20 cases (2012–2014)
PMID: 29035661
Gene: VWF
HGNCID: 12726
Table 2
Probands: Pt36, 76, 77 same family
Labs: for Pt.36, VWF:Ag 17 IU/dL, VWF:RCo/VWF:Ag 0.37, VWF:GPIb/VWF:Ag 0.38, and normal multimers per data in table S1
CAID: CA383506019
Comment on: Generation and optimization of the self-administered pediatric bleeding questionnaire and its validation as a screening tool for von Willebrand disease
PMID: 28727265
Gene: VWF
HGNCID: 12726
CII:6
Proband: FC_II:6, male age unknown
FamilyDetails: parents are unaffected hets, first cousins, fathers VWF:Ag at very low end of reference
Labs: prolonged bleeding time (>20min), reduced VWF:Ag (less than 0.01 IU/mL), FVIII:Ag (0.06 IU/mL), FVIII:C (0.09 IU/mL), and VWF:RiCoF (less than 0.01 IU/mL), absent multimers
Genotype: p.Arg273Trp reported as c.1067C>T (MANE transcript is 817C>T)
CAID: CA228829
The Chaperonin GroEL: A Versatile Tool for Applied Biotechnology Platforms
PMID: 29868607
Gene: VWF
HGNC: 12726
Disease: von Willebrand disease type 2M
MONDO: 0015630
InheritancePattern: Autosomal Dominant
Prevalence: Overall VWD prevalence is estimated to be as high as 1 in 100 in the general population, with 1 in 10,000 pursuing tertiary care referral (PMID: 28847738).
Penetrance: Fully penetrant / nearly fully penetrant for most pathogenic type 2 variants
III-1
III-1, Female 10 years old
disease assertion: VWD
**positive family history **
Parental Genotype: each has heterozygous, 3251G>A
CasePresentingHPOs: CaseHPOFreeText: BS 4, VWF Ag:0.38, *VWF:GPIbM:0.15,VWF:CB:0.13, VWFpp :0.76, FVIII:C:0.10
CaseNOTHPOs:* N.a.
CaseNOTHPOFreeText: n.a.
CasePreviousTesting: *GenotypingMethod: Sanger seqencing;
*PreviouslyPublished:n.a.
Gene:VWF Variant:c.3251G>A*
*HGVS:NM_000552.5:c.3251G>A
*CAID:n.a.
*gnomAD:n.a.
The co-influence of VWD type 2B/2M mutations in the A1 domain and platelet GPIbα on the rate of cleavage to VWF by ADAMTS13
PMID: 26345337
Gene: VWF
HGNC: 12726
Disease: von Willebrand disease type 2B
MONDO: 0015629
InheritancePattern: Autosomal Dominant
Prevalence: Overall VWD prevalence is estimated to be as high as 1 in 100 in the general population, with 1 in 10,000 pursuing tertiary care referral ((PMID: 28847738).
Penetrance: Fully penetrant / nearly fully penetrant for most pathogenic type 2 variants
Recessive von Willebrand disease type 2 Normandy: variable expression of mild hemophilia and VWD type 1
PMID: 19506358
Case 13
Case: Case 13, ages 2-17, Croatian
DiseaseAssertion: VWF3
FamilyInfo:
ParentalGenotypes(s):
CasePresentingHPOs:
CaseHPOFreeText:
CaseNOTHPOs:
CaseNOTHPOFreeText: bleeding score= 5, VWF:GPIbM (%)= 7.8, VWF:Ag (%)= 9.7, vWF:GPIbM/vWF:Ag ratio= 0.80, FVIII:C (%): 34, VWF: CBA (%)= 7.8
CasePreviousTesting:
Gene: VWF
Variant: c.4975C>T, p.Arg1659Ter
HGVS: NM_000552.5:c.4975C>T
ClinVar: 297
gnomAD: https://gnomad.broadinstitute.org/variant/12-6127609-G-A?dataset=gnomad_r2_1
10*ItalyF/30<1—YesSevere4626C→GY1542X28HomozygousRsaI (−)
Case: 10, F, 30, Italian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: yes
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: VWF:Ag (U/dl): <1, Bleeding symptoms: Severe
CaseNotHPOs: n/a
CaseNotHPOFreeText: Anti-VWF alloantibodies: no
CasePreviousTesting: n/a
Gene: VWF
Variant:
4626C→G (Tyr1542X), Exon 28, Homozygous
35*IndiaM/42<1—NoMild8411G→AC2804Y52HomozygousRsaI (+)
Case: 35, M, 42, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: No
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: VWF:Ag (U/dl): <1, Bleeding symptoms: Mild
CaseNotHPOs: n/a
CaseNotHPOFreeText: Anti-VWF alloantibodies: no
CasePreviousTesting: n/a
Gene: VWF
Variant:
8411G→A (Cys2804Tyr), Exon 52, Homozygous
Note: It is possible that the homozygous zygosity was detected from a PCR artifact (e.g. presence of a large gene deletion or point mutation that prevents amplification); different sets of primers were used, providing conformation and excluding the possibility for a PCR artifact due to point mutation.
7*ItalyF/36<1—NoSevere2435delC/5170+10C→T 253T→CFS/FS-S85P18/29-4HeterozygousBglI (−)/N.A.
Case: 7 , F, 36, Italian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: no
ParentalGenotype:
2435delC on the maternal allele
5170+10C→T on the paternal allele
253T→C on the paternal allele
CasePresentingHPOs: n/a
CaseHPOFreeText: VWF:Ag (U/dl): <1, Bleeding symptoms: Severe
CaseNotHPOs: n/a
CaseNotHPOFreeText: Anti-VWF alloantibodies: no
CasePreviousTesting: n/a
Gene: VWF
Variant:
2435delC (FS), Exon 18
5170+10C→T (Intronic), Exon 29
253T→C (Ser85Pro), Exon 4
Compound Heterozygous
Note: Article assumes that 5170+10C→T would be a frameshift mutation. No potential splice site mutation was confirmed at the mRNA level; “Splice Site Prediction program” found all mutations likely to disrupt normal splicing. No possible splice site mutation could be identified on 100 chromosomes from a group of 50 normal subjects with same genetic background as patients, excluding the possibility that these mutations represent common polymorphisms.
39IndiaM/33<1—NoMild4092delAC/7130insCFS/FS28/42HeterozygousN.A./N.A.
Case: 39, M, 33, Indian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: No
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: VWF:Ag (U/dl): <1, Bleeding symptoms: Mild
CaseNotHPOs: n/a
CaseNotHPOFreeText: Anti-VWF alloantibodies: no
CasePreviousTesting: n/a
Gene: VWF
Variant:
4092delAC (FS), Exon 28
7130insC (FS), Exon 42
Compound Heterozygous
Biochemical characterization of a recombinant von Willebrand factor (VWF) with combined type 2B and type 1 defects in the VWF gene in two patients with a type 2A phenotype of von Willebrand disease
PMID: 17155947
Gene: VWF
HGNC: 12726
Disease: von Willebrand disease type 2B
MONDO: 0015629
InheritancePattern: Autosomal Dominant
Prevalence: Overall VWD prevalence is estimated to be as high as 1 in 100 in the general population, with 1 in 10,000 pursuing tertiary care referral ((PMID: 28847738).
Penetrance: Fully penetrant / nearly fully penetrant for most pathogenic type 2 variants
Case#: Elayaperumal_2018_V-281, M, 2 y.o. (onset), origin in India
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity, no family history of bleeding
ParentalGenotype: not reported
CasePresentingHPOs:
CaseHPOFreeText: bleeding score of 9, VWF:Ag of 0, FVIII:C of 3.5%
CaseNotHPOs:
CaseNotHPOFreeText:
CasePreviousTesting: not reported
GenotypingMethod: CSGE and Sanger sequencing of VWF gene only.
Gene: VWF
Variant: homozygous c.4696C>T (p.Arg1566*)
HGVS: NM_000552.3:c.4696C>T
ClinVarID: 100382
CAID: CA228639
gnomAD: MAF of 0.00001762 (2/113480 alleles, European non-Finnish) https://gnomad.broadinstitute.org/variant/12-6127888-G-A
MultipleGeneVariants: n/a
Case#: Elayaperumal_2018_V-290 , Male, 7 months (onset), origin in India
DiseaseAssertion: VWD type 3
FamilyInfo: no consanguinity reported. positive family history
ParentalGenotype: not reported
CasePresentingHPOs:
CaseHPOFreeText: bleeding score of 12, VWF:Ag 0, FVIII:C 9.2%
CaseNotHPOs:
CaseNotHPOFreeText:
CasePreviousTesting: not reported
GenotypingMethod: CSGE and Sanger sequencing of VWF gene only.
Gene: VWF
Variant: heterozygous c.6798+1G>C
HGVS: NM_000552.3:c.6798+1G>C
ClinVarID: not found
CAID: CA383489728
gnomAD: not found
MultipleGeneVariants:
Note: other allele not identified. Large deletion possible.
A case report of type 2M Von Willebrand disease withunique mutations
Gene: VWF
HGNCID: 12726
Case: 55 year old female
DiseaseAssertion: type 2M VWD
FamilyInfo: one sister with VWD of unknown type. Four other siblings with no bleeding history.
CasePresentingHPOs: HP:0002239 (Gastrointestinal hemorrhage), Gastrointestinal angiodysplasia HP:0000471, Hemoptysis HP:0002105, Epistaxis HP:0000421, Menorrhagia HP:0000132
CaseHPOFreeRext: normal PT/aPTT. Von Willebrand panel shows vWF antigen of 33%, VWF ristocetin cofactor activity of 15%, and Factor VIII of 87%. The ratio (VWF: RCo/VWF: Ag) is low (0.45) and the multimer pattern is normal.
Gene: VWF
Variant: c.4241T>G (p.Val1414Gly) and c.5227G>A (p.Val1743Met)
ClinVarID: 619752, 801307
Functional characterization of a 13-bp deletion (c.-1522_-1510del13) in the promoter of the von Willebrand factor gene in type 1 von Willebrand disease
PMID: 20696945
Gene: VWF
HGNCID: 12726
2A
Case: 2A, female, 72yo
DiseaseAssertion: VWD2A
FamilyInfo:
ParentalGenotype(s):
CasePresentingHPOs:
CaseHPOFreeText: Blood type: O+, bleeding score = 19, VWF:Ag (IU/mL) = 0.07; VWF:RCo (IU/mL) = 0.06; FVIII:C (IU/mL) = 0.21
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting:
GenotypingMethod: qRT-PCR
PreviouslyPublished:
Gene: VWF
Variant: c.7130dupC (p.Pro2377Profs*14)
HGVS: n/a
ClinVarID: n/a
CAID: n/a
gnomAD: n/a
Case#: Kumar_2016_ , M, 9 months (report)
DiseaseAssertion: VWD type 2B
FamilyInfo: no family history, de novo assertion but no testing to prove it.
ParentalGenotype: not reported
CasePresentingHPOs:
CaseHPOFreeText: low von Willebrand factor (vWF) antigen (32%) and ristocetin cofactor activity (<8%). loss of high-molecular-weight multimers, bruising, extensive bleeding
CaseNotHPOs:
CaseNotHPOFreeText:
CasePreviousTesting: not reported
GenotypingMethod: exon 28 sequencing
Gene: VWF
Variant:
HGVS: NM_000552.5(VWF):c.3940G>C, p.V1314L
ClinVarID: 302
CAID:
gnomAD: not reported
MultipleGeneVariants:
Decreased severity of Shiga toxin-producing Escherichia coli haemolytic uraemic syndrome (STEC-HUS) in a child with type 1 von Willebrand disease
PMID: 28855217
Gene: VWF
HGNCID: 12726
Laboratory monitoring of replacement therapy for major surgery in von Willebrand disease
PMID: 28111840
Gene: VWF
HGNCID: 12726
p.(Val510 = ) variant
PMID: 33134807
Gene: VWF
HGNCID:12726
Case: Female patient from the French Caribbean island of Martinique
DiseaseAssertion: VWF Type 3
FamilyInfo: The proband had a combination of two variants p.(Val510+) and p.(Pro21452145Thrfs*5) in a heterozygous state. Her biological profile indicated VWD3: VWF:Ag = 1 to 5%, VWF:RCo = 5%, FVIII:C = 2 to 3%, VWFpp = 6%, and a total absence of multimers assessed by electrophoresis. She was usually treated with plasma-derived VWF concentrates. Interestingly, the VWFpp level in this patient was higher than expected for typical VWD3. The sister who died from a nonhemorrhagic cause had the same clinical-biological profile.
ParentalGenotype(s): The mother had a normal biological assessment and was asymptomatic without any bleeding. Sequencing of the mother's VWF gene revealed a single variant on exon 37: resulting in the nucleotide change c.6432dup / a.a. change p.(Pro2145THRfs*5) which results in a stop codon. This molecular abnormality favors VWD3, even though the mother is asymptomatic. The father experienced excessive bleeding only as a result of trauma or surgery. Sequencing of the father's VWF gene led to the identification of one potential causative variant: p.(Val510 = ), on exon 13 with a nucleotide change c.1530G>A. A second sister of the proband has a clinical and biological phenotype similar to that of her father.
CasePresentingHPOs:HP:0012147, HP:0030132, HP:0030129
CaseHPOFreeText: The proband presented with severe hemorrhagic manifestations.
CaseSubsequentTesting:N/A
GenotypingMethod:NGS
PreviouslyPublished: No
SupplementalData: The prediction softwares used (SpliceSiteFinder-like, MaxEntScan, GeneSplicer, NSPLICE, ESEFinder, RESCUE-ESE, and EX-SKIP) regarding c.1530G > A (p.(Val510 = )) interpreted the appearance of a donor site at 6 base pairs at the end of exon 13 which could potentially alter splicing. This synonymous mutation could therefore have an effect on VWF messenger ribonucleic acid processing, causing a shift in the reading frame and the appearance of a termination codon deletion of two codons. The ACMG predicted that this variant would probably be pathogenic.
VariantEvidence: An additional 21 patients from Martinique were identified with the p.(Val510=) variant. Median age was 63 years (interquartile range [IQR], 45–77) and 65% were female. The striking feature in these patients was a significantly increased VWFpp/VWF:Ag ratio with a median of 5.62 (IQR, 4.36–6,14). This ratio could be calculated only for the 14 patients for whom the VWFpp level was measured. An increased VWFpp/VWF:Ag ratio (> 2.2) is indicative of an accelerated clearance of VWF. Addition testing in four patients involved DDAVP infusion compared to a patient with a VWD1 mutation that does not cause a clearance defect. The results showed accelerated VWF clearance compared to the control. The author propose to classify patient with the p.(Val510=) variant as Type 1C, a rare subtype that removes VWF more quickly than normal in the blood.
Compound Heterozygote:
GeneName:VWF
Variant: NM_00055.2.5:c.6432dup. (Pro2145Thrfs*5)
ClinVarID1330387
gnomAD:N/A
GeneName: VWF
Variant:NM_000552.3:c.1530G>A, p.(Val510=)
CAIDCA6403368
gnomAD: 0.000001240
An Arg545----Cys545 substitution mutation of the von Willebrand factor in type IIB von Willebrand's disease
PMID: 1761120
Gene: VWF
HGNC: 12726
Disease: von Willebrand disease type 2B
MONDO: 0015629
InheritancePattern: Autosomal Dominant
Prevalence: Overall VWD prevalence is estimated to be as high as 1 in 100 in the general population, with 1 in 10,000 pursuing tertiary care referral ((PMID: 28847738).
Penetrance: Fully penetrant / nearly fully penetrant for most pathogenic type 2 variants
von Willebrand Disease: A Concise Review and Update for the Practicing Physician
PMID: 27920237
Gene: VWF
HGNCID: 12726
In family 3, the female proposita (3G)
Case#: 3G
DiseaseAssertion:
FamilyInfo: Her father (3F), who reported mild bruising symptoms, and both asymptomatic younger male siblings (3H and 3J) were also investigated. All family members were found to be heterozygous for a previously described mutation in exon 30:c.5191 T → A, resulting in Ser1731Thr.
CaseHPOFreeText4: In family 3, the female proposita (3G) presented in childhood with epistaxis and easy bruising. VWF:Ag and VWF:RCo were borderline low in 3F and 3G but normal in the asymptomatic brothers, 3H and 3J. Multimer analysis was normal in all family members tested (Figure 1). VWF:CB binding to type I collagen was reduced in all family members (CB/Ag ratio 0.4-0.7), whereas only one (3G) showed a reduction in CB:Ag ratio with type III collagen.
CasePreviousTesting: Fifty-one primer sets were used to amplify the essential regions of VWF (52 exons, flanking intronic regions, 5′ promoter region, and the 3′ untranslated region).
Gene: VWF
Variant: heterozygous for a previously described mutation in exon 30:c.5191 T → A, resulting in Ser1731Thr
HGVS: NM_000552.5(VWF):c.5191T>A (p.Ser1731Thr)
ClinVar: 100420
CAID: CA228704
gnomAD: 0.004289 in middle eastern pop
The proposita (2D) in family 2
Case#: 2D
DiseaseAssertion:
FamilyInfo: Her son 2E had mild bruising and epistaxis.
CaseHPOFreeText: The proposita (2D) in family 2 was investigated after a postpartum hemorrhage requiring blood transfusion. She gave a longstanding history of menorrhagia, and her calculated bleeding score was 10, the highest of all the persons in this study. VWF:Ag, VWF:RCo, and multimer analysis were all normal. VWF:CB was significantly reduced with both types I and III collagen, resulting in CB:Ag ratios of 0.2 to 0.4. Closure times in the PFA-100 were normal in 2D with both cassettes (Coll/Epi, 111 seconds; Coll/ADP, 98 seconds). The discrepant reduction in VWF:CB persisted after DDAVP administration to 2D despite normalization of both VWF:Ag and VWF:CB (samples taken 90 minutes after DDAVP administration showed VWF:Ag 191 IU/dL, VWF:CB 67 IU/dL, CB:Ag ratio = 0.35).
CasePreviousTesting: Fifty-one primer sets were used to amplify the essential regions of VWF (52 exons, flanking intronic regions, 5′ promoter region, and the 3′ untranslated region).
Gene: VWF
Variant: Her and son were shown to be heterozygous for a novel mutation in exon 31:c.5347 T → G resulting in Ser1783Ala
HGVS: NM_000552.5(VWF):c.5347T>G (p.Ser1783Ala)
ClinVar: 31012
CAID: CA228715
gnomAD: 0.0006918 in south asian pop
V‐136
Case#: Elayaperumal_2018_ , M, 4 y.o. (onset), origin in India
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity, no family history
ParentalGenotype: not reported
CasePresentingHPOs:
CaseHPOFreeText: bleeding score of 14. VWF:Ag 0.83, FVlll:C of 1.9%.
CaseNotHPOs:
CaseNotHPOFreeText:
CasePreviousTesting: not reported
GenotypingMethod: CSGE and Sanger sequencing of VWF gene only.
Gene: VWF
Variant: homozygous c.757_770del
HGVS: NM_000552.3:c.757_770del (p.Thr253Cysfs*45)
ClinVarID: not found
CAID: CAR unable to parse. Error: unknown
gnomAD: not found
MultipleGeneVariants: not reported
Proband: F4_AM, 27yo (at report) female
Phenotypes: HP:0030134, HP:0003010, HP:0030129
Family: Both parents carry the variant. All het carriers were classified type 1
Labs: FVIII 0.02 IU/mL, VWF 0.03 IU/mL (below detection threshold)
Variant: NM_000552.5:c.4975C>T
CAID: CA114141
Cohort description
Case#: MK0251
DiseaseAssertion: Type 2 VWD
CaseHPOFreeText: 51 year old, female, VWF:AG LEVELS = 60
Gene: VWF
Variant: compound heterozygous for 4751A>G (p.Y1584C) and c.7483del (p.Leu2495CysfsTer8) variants
ClinVar: 310 (p.Y1584C) and 631687 (p.Leu2495CysfsTer8)
gnomAD: absent grpmax (p.Leu2495CysfsTer8), grpmax of 0.004019 based on european non finnish pop (p.Y1584C)
The Defective Interaction Between von Willebrand Factor and Factor VIII in a Patient With Type 1 von Willebrand Disease Is Caused by Substitution of Arg19 and His54 in Mature von Willebrand Factor
PMID: 8562925
Gene: VWF
HGNC: 12726
Disease: von Willebrand Disease Type 2N
MONDO: 0015631
InheritancePattern: Autosomal Recessive
Prevalence: Various sources (PMID: 28847738, PMID:19809303, PMID:29115006) can be combined to estimate the prevalence of VWD Type 2N between 1:15,000 and 1:80,000.
Penetrance: VWD type 2 is fully penetrant / nearly fully penetrant for most pathogenic variants.
Dominant vWD Type 1 Secretion Defect (High FVIII/vWF:Ag Ratio) Caused by S2179F Mutation in D4 Domain in 3 Families With vWD SD
Case: Proband 2 (Family 2)
DiseaseAssertion: VWD1
FamilyInfo: 2 family members diagnosed with VWD1
ParentalGenotype(s): NA
CasePresentingHPOs: HP:0012147, HP:0001892, HP:0030130, HP:0011871
(Reduced quantity of Von Willebrand factor, Abnormal bleeding, Impaired von Willibrand factor collagen binding activity)
CaseHPOFreeText: normal to slightly prolonged Ivy BT, FVIII:C % = 19, VWF:Ag % = 13, VWF:RCo % = 12, VIII C/vWF:AG ratio = 1.5, vWF:Rco/vWF:AG ratio = 0.9
CaseNOTHPOs: HP:0030132
(Absence of large von Willibrand factor multimers)
CaseNOTHPOFreeText:
CasePreviousTesting: NA
GenotypingMethod: NA
PreviouslyPublished: PMID: 11992235
Gene: VWF
Variant: c.6536C>T (p.Ser2179Phe)
HGVS: NM_000552.4(VWF):c.6536C>T (p.Ser2179Phe)
ClinVarID: 100442; https://www.ncbi.nlm.nih.gov/clinvar/variation/100442/
CAID:
gnomAD: absent
8 M/46 <1 7 No 19 c.4576C>Ta/c.6973T>Aa p.Q1526Xa/p.C2325Sa 28/40 Heterozygous
Case: 8, M, 46, Italian
DiseaseAssertion: VWD type 3
FamilyInfo: Consanguinity: no
ParentalGenotype: n/a
CasePresentingHPOs: n/a
CaseHPOFreeText: VWF:Ag (IU/dL): <1, FVIII:C (IU/dL): 7, Bleeding Score: 19
CaseNotHPOs: n/a
CaseNotHPOFreeText: Anti-VWF alloantibodies: no
CasePreviousTesting: n/a
Gene: VWF
Variant:
c.4576C>T (p.Gln1526X), Exon 28
c.6973T>A (p.Cys2325Ser), Exon 40, B1 Domain
Compound Heterozygous
Outgrowing the laboratory diagnosis of type 1 von Willebrand disease: A two decade study Mouhamed Yazan Abou-Ismail, Corresponding Author Mouhamed Yazan Abou-Ismail yazan.abouismail@case.edu orcid.org/0000-0002-6682-4366 Department of Medicine, Rochester General Hospital, Rochester, New YorkCorrespondence M. Yazan Abou-Ismail, University Hospitals, Cleveland Medical Center, Division of Hematology & Oncology, 11100 Euclid Avenue, Cleveland, OH 44106, USA. Email: yazan.abouismail@case.eduSearch for more papers by this authorGbolahan O. Ogunbayo, Gbolahan O. Ogunbayo orcid.org/0000-0002-4140-8067 Department of Medicine, Rochester General Hospital, Rochester, New YorkSearch for more papers by this authorMichelle Secic, Michelle Secic Secic Statistical Consulting Inc, Chardon, OhioSearch for more papers by this authorPeter A. Kouides, Peter A. Kouides orcid.org/0000-0002-3857-8313 Department of Medicine, Rochester General Hospital, Rochester, New York Mary M. Gooley Hemophila Center, Rochester, New YorkSearch for more papers by this author
PMID: 29098718
Gene: VWF
HGNC: 12726 (type 1)
Note: This article is about how VWF levels change as VWD patients age.
homozygous small deletion in exon 45 (p.Gln2551AlafsX16)
Case: IP-2
DiseaseAssertion: VWD3
FamilyInfo: The mother reported no history of bleeding episodes and the laboratory data were in the border line of the normal range.
ParentalGenotype(s): mother is heterozygous for the p.Gln2551AlafsX16 in the VWF gene
CasePresentingHPOs: HP:0000421
CaseHPOFreeRext: VWF:Ag <6%, VWF:RCo <6% and FVIII:C 2%. Clinically, repetitive severe epistaxis and subcutaneous hematomas were observed.
CaseNOTHPOs:
CaseNOTHPOFreeText:
CasePreviousTesting: Direct sequencing of exons 2–52 including exon/intron boundaries of the VWF gene
GenotypingMethod: multiple ligation‐dependent probe amplification (MLPA; using kit P011 and P012; MRC Holland, Amsterdam, the Netherlands) according to the manufacturer’s instructions. The PCR products were run on an ABI PRISM 3130XL sequencer with the GeneScan 500 LIZ size standard and analyzed using GeneMapper Software 5.0 (Applied Biosystems, Darmstadt, Germany).
PreviouslyPublished: NA
Gene: VWF
Variant: p.Gln2551AlafsX16
HGVS:
ClinVarID:
CAID:
gnomAD:
MultipleGeneVariants:
GeneName: VWF
Variant: whole gene deletion
ClinVarID or CAID:
gnomAD:
Quantitative 3D microscopy highlights altered von Willebrand factor α‐granule storage in patients with von Willebrand disease with distinct pathogenic mechanisms
PMID: 34532631
Notes: Homozygous instance of an otherwise type 2 variant, Cys1190Arg
2
Case#: 2, female, 25yo
DiseaseAssertion: VWD1
FamilyInfo: N/A
ParentalGenotype: N/A
CasePresentingHPOs: HP:0000978, HP:0000421, HP:0000132, HP:0011891, HP:0004846, HP:0012147 (bruising susceptibility, epistaxis, Menorrhagia, Post-partum hemorrhage, Reduced quantity of VWF, Impaired ristocetin cofactor assay activity)
CaseHPOFreeText: Type A blood, VWF:Ag (0·55–2 iu/ml) pre = 0·48, VWF:RCo (0·55–2 iu/ml) pre = 0·53, FVIII:C (0·55–2 iu/ml) pre = 0·25, FVIII:C/VWF:Ag ratio = 0·52, VWF:FVIII binding (>20%) = N/A, VWF:FVIII binding/VWF:Ag (>0·7) = N/A, multiple surgical interventions with VWF concentrate with adequate haemostasis
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
ProteinExpression: N/A
CasePreviousTesting: RFLP; confirmatory sequencing
Gene: VWF
Variant 1: NM_000552.4(VWF):c.2561G>A (p.Arg854Gln)
ClinVar: 296; https://www.ncbi.nlm.nih.gov/clinvar/variation/296/
gnomAD: MAF = 0.005692 (European Non-Finnish); https://gnomad.broadinstitute.org/variant/12-6143978-C-T
Variant 2: N/A - stated to be a compound heterozygote for a 2N VWD and a presumed null mutation
A COVID Constellation: A Case of Transverse Myelitis and Acquired von Willebrand Syndrome
PMID: 35927967 Gene: VWF HGNCID: 12726
Von Willebrand Disease type 2 in pregnancy - A critical clinical association
PMID: 28559097
Gene: VWF
HGNCID: 12726
IC
Case 1: index case of family 3.
DiseaseAssertion: previous diagnosis of type 1 VWD
FamilyInfo: not provided
ParentalGenotype(s): unknown
CasePresentingHPOs: unknown
CaseHPOFreeRext: unknown
CaseNOTHPOs: unknown
CaseNOTHPOFreeText: unknown
CasePreviousTesting: no
GenotypingMethod: Sanger sequencing of exon 28
PreviouslyPublished: n/a
Gene: VWF
Variant: c.3797C>A
HGVS:
ClinVarID: 100279
CAID:
gnomAD: AF = 0.0005419 (874/1612906) https://gnomad.broadinstitute.org/variant/12-6019621-G-T?dataset=gnomad_r4