Case: 29, F, 0.8 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: yes, family history of disease

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.7558C>T (p.Gln2520* ), Exon 45, Homozygous

Case: 15, M, 29 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: no, family history of disease

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: FVIII:C: (U/dl): 1.8, VWF:Ag (U/dl): <1, Bleeding Score: 16

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.5335C>T (p.Arg1779*), Exon 31, Homozygous

Case: 23, F, 10 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: yes, family history of disease

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: FVIII:C: (U/dl): 3.1, VWF:Ag (U/dl): <1, Bleeding Score: 8

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.2430C>A (p.Cys810*), Exon 18, Heterozygous

Case: 12, F, 16 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: no, family history of disease

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: FVIII:C: (U/dl): 6, VWF:Ag (U/dl): <1, Bleeding Score: 16

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.5335C>T (p.Arg1779*), Exon 31, Homozygous

Case: 20, M, 10 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: no, family history of disease

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: FVIII:C: (U/dl): <1, VWF:Ag (U/dl): <1, Bleeding Score: 8

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.7603C>T (p.Arg2535*), Exon 45, Homozygous

Case: T090, M, 2

DiseaseAssertion: VWD type 3

FamilyInfo: inherited heterozygous gene conversion from the father

CasePresentingHPOs: n/a

CaseHPOFreeText: Bleeding Score: 8 (Kruskal–Wallis followed by Mann–Whitney U post-hoc testing Post-hoc testing ), VWF:Ag (IU/ml): 0.01, VWF:RCo (IU/ml): 0.04, FVIII:C (IU/ml): 0.01

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.1117C>T (p.Arg373*)

Gene Conversion (

c.3931C>T (p.Gln1311*)

c.4027A>G (p.Ile1343Val)

c.4079T>C (p.Val1360Ala)

c.4105T>A (p.Phe1369Ile)

)

Exon 10/28

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

Case: T078, F, 5

DiseaseAssertion: VWD type 3

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: Bleeding Score: 9 (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.5455 + 2 T>C, Exon 31, 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

Case: T028, M, 34

DiseaseAssertion: VWD type 3

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: Bleeding Score: 16 (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): 0.03

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.7730-1 G>T, Exon 46, Homozygous

c.7906A>T (p.Asn7906Tyr), Exon 48, Heterozygous

Note: ELISA-based assay for detecting alloantibodies, genomic analysis via sequecning 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

Case: 4 , M, 55, Italian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: no

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:

1093C→T (Arg365X), Exon 9

1830C→A (Tyr610X), Exon 15

Compound Heterozygous

Case: 30, F, 32, 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:

6977-1G→C (intronic), Exon 41, Homozygous

Note: The article assumes 6977-1G→C would be a frameshift mutation. 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. 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

Case: 18, M, 21, Iranian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: Yes

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: VWF:Ag (U/dl): 2, Bleeding symptoms: Severe

CaseNotHPOs: n/a

CaseNotHPOFreeText: Anti-VWF alloantibodies: no

CasePreviousTesting: n/a

Gene: VWF

Variant:

1930G→T (Glu644X), Exon 15, Homozygous

Case: 37, F, 29, 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:

1896G→A (Trp642X), Exon 15

3212G→T (Cys1071Phe), Exon 24

Compound Heterozygous

Case: 2, M, 40, Italian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: yes

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: VWF:Ag (IU/dL): <1, FVIII:C (IU/dL): 6, Bleeding Score: 21

CaseNotHPOs: n/a

CaseNotHPOFreeText: Anti-VWF alloantibodies: no

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.8155+1G>T (p.Gly2706_Cys2719delfsX25), Intron 50, Homozygous

Note: patient also has heterozygous insertion of five intronic nucleotides (GTAAG) between exons 45 and 46; c.8155+1G>T resulted in altering the normal mRNA splicing process

Case: 4, M, 5, Italian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: not reported

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: VWF:Ag (IU/dL): <1, FVIII:C (IU/dL): 17, Bleeding Score: 6

CaseNotHPOs: n/a

CaseNotHPOFreeText: Anti-VWF alloantibodies: no

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.2269delCT (p.Leu757ValfsX22), Exon 17, Homozygous

Note: paretns investigated for the probands defects and confirmed to carry the expected mutation at the heterozygous state

Case: 6, M, 28, Italian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: no

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: VWF:Ag (IU/dL): <1, FVIII:C (IU/dL): 9, Bleeding Score: 15

CaseNotHPOs: n/a

CaseNotHPOFreeText: Anti-VWF alloantibodies: no

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.2157delA (p.Asp20ThrfsX21), Exon 16

c.7729+7C>T (p.Glu2577GlyfsX21), Intron 45

Compound Heterozygous

Note: patient also has homozygous deletion of 40 bp (NP_000543.2, where 1 is adenine in ATG initiation codon) due to the skipping of exon 50; c.7729+7C>T resulted in altering the normal mRNA splicing process

Case: 3, F, 5, Italian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: yes

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: VWF:Ag (IU/dL): <1, FVIII:C (IU/dL): 4, Bleeding Score: 9

CaseNotHPOs: n/a

CaseNotHPOFreeText: Anti-VWF alloantibodies: no

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.658–2A>G (p.Gly220_Ser292delfsX27), Intron 6, Homozygous

Note: patient also has homozygous deletion of 217 bp (NP_000543.2, where 1 is adenine in ATG initiation codon) due to the skipping of exon 7; c.658–2A>G resulted in altering the normal mRNA splicing process

Case: P36, Chinese, male, 56yo

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type A blood, bleeding score = 10; VWF:Ag (%) = 1.0, VWF:RCo (%) = 0.9, FVIII:C (%) = 4.1, VWF:CB (%) = 0.9, VWFpp (%) = 0.9, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 0.9, VWFpp/VWF:Ag = 0.9, FVIII:C/VWF:Ag = 4.1

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.5870delA - unregistered variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Case: P22, Chinese, male, 22yo

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 10; VWF:Ag (%) = 1.4, VWF:RCo (%) = 1.2, FVIII:C (%) = 5.1, VWF:CB (%) = 1.3, VWFpp (%) = 1.0, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 0.9, VWFpp/VWF:Ag = 0.7, FVIII:C/VWF:Ag = 3.6

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.8116–2delA - Unregistered variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Case: P33, Chinese, female, 35yo

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type A blood, bleeding score = 10; VWF:Ag (%) = 0.5, VWF:RCo (%) = <0.5, FVIII:C (%) = 5.0, 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 = 10.0

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.813C>G (p.Tyr271Ter)

HGVS: NM_000552.5:c.813C>G (p.Tyr271Ter)

ClinVarID: NA

CAID: CA383508522; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383508522

gnomAD: MAF = 0.0001088 (2/18380 alleles) in the East Asian popualtion; https://gnomad.broadinstitute.org/variant/12-6184562-G-C

Case#: Elayaperumal_2018_V-260 , M, 3y.o. (onset), origin in India

DiseaseAssertion: VWD type 3

FamilyInfo: consanguinity reported. No family history of bleeding

ParentalGenotype: not reported

CasePresentingHPOs:

CaseHPOFreeText: bleeding score of 9, VWF:Ag of 0, FVIII:C of 7.4%

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: not reported

GenotypingMethod: CSGE and Sanger sequencing of VWF gene only.

Gene: VWF

Variant: homozygous c.665G>A (p.Trp222*)

HGVS: NM_000552.3:c.665G>A

ClinVarID: not found

CAID: CA383509511

gnomAD: not found

MultipleGeneVariants: n/a

Case#: Elayaperumal_2018_V-312 , M, 2.5 y.o. (onset), origin in India

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: Yes, Family history: No

ParentalGenotype: not reported

CasePresentingHPOs:

CaseHPOFreeText: Bleeding score: 7, VWF:Ag 0, FVIII:C 3.6%

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: not reported

GenotypingMethod: CSGE and Sanger sequencing of VWF gene only.

Gene: VWF

Variant: homozygous c.3560delT

HGVS: NM_000552.3:c.3560delT (p.Leu1187Cysfs*28)

ClinVarID: not present

CAID: CA2580612141

gnomAD: not present

MultipleGeneVariants:

Case#: Elayaperumal_2018_V-316, F, 1.5 y.o. (onset), origin in India

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: Yes, Family history: Yes

ParentalGenotype: not reported

CasePresentingHPOs:

CaseHPOFreeText: Bleeding score: 0, VWF:Ag 0, FVIII:C 3.4%

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: not reported

GenotypingMethod: CSGE and Sanger sequencing of VWF gene only.

Gene: VWF

Variant: homozygous c.2749 2752dupCCCT (p.Val919Leufs*18)

HGVS: NM_000552.3:c.2749 2752dupCCCT

ClinVarID: not present

CAID: CA2695215955

gnomAD: not present

MultipleGeneVariants:

Case#: Elayaperumal_2018_V-115, female, 1 year old (onset), origin in India

DiseaseAssertion: VWD type 3

FamilyInfo: consanguinity

ParentalGenotype: not reported. family history of bleeding.

CasePresentingHPOs:

CaseHPOFreeText: bleeding score of 13. VWF:Ag of 0. FVIII:C of 1.9%

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: not reported

GenotypingMethod: CSGE and Sanger sequencing of VWF only.

Gene: VWF

Variant: homozygous c.6321G>A (p.Trp2107*)

HGVS: NM_000552.3:c.6321G>A (p.Trp2107*)

ClinVarID: not found

CAID: CA383491677

gnomAD: not found

MultipleGeneVariants: not reported

Case: Patient 17, F, Hungarian

DiseaseAssertion: VWD type 3

FamilyInfo: compatible with recessive inheritance

ParentalGenotype(s): n/a

CasePresentingHPOs: n/a

CaseHPOFreeRext: Bleeding score: 18, VWF:Ag (IU dL−1): < 1, VWF:CB (IU dL−1): < 1, FVIII:C (IU dL−1): 4, VWF:RCo below detection limit (<10 IU dL−1), not detectable VWF on multimer gels, bleeding episode severity increased after the menarche

CaseNOTHPOs: n/a

CaseNOTHPOFreeText: no inhibitor detecteddid not become refractory to factor replacement therapy

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.7333delG (p.Glu2445ArgfsX16), Exon 43

c.7703C>A (p.Ser2568X), Exon 45

Intron 40 VNTR 17/18

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

Case: Patient 12, F, Hungarian

DiseaseAssertion: VWD type 3

FamilyInfo: compatible with recessive inheritance

ParentalGenotype(s): n/a

CasePresentingHPOs: n/a

CaseHPOFreeRext: Bleeding score: 32, VWF:Ag (IU dL−1): 1, VWF:CB (IU dL−1): 1, FVIII:C (IU dL−1): 7, VWF:RCo below detection limit (<10 IU dL−1), not detectable VWF on multimer gels, bleeding episode severity increased after the menarche

CaseNOTHPOs: n/a

CaseNOTHPOFreeText: no inhibitor detected, did not become refractory to factor replacement therapy

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.2124_2125delCT (p.Cys709LeufsX3), Exon 16, 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

Case: Patient 8, M, Hungarian

DiseaseAssertion: VWD type 3

FamilyInfo: compatible with recessive inheritance

ParentalGenotype(s): n/a

CasePresentingHPOs: n/a

CaseHPOFreeRext: Bleeding score: 19, 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

CaseNOTHPOs: n/a

CaseNOTHPOFreeText: no inhibitor detected, did not become refractory to factor replacement therapy

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.2435delC (p.Pro812ArgfsX31), Exon 18, Homozygous

Intron 40 VNTR: 19/19

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

Case: Patient 15, F, Hungarian

DiseaseAssertion: VWD type 3

FamilyInfo: compatible with recessive inheritance

ParentalGenotype(s): n/a

CasePresentingHPOs: n/a

CaseHPOFreeRext: 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, bleeding episode severity increased after the menarche

CaseNOTHPOs: n/a

CaseNOTHPOFreeText: no inhibitor detected, did not become refractory to factor replacement therapy

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.3379+1G>A (Splice), Exon 25, Homozygous

(p.Arg924Gln), Exon 21, 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

Case: Croatian adult patient

DiseaseAssertion: VWD3

FamilyInfo: No variant detected in a family member with VWD3.

ParentalGenotype(s): Not specified

CasePresentingHPOs: HP:0001892, HP:0011890, HP:0000132, HP:0002239, HP:0000790, HP:0001342

CaseHPOFreeText: Reduced VWF:Ag of <4.0%, VWF:GPIbM of 8.3%, FVIII:C of 5% and VWF:CBA below 1%.

CaseNOTHPOs: Not specified

CaseNOTHPOFreeText: Not specified.

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.6151A>T

HGVS: NM_000552.4:c.6151A>T (c.6151A>T)

ClinVarID: Not available

CAID: CA383492290

gnomAD: Not available