Case#: Functional assay variant with a clinical significance of being a VUS.

DiseaseAssertion: MPS-I

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1757C>T (p.S586P)

Variant1ClinVarID: 571910

Variant1CAID: CA2802396

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Functional assay variant with a clinical significance of pathogenic.

DiseaseAssertion: MPS-I

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1469T>C (p.L490P)

Variant1ClinVarID: 11919

Variant1CAID: CA220503

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

PMID:32829671

Case#: No additional case information provided

DiseaseAssertion: MPSI-H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 0.09 umol/g hr, reference range 10–50 umol/g hr.

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1278_1284dupCCCCCAG (p.G429PfsTer82)

Variant1ClinVarID: N/A

Variant1CAID: CA645372299

Variant2: c.208C>T (p.Q70X)

Variant2ClinVarID: 11909

Variant2CAID: CA204563

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

PMID:33208168

Gene:IDUA

Disease:NoDiseaseAssertion"

Case#: Patient 20, born in 2003 (paper published in 2017), 20 months (age at first treatment)

DiseaseAssertion: MPSI-H

FamilyInfo: N/A

CasePresentingHPOs: Corneal clouding (HP:0007957)

CaseHPOFreeText: N/A

CaseNotHPOs: Retinopathy, cataract (HP:0000488, HP:0000518)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 57.2 ng/mol (26 weight matched enzyme reference assay)

CaseUrineGAGs: 0.63 DS/CS

CaseERT: No

CaseBMT: Yes, Cord

Variant1: c.208C>T (p.Q70X)

Variant1ClinVarID: 11909

Variant1CAID: CA204563

Variant2: c.1898C>A (p.S633X)

Variant2ClinVarID: 1068474

Variant2CAID: CA355966009

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 24, 1 years old (age at report), female, Indian

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Coarse facial features, joint contractures, corneal clouding, dysostosis multiplex, intellectual disability (HP:0000280, HP:0002828, HP:0007957, HP:0000943, HP:0001249)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: 2.7% (Range of residual enzyme activity: 0.0%-4.8%)

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1096_1099del (p.Thr366Argfs*73)

Variant1ClinVarID: 1065522

Variant1CAID: CA2499217017

Variant2: c.1096_1099del (p.Thr366Argfs*73)

Variant2ClinVarID: 1065522

Variant2CAID: CA2499217017

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

PMID: 25102484

Gene: IDUA

Disease: MPS1

Inheritance: Autosomal recessive

Case#: 10, Male, 2 months (onset), 2 months (diagnosed), 2 months (report), deceased (due to severe graft versus host disease)

DiseaseAssertion: Hurler Syndrome

FamilyInfo: Not Provided

CasePresentingHPOs: HP:0002240, HP:0001744, HP:0001537, HP:0000158, HP:0000280, HP:0000943, HP:0007957 (Hepatomegaly (moderate), Splenomegaly (moderate), Umbilical Hernia, Large Tongue, Coarse Facial Features, Dysostosis Multiplex, Corneal Clouding)

CaseHPOFreeText: Mental Development (Delayed since early infancy)

CaseNotHPOs: HP:0000256 (Macrocephaly)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: Hematopoietic Stem Cell Transplantation at 5m

GenotypingMethod: Not Provided

Variant1: p.Q70X

Variant1ClinVarID: 11909

Variant1CAID: CA204563

Variant2: p.Q70X

Variant2ClinVarID: 11909

Variant2CAID: CA204563

AdditionalVariants: p.Q33H/Q33H, p.L118/L118

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient V, origin of proband is United Kingdom

DiseaseAssertion: Hurler syndrome (H)

FamilyInfo: No family information is provided

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: IDUA enzyme activity for this proband is N/A. The reference range is also N/A.

CaseUrineGAGs: Information not stated in this paper

CaseERT: Don't know

CaseBMT: Don't know

Variant1: c.1598C>G, p.P533R

Variant1ClinVarID: 11910

Variant1CAID: CA256112

Variant2: c.(157 + 1_158‐1)_(1727 + 1_1728‐1)dup

Variant2ClinVarID: Not sure how to look up in CAR

Variant2CAID: Not sure how to look up in CAR

AdditionalVariants: No additional variants mentioned

ParentalGenotype: No parental genotype information provided

PreviouslyPublished: I do not believe this proband was previously published. The paper states that variant "c.1598C>G have been found in patients previously." It does not link the variant to a specific paper but instead references a list of papers. Here are the PMIDs of those paper: 7951228, 1301196, 1301941, and 7550232

Case#: 2, Male, 0.9 years (diagnosed), 4.2 years (report), 11 kg (weight), 65 cm (height), Iranian

DiseaseAssertion: Hurler-Scheie Syndrome

FamilyInfo: Parents are consanguineous

CasePresentingHPOs: HP:0000943, HP:0001387 (Multiple Dysostosis, Joint Stiffness)

CaseHPOFreeText: HM/HSM,

CaseNotHPOs: HP:0001249, HP:0001999, HP:0100790, HP:0000365, HP:0007957, HP:0000238 (Mental Retardation, Facial Dysmorphic Features, Hernia, Deafness, Corneal Opacity, Hydrocephalus)

CaseNotHPOFreeText: NM/HSM, Chronic Rhinorrhea, Cardiac Manifestations

CaseEnzymeAssay: IDUA activity 7.06 (μmol/spot.20h)

CaseUrineGAGs: Quantitative urinary GAG 14.22 (mg/gCr)

CaseERT: N/A

CaseBMT: N/A

GenotypingMethod: Sanger Sequencing

Variant1: p.S157P

Variant2: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: 4 (Thai, female, diagnosed at 4y6m)

DiseaseAssertion: MPS1

FamilyInfo: Thai, no consanguinity

CasePresentingHPOs: 0007759 (cloudy cornea); 0002240 (hepatomegaly); 0002857 (knock knee)

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText: no neurological symptoms detected

CaseEnzymeAssay: 3.23 nmole/18 h/mg protein

CaseUrineGAGs:

CaseERT:

CaseBMT:

Variant1:IDUA c.935G>A: Ex7 (p.W312X)

Variant1ClinVarID: 8555322

Variant1CAID:

Variant2: IDUA c.*1T>C Ex14 (p.X654Rext38)

Variant2ClinVarID:

Variant2CAID:

AdditionalVariants:

ParentalGenotype:

PreviouslyPublished

Case#: Patient 2, female, 2 years (age of onset), 5 years (age at report)

DiseaseAssertion: MPS1

FamilyInfo: Born from a consanguineous marriage (second cousin parents), she had a twin sister that died a few weeks after birth. Her mother experienced intrauterine fetal death (IUFD) during her first pregnancy and after the second pregnancy infant died of congenital heart defects (CHD).

CasePresentingHPOs: Claw hand deformity, deafness, coarse facial features, dolichocephaly, neurodevelopmental delay, developmental regression (HP:0034337, HP:0000365, HP:0000256, HP:0000268, HP:0012758, HP:0002376)

CaseHPOFreeText: Began pronouncing words at 9 months, sitting at 10 months, and started walking at the age of 2. Her developmental conditions lapsed after the age of 2.

CaseNotHPOs: Intellectual disability (HP:0001249)

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: N/A

CaseUrineGAGs: GAG electrophoresis revealed increased amounts of DS and CS

CaseERT: She currently is taking Aldorazyme medication

CaseBMT: N/A

Variant1: c.612_615dupCTGC

Variant1ClinVarID: 226413

Variant1CAID: CA10576338

Variant2: c.612_615dupCTGC

Variant2ClinVarID: 226413

Variant2CAID: CA1057633

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: No additional case information provided

DiseaseAssertion: MPSI-H

FamilyInfo: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CaseEnzymeAssay: Abnormal

CaseUrineGAGs: Abnormal

CaseERT: N/A

CaseBMT: N/A

Variant1: c.208C>T (p.Q70X)

Variant1ClinVarID: 11909

Variant1CAID: CA204563

Variant2: c.1269C>A (p.S423R)

Variant2ClinVarID: 856833

Variant2CAID: CA91169964

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished N/A

Case#: Patient 35, female, Han origin, 3 years old (age at diagnosis)

DiseaseAssertion: MPS1-H

FamilyInfo: N/A

CasePresentingHPOs: Global Developmental Delay, Macrocephaly, Joint stiffness, Hepatosplenomegaly, Hernia, Airway obstruction (HP:0001263, HP:0000256, HP:0001387, HP:0001433, HP:0100790, HP:0006536)

CaseHPOFreeText: N/A

CaseNotHPOs: Mongolian macula (HP:0011369)

CaseNotHPOFreeText: Cardiac disease

CaseEnzymeAssay: IDUA activity 1.2 nmol/h/mg protein. The normal range in Chinese controls was found to be 27.2–52 nmol/h/mg protein.

CaseUrineGAGs: Diagnosis was confirmed biochemically by the demonstration of an increased excretion of urinary dermatan sulfate and heparan sulfate.

CaseERT: N/A

CaseBMT: N/A

Variant1: c.1227dupG (paper says c.1225dupC but according to the variant sequence this should be c.1227dupG - a known variant)

Variant1ClinVarID: 929237

Variant1CAID: CA1139658406

Variant2: c.1244_1271del27 - Allele registry states that the range is off by 1, noting a deletion of 28 being found instead of 27.

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: The transmission of sequence variations found in each patient was inferred by sequencing the corresponding exons of the patient's parents - confirmed in trans by parental testing.

PreviouslyPublished N/A

Case#: Variant not associated with a proband. Variant listed in supplementary materials in Supplementary Table 4

DiseaseAssertion: Mucopolysaccharidosis type I, MPS I

FamilyInfo: N/A

CasePresentingHPOs:

CaseHPOFreeText:

CaseNotHPOs:

CaseNotHPOFreeText:

CaseEnzymeAssay: N/A

CaseUrineGAGs: N/A

CaseERT: N/A

CaseBMT: N/A

Variant1: P533R

Variant1ClinVarID: 11910

Variant1CAID: CA256112

Variant2: N/A

Variant2ClinVarID: N/A

Variant2CAID: N/A

AdditionalVariants: N/A

ParentalGenotype: N/A

PreviouslyPublished: N/A

Case#: 02059, Age 38, Male, Blood type A+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: Patient is a member of family # 02059. There is one other member of the family (patient 02060). 02060 has the same exonic variant (c.3614G>A), but has a different intronic variant ( c.7438-169G>A).

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding score 12, VWF:Ag: 5.4, VWF:RCo: 6.1, FVIII:C:11, VWF:CB: 4.5

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.3614G>A (p.Arg1205His) and

ClinVar: 308 ClinVar

CAID: CA114160 CAID1

gnomAD:

Case#: 02001, Age 63, Female, Blood Type A+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo:( Family 0201) 8 family members were included in the study. All of them had type VWD type 1. All had the same variant besides patient 02019.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 14, VWF:Ag: 9.7, VWF:RCo: 2.6, FVIII:C: 19, 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

Case#: 02069, Age 45, Female, Blood Type O+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patients was 1 of 3 members of family #0226.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 5, VWF:Ag: 30, VWF:RCo:27, FVIII:C: 81, VWF:CB: 40

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.3467C>T (p.Thr1156Met) and NM_000552.3:c.-3151T>G

ClinVar: 100264 ClinVar

CAID: CA228414 CAID

gnomAD: N/A

Case#: 27030, Age 23, Male, Blood Type O+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient is one of 6 members in Family #2703. All members have the same variant.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: VWF:Ag:26, VWF:RCo:28.6, FVIII:C:81, VWF:CB: 30

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.1533+15G>A (p.=)

ClinVar: 100182 ClinVar

CAID: CA228275 CAID

gnomAD: MAF of 0.002649 ( 93/ 35104 alleles) in the Latino Population. gnomAD

Case#: 01037, Age 16, Male, Blood Type O- (Table S3)

Disease Assertion: VWD 1

FamilyInfo: Not listed

Parental Genotype: Not listed

CasePresentingHPOs:

CaseHPOFreeText: Bleeding type 14, VWF:Ag: 22, VWF:RCO: 32, FVIII:C: 28, 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.3426T>C (p.Cys1142=) and NM_000552.4:c.3485_3486inv (p.Pro1162Leu)

ClinVar: 256668 and 619934

ClinVar1 ClinVar2

CAID: CA6402757 and CA658683073

CAID1 CAID2

gnomAD: MAF of 0.2228 (2240/10052 alleles) in the African population (CA6402757).

gnomAD1

Case#: 03015, Age 37, Female, Blood Type O+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: Patient is the only member of family #0399.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding score 0, VWF:Ag: 17, VWF:RCo: 17.7, FVIII:C 15, 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: Not determined

ClinVar: N/A

CAID: N/A

gnomAD: N/A

Case#: 10013, Age 23, Female, Blood Type O+ (Table S3)

Disease Assertion: VWD1

FamilyInfo: The patient is the only member of Family#1011.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 3, VWF:Ag:7.2, VWF:RCo:5.6, FVIII:C:19, VWF:CB:6.5

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.5198T>C (p.Leu1733Pro)

ClinVar: N/A

CAID: CA383496267 CAID

gnomAD: N/A

Case#: 02047, Age 71, Male, Blood Type: O+ (Table S3)

Disease Assertion:VWD 1

FamilyInfo: Family# 0218; 3 Family members were included in the study. All 3 members had VWD type 1. All 3 have the same variant as patient 02047.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 9, VWF:Ag: 9.3, VWF:RCo:6.4, FVIII:C: 30, VWF:CB: 6.1

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.5471C>A (p.Pro1824His)

ClinVar: 100430 ClinVar

CAID:CA228725

CAID

gnomAD: N/A

Case#: 32010, Age 21, Male, Blood Type not determined (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient is one of two members of Family#3210. The second member is a carrier of the variant c.3931C>T.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 12, VWF:Ag:7.2, VWF:RCo: 5.7, FVIII:C: 21, VWF:CB: 6.8

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_000552.4:c.3931C>T (p.Gln1311Ter) and NM_000552.4:c.55G>A (p.Gly19Arg)

ClinVar: 100307 and 100432 ClinVar1 ClinVar

CAID: CA228496 and CA228729 CAID1 CAID2

gnomAD: MAF of 0.0003921 (12/ 30604 alleles) in the South Asian population (CA228496). gnomAD

MAF of 0.0008819 (27/ 30616 alleles) in the South Asian population.

gnomAD

Case#: 06002, Age 39, Female,Blood Type O+ (Table S3)

Disease Assertion: VWD1

FamilyInfo: Two total members in Family #0602. Patient 06003 has the c.2685G>C variant and a seperate intronic variant.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding score 8, VWF:Ag: 25, VWF:RCo: 19.1, FVIII:C:88, VWF:CB:24

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.2685G>C (p.Gln895His) and NM_000552.4:c.4751A>G (p.Tyr1584Cys)

ClinVar: 310

ClinVar

CAID: CA383519910 and CA114162

CAID1 CAID2

gnomAD: MAF of 0.004024 (519/128972 alleles) in the European (non-Finnish) population.

gnomAD

Case#: 06009, Age 60, Female, Blood Type O+ (Table S3)

Disease Assertion: VWD1

FamilyInfo: The patient is the only member of family#0607.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 2, VWF:Ag:23, VWF:RCo: 25, FVIII:C 83, VWF:CB: 23

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.2435del (p.Pro812fs)

ClinVar: 303 ClinVar

CAID: CA114153 CAID

gnomAD: MAF of 0.0003601(9/ 24994 alleles) in the European (Finnish) population.

gnomAD

Case#: 13006, Age 66, Male, Blood Type A-

Disease Assertion: VWD 1

FamilyInfo: The patient is the only member of Family# 1304.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 8, VWF:Ag:10, VWF:RCo: 6, FVIII:C:16, VWF:CB:6.1

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

Case#: 13014, Age20, Male, Blood type O+ (TableS3)

Disease Assertion: VWD 1

FamilyInfo: The patient is the only member of Family#1311.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 6, VWF:Ag:24, VWF:RCo: 22.5, FVIII:C:40, VWF:CB: 20

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)

ClinVar: 310 ClinVar

CAID: CA114162 CAID

gnomAD: MAF of 0.004024 (519/ 128972 alleles) in the European (non-Finnish) population

Case#: 03044, Age 27, Female (Table S3)

Disease Assertion: VWD 1

FamilyInfo: Patient was the only member of family #03230

Parental Genotype: not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding Score 3, VWF:Ag: 22, VWF:RCo:18, FVIIIC:29, VWF:CB: 17

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: c.6699_6702dup (p.Cys2235ArgfsTer8)

ClinVar:

CAID:

gnomAD:

Case#: 27012, Age 24, Female, Blood Type O+ (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient is the only member of Family #2707.

Parental Genotype: Not listed

CasePresentingHPOs: N/A

CaseHPOFreeText: VWF:Ag: 33, VWF:RCo: 29, FVIII:C: 91, VWF:CB: 32

CaseNotHPOs: N/A

CaseNotHPOFreeText: Bleeding score 0

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.3467C>T (p.Thr1156Met) and c.-3151T>G

ClinVar: 100264 ClinVar

CAID: CA228414 CAID

gnomAD:

Case#: 22011, Age 67, Male, Blood Type A- (Table S3)

Disease Assertion: VWD 1

FamilyInfo: The patient is the only member of Family#2207.

Parental Genotype: N/A

CasePresentingHPOs: N/A

CaseHPOFreeText: Bleeding score 7, VWF:Ag: 18, VWF:RCo:16, FVIII:C:46, VWF:CBNM_0:14

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.6799-47G>A (p.=), NM_000552.4:c.7464C>T (p.Gly2488=), NM_000552.4:c.998-46C>T (p.=)

ClinVar: 619755 ClinVar1

CAID: CA6401901, CA232284628, CA6403602 CAID1 CAID2 CAID3

gnomAD: MAF of 0.0005876 (17/ 28930 alleles) in the South Asian population (CA6401901). gnomAD1

MAF of 0.000008799 (1/ 113644 alleles) in the European (non-Finnish) population (CA232284628). gnomAD2

MAF of 0.00007581 (8/105528 alleles) in the European (non-Finnish) population (CA6403602) gnomAD3

Case: Patient 11, F, Hungarian

DiseaseAssertion: VWD type 3

FamilyInfo: compatible with recessive inheritance

ParentalGenotype(s): n/a

CasePresentingHPOs: n/a

CaseHPOFreeRext: Bleeding score: 21, 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 detected, did not become refractory to factor replacement therapy

CasePreviousTesting: n/a

Gene: VWF

Variant:

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

c.7514C>A (p.Ser2505X), Exon 44

Intron 40 VNTR: 18/19

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 21, M, Hungarian

DiseaseAssertion: VWD type 3

FamilyInfo: compatible with recessive inheritance

ParentalGenotype(s): n/a

CasePresentingHPOs: n/a

CaseHPOFreeRext: Bleeding score: 15, VWF:Ag (IU dL−1): 1, VWF:CB (IU dL−1): 1, FVIII:C (IU dL−1): 5, VWF:RCo below detection limit (<10 IU dL−1), low‐molecular‐weight multimer 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.1868G>A (p.Cys623Thr), Exon 15

c.3712C>T (p.Gln1238X), Exon 28

Intron 40 VNTR: 16/17

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 9, F, Hungarian

DiseaseAssertion: VWD type 3

FamilyInfo: compatible with recessive inheritance

ParentalGenotype(s): n/a

CasePresentingHPOs: n/a

CaseHPOFreeRext: Bleeding score: 10, 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.2435delC (p.Pro812ArgfsX31), Exon 18

c.5557C>T (p.Arg1853X), Exon 32

Intron 40 VNTR: 16/19

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 2, F, Hungarian

DiseaseAssertion: VWD type 3

FamilyInfo: compatible with recessive inheritance

ParentalGenotype(s): n/a

CasePresentingHPOs: n/a

CaseHPOFreeRext: Bleeding score: 23, VWF:Ag (IU dL−1): < 1, VWF:CB (IU dL−1): 1, FVIII:C (IU dL−1): 10, 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:

delEx1‐3 (delEx1‐3), Exon 1–3

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

Intron 40 VNTR: 18/19

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 24, 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): 5, VWF:CB (IU dL−1): 1.5, FVIII:C (IU dL−1): 7, VWF:RCo below detection limit (<10 IU dL−1), low‐molecular‐weight multimer on multimer gels (distribution of the very small amount of multimers seems almost normal)

CaseNOTHPOs: n/a

CaseNOTHPOFreeText: no inhibitor detected, did not become refractory to factor replacement therapy, gene dosage analysis performed in exon 3 gave normal results

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.1786C>A (p.His596Asn), Exon 15

Intron 40 VNTR: 15/19

SNPs, sequenced throughout the VWF gene (Table S1) were heterozygous and homozygous alternately

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: 63, M, 14 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: no family history of disease, Consanguinity: yes

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: FVIII:C: (U/dl): 7.5, VWF:Ag (U/dl): <1, Bleeding Score: 16

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.3931C>T (p.Gln1311*), Exon 28

c.4027A>G (p.Ile1343Val), Exon 28

c.4079T>C (p.Val1360Ala), Exon 28

Homozygous

Case: 89, F, 16 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): 3.9, VWF:Ag (U/dl): 3, Bleeding Score: 16

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.4525A>G (p.Ile1509Val), Exon 28

Compound Heterozygous

Case: 33, M, 4.5 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): 2.3, VWF:Ag (U/dl): <1, Bleeding Score: 10

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.2908delC (p.Leu970del), Exon 22, Homozygous

Case: 27, F, 16 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): 2, VWF:Ag (U/dl): 3.6, Bleeding Score: 11

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.7651C>T (p.Gln2551*), Exon 45, Homozygous

Case: 14, F, 2 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: family history of disease, Consanguinity: yes

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: FVIII:C: (U/dl): 3, VWF:Ag (U/dl): 2.6, Bleeding Score: 6

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.3862C>G (p.Leu1288Val), Exon 28

Heterozygous

Case: 16, F, 16 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, VWF:Ag (U/dl): <1, Bleeding Score: 16

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.7300C>T (p.Arg2434*), Exon 43, Homozygous

Note: Look over exon

Case: 85, F, 6 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: no family history of disease, Consanguinity: yes

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: FVIII:C: (U/dl): <1, VWF:Ag (U/dl): 2, Bleeding Score: 2

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.2282-2A>G, Exon 18

Heterozygous

Case: 17, M, 8 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: 7

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.7300C>T (p.Arg2434*), Exon 46, Homozygous

Note: Look over exon

Case: 80, F, 12 years, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: no, family history of disease

ParentalGenotype: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: FVIII:C: (U/dl): 3.2, VWF:Ag (U/dl): <1, Bleeding Score: 2

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.3931C>T (p.Gln1311*), Exon 28, Homozygous

Case: 4, M, 20 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, 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

Case#: Ahmad_2014_125

DiseaseAssertion: VWD type 2A

FamilyInfo: heterozygous (probably affected according to multimer analysis) mother

ParentalGenotype: heterozygous mother, homozygous wt father and sibling

CasePresentingHPOs: none described

CaseHPOFreeText: none described

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: not reported

GenotypingMethod: PCR, restriction digest

Gene: VWF

Variant: NM_000552.5(VWF):c.4883T>C (p.Ile1628Thr)

HGVS:

ClinVarID: 284

CAID:

gnomAD: not reported

MultipleGeneVariants:

PMID: 24712919

Gene: VWF

HGNCID: 12726

Note: abnormal multimers found in patient with p.I1628T variant

PMID: 28083987

Gene: VWF

HGNCID: 12726

Case: P2, male, 32yo

DiseaseAssertion: VWD2M

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147, HP:0030129, HP:0030130

(Reduced quantity of VWF, Impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity)

CaseHPOFreeText: bleeding score = 7; VWF:Ag (%) = 32, VWF:RCo(%) = 19, VWF:RCo/VWF:Ag ratio = 0.59, VWF:CIIIB (%) = 35, VWF:CIIIB/VWF:Ag ratio = 1.09, VWF:CVIB (%) = 32, VWF:CVIB/VWF:Ag ratio = 1.00

CaseNOTHPOs: HP:0030132

(Absence of large von Willebrand factor multimers)

CaseNOTHPOFreeText: NA

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: If applicable.

Gene: VWF

Variant: c.4117G>T (p.Asp1373Tyr)

HGVS: NM_000552.3:c.4117G>T (p.Asp1373Tyr)

ClinVarID: NA

CAID: CA383504503; http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA383504503

gnomAD: MAF = 0.00002891 (1/34588 alleles) in Latino/AdMixed American population; https://gnomad.broadinstitute.org/variant/12-6128467-C-A

Case: Patient 8, male, 9yo

DiseaseAssertion: VWD2M

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0030129, HP:0030130

(Impaired ristocetin cofactor assay activity, Impaired von Willebrand factor collagen binding activity)

CaseHPOFreeText: bleeding score = 3; VWF:Ag (%) = 57, VWF:RCo(%) = 43, VWF:RCo/VWF:Ag ratio = 0.75, VWF:CIIIB (%) = 35, VWF:CIIIB/VWF:Ag ratio = 0.61, VWF:CVIB (%) = 18, VWF:CVIB/VWF:Ag ratio = 0.32

CaseNOTHPOs: HP:0030132

(Absence of large von Willebrand factor multimers)

CaseNOTHPOFreeText: NA

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4196G>A

HGVS: NM_000552.5(VWF):c.4196G>A

ClinVarID: 293; https://www.ncbi.nlm.nih.gov/clinvar/variation/293/

CAID:

gnomAD: MAF = 0.01670 (173/10360 alleles) in the Ashkenazi Jewish population; https://gnomad.broadinstitute.org/variant/12-6128388-C-T?dataset=gnomad_r2_1

Case: T114, M, 48

DiseaseAssertion: VWD type 37 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): 0.03, VWF:RCo (IU/ml): 0.02, FVIII:C (IU/ml): 0.05

CaseNotHPOs: n/a

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

Case: T015, M, 72

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): 0.02, FVIII:C (IU/ml): 0.07

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

Case: T040, F, 4

DiseaseAssertion: VWD type 3

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: Bleeding Score: 11 (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.874 + 5 G>A, 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

Case: T143, F, 64

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): 0.04, VWF:RCo (IU/ml): 0.04, FVIII:C (IU/ml): 0.03

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.8043_8044delAG (p.Arg2681 fs), Exon 49, 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: T076, M, 12

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): 0.03, FVIII:C (IU/ml): 0.01

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.1897T>C (p.Cys633Arg ), Exon 15, 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: T006B, F, 11

DiseaseAssertion: VWD type 3

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: Bleeding Score: 11 (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.4006C>T (p.Arg1336*), Exon 28, Homozygous

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: T108, F, 60

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): 0.07, VWF:RCo (IU/ml): 0.01, FVIII:C (IU/ml): 0.06

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.4146G>T, p.(=)

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: T046, F, 16

DiseaseAssertion: VWD type 3

FamilyInfo: n/a

CasePresentingHPOs: n/a

CaseHPOFreeText: Bleeding Score: 21 (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): 0.02

CaseNotHPOs: n/a

CaseNotHPOFreeText: n/a

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.385C>A (p.Leu129Met), Exon 5

c.813C>A (p.Tyr271*), Exon 7

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

PMID: 28120508

Gene: VWF

HGNCID: 12726

Case: Patient 33, Family K (Table 1.), F/49, Afro-Caribbean

DiseaseAssertion: VWD2A (IIE)

FamilyInfo: Patient 18 (F/53, Afro-Caribbean), Patient 29 (F/33, Afro-Caribbean), Patient 32 (F/17, Afro-Caribbean) also from Family K. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT =17, FVIII:C (IU/dL) = 3, VWF:Ag (IU/dL) = 3, VWF:Act (IU/dL) = 7

CaseNOTHPOs:

CaseNOTHPOFreeText: Blood type 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.1661del, p.(Lys554Serfs*23)

HGVS: NM_000552.5:c.1661del (p.Lys554Serfs*23)

ClinVarID:

CAID: CA2617232671

gnomAD: MAF is 0.00001332 (1/75048 alleles) in African/African/American population https://gnomad.broadinstitute.org/variant/chr12-6057916-CT-C?dataset=gnomad_r4

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/chr12-6044368-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/chr12-6044348-A-G?dataset=gnomad_r4

Variant: c.2880G > A, p.(Arg960 =)

HGVS: NM_000552.5:c.2880G>A (p.Arg960=)

ClinVarID: 195657

CAID: CA201877

gnomAD: MAF of 0.3169 (23737/74896 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6029429-C-T?dataset=gnomad_r4

Variant: c.3505T > A, p.(Cys1169Ser)

HGVS: NM_000552.5:c.3505T>A (p.Cys1169Ser)

ClinVarID:

CAID: CA383511219

gnomAD:

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

Case: Patient 29, Family K (Table 1.), F/33, Afro-Caribbean

DiseaseAssertion: VWD2A (IIE)

FamilyInfo: Patient 18 (F/53, Afro-Caribbean), Patient 32 (F/17, Afro-Caribbean), Patient 33 (F/49, Afro-Caribbean) also from Family K. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT =13, FVIII:C (IU/dL) = 75, VWF:Ag (IU/dL) = 25, VWF:Act (IU/dL) = 18

CaseNOTHPOs:

CaseNOTHPOFreeText: Blood type 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.3505T > A, p.(Cys1169Ser)

HGVS: NM_000552.5:c.3505T>A (p.Cys1169Ser)

ClinVarID:

CAID: CA383511219

gnomAD:

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

Case: Patient 31, Family O (Table 1.), F/73, Afro-Caribbean

DiseaseAssertion: VWD2A (IIE)

FamilyInfo: Patient 30 (M/42, Afro-Caribbean) also from Family O. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT = 2, FVIII:C (IU/dL) = 31, VWF:Ag (IU/dL) = 20, VWF:Act (IU/dL) = 22

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

Case: Patient 49, Family W (Table 1.), F/57, Afro-Caribbean

DiseaseAssertion: VWD2M

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT = NA, FVIII:C (IU/dL) = 57, VWF:Ag (IU/dL) = 50, VWF:Act (IU/dL) = 29

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.4315G > A, p.(Val1439Met)

HGVS: NM_000552.5:c.4315G>A (p.Val1439Met)

ClinVarID: 1334625

CAID: CA6402550

gnomAD: MAF of 0.005146 (386/75012 alleles) in African American population https://gnomad.broadinstitute.org/variant/chr12-6019103-C-T?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: Patient 18, Family K (Table 1.), F/53, Afro-Caribbean

DiseaseAssertion: VWD2A (IIE)

FamilyInfo: Patient 29 (F/33, Afro-Caribbean), Patient 32 (F/17, Afro-Caribbean), Patient 33 (F/49, Afro-Caribbean) also from Family K. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT =27, FVIII:C (IU/dL) = 19, VWF:Ag (IU/dL) = 16, VWF:Act (IU/dL) = 4

CaseNOTHPOs:

CaseNOTHPOFreeText: Blood type 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.1661del, p.(Lys554Serfs*23)

HGVS: NM_000552.5:c.1661del (p.Lys554Serfs*23)

ClinVarID:

CAID: CA2617232671

gnomAD: MAF is 0.00001332 (1/75048 alleles) in African/African/American population https://gnomad.broadinstitute.org/variant/chr12-6057916-CT-C?dataset=gnomad_r4

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/chr12-6044368-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/chr12-6044348-A-G?dataset=gnomad_r4

Variant: c.2880G > A, p.(Arg960 =)

HGVS: NM_000552.5:c.2880G>A (p.Arg960=)

ClinVarID: 195657

CAID: CA201877

gnomAD: MAF of 0.3169 (23737/74896 alleles) in African/African American population https://gnomad.broadinstitute.org/variant/chr12-6029429-C-T?dataset=gnomad_r4

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

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

Case: Patient 23, Family I (Table 1.), F/86, 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 24 (F/92, Afro-Caribbean), Patient 25 (F/62, Afro-Carribean) also from Family I. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT =16, FVIII:C (IU/dL) = 24, VWF:Ag (IU/dL) = 15, 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.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

PMID: 40123275

Gene: VWF

HGNCID: 12726

Case: Patient 41, Family S (Table 1.), M/63, Afro-Caribbean

DiseaseAssertion: Indeterminant

FamilyInfo: Patient 39 (F/76, Afro-Caribbean), Patient 40 (F/38, Afro-Caribbean)and Patient 52 (F/48, Afro Caribbean) also from Family S. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT = 0, FVIII:C (IU/dL) = 100, VWF:Ag (IU/dL) = 92, VWF:Act (IU/dL) = 36

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.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.4628C > G p.(Ser1543Cys)

HGVS: NM_000552.5:c.4628C>G (p.Ser1543Cys)

ClinVarID: 4533008

CAID: CA383500651

gnomAD:

Case: Patient 28, Family F (Table 1.), F/55, Afro-Caribbean

DiseaseAssertion: VWD2A (IIE)

FamilyInfo: Patient 8 (M/86, Afro-Caribbean) and Patient 9 (F/76, Afro-Caribbean) also from Family F. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT = 6, FVIII:C (IU/dL) = 112, VWF:Ag (IU/dL) = 10, 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.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) 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

Case: Patient 38, Family R (Table 1.), F/51, Afro-Caribbean

DiseaseAssertion: VWD2A (IIE)

FamilyInfo: Patient 36 (M/22, Afro-Caribbean) and Patient 37 (M/20, Afro-Caribbean) also from Family R. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT = 6, FVIII:C (IU/dL) = 30, VWF:Ag (IU/dL) = 20, 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.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

Case: Patient 15, Family J (Table 1.), F/64, Afro-Caribbean

DiseaseAssertion: Indeterminate effect of the VWF defect due to ISTH BAT at 0

FamilyInfo: Patient 14 (M/36, Afro-Carribean) also from Family J. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT =0, FVIII:C (IU/dL) = 110, VWF:Ag (IU/dL) = 102, VWF:Act (IU/dL) = 40

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:

Case: Patient 52, Family S (Table 1.), F/48, Afro-Caribbean

DiseaseAssertion: VWD1

FamilyInfo: Patient 39 (F/76, Afro-Caribbean), Patient 40 (F/38, Afro-Caribbean)and Patient 41 (m/63, Afro Caribbean) also from Family S. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT = 4, FVIII:C (IU/dL) = NA, VWF:Ag (IU/dL) = 30, 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

Gene: VWF

Variant: deletion of exons 9-10

HGVS: NM_000552.5:c.1030_1317del (p.Gly344_Arg439del)

ClinVarID:

CAID: CA3260663889

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

Case: Patient 5, Family B (Table 1.), F/47, Afro-Caribbean

DiseaseAssertion: VWD2A (IIE)

FamilyInfo: Patient 3 (M/30, Afro-Caribbean) from same family. (Table 1.)

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeRext: BAT = 7, FVIII:C (IU/dL) = 30, VWF:Ag (IU/dL) = 15, VWF:Act (IU/dL) = 17

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

Case: 1, M, 10, 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): 5, Bleeding Score: 7

CaseNotHPOs: n/a

CaseNotHPOFreeText: Anti-VWF alloantibodies: no

CasePreviousTesting: n/a

Gene: VWF

Variant:

c.6634T>C (p.Cys2212Arg), Exon 38, D4 domain, Homozygous

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

PMID: 31064749

Gene: VWF

HGNC: 12726

Disease: von Willebrand Disease Type 2

MONDO: 0013304

InheritancePattern: Autosomal Dominant (for Types 2A, 2B and 2M) or Autosomal Recessive (for Type 2N)

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 variants

Case: 24, F, 17, Iranian

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:

6520T→G (Cys2174Gly), Exon 37, Homozygous

Case: 12, F, 15, Italian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: no

ParentalGenotype:

2748delHYC was confirmed to be in both parents

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:

8241del9, 2748delHisTyrCys, Exon 51, Homozygous

Case: 5 , F, 21, 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:

1946-4C→T (intronic), Exon 16

7630C→T (Gln2544X), Exon 45

Compound Heterozygous

Note: Article assumes that 1946-4C→T is 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.

Case: 13, M, 8, Iranian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: Yes

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:

139G→C (Asp47His), Exon 3, Homozygous

Case: 31, M, 32, Indian

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: 7130insC (FS), Exon 42, Homozygous

Case: 21, F, 52, Iranian

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: 10

CasePreviousTesting: n/a

Gene: VWF

Variant:

4036C→T (Gln1346X), Exon 28, Homozygous

Note: One unit (U) of alloantibody to VWF is the concentration that binds 50% of the VWF added to the system, with the total potency calculated as the reciprocal of the dilution containing 1 anti-VWF U (total U).

Case: 9, M, 34, 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:

3108+5G→A (Intronic), Exon 23, Homozygous

Note: Article assumes that 3108+5G→A is 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.

Case: 32, M, 30, 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:

7130insC (FS), Exon 42, 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.

Case: 25, M, 20, Iranian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: Yes

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:

7674insC (FS), Exon 45, Homozygous

Case: 28, M, 25, Indian

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity: Yes

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:

421G→A (Asp141Asn), Exon 5, Homozygous

Case: 29, M, 16, Indian

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:

1117C→T (Arg373X), Exon 10, Homozygous

Case: 17, M, 19, 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:

1110-1G→A (intronic), Exon 10, Homozygous

Note: Article assumes 1110-1G→A 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.

Case: 6 , F, 15, 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:

2269delCT (FS), Exon 17

7729+7C→T (intronic), Exon 45

Compound Heterozygous

Note: Article assumes that 7729+7C→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.

PMID: 28394285

Gene: VWF

HGNCID: 12726

Case#: Elayaperumal_2018_V-138, F, 2 y.o. (onset), origin in India

DiseaseAssertion: VWD type 3

FamilyInfo: Consanguinity, family history of bleeding

ParentalGenotype: not reported

CasePresentingHPOs:

CaseHPOFreeText: bleeding score of 19, VWF:Ag of 0, FVIII:C of 1.9%

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: not reported

GenotypingMethod: CSGE and Sanger sequencing of VWF gene only.

Gene: VWF

Variant: Heterozygous c.3379+1G>A

HGVS: NM_000552.3:c.3379+1G>A

ClinVarID: 100257

CAID: CA228398

gnomAD: MAF 0.0001508 (3/19892 alleles, East Asian population) https://gnomad.broadinstitute.org/variant/12-6132796-C-T

MultipleGeneVariants: Since this patient was reportedly heterozygous, they should have another variant. However, only one was reported.

PMID: 29984440

Gene: VWF

HGNCID: 12726

Case: 2B-7

DiseaseAssertion: VWD2B

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.43; AcuStar CB/Ag = 0.17; ELISA CB/Ag = 0.20

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: 9858249

Gene: VWF

Variant: c.3922C>T (p.Arg1308Cys)

HGVS: NM_000552.5(VWF):c.3922C>T (p.Arg1308Cys)

ClinVarID: 289; https://www.ncbi.nlm.nih.gov/clinvar/variation/289/?new_evidence=false

CAID:

gnomAD: absent

PMID: 28980759

Gene: VWF

HGNCID: 12726

Case: Case 7, ages 2-17, Croatian

DiseaseAssertion: VWD2B

FamilyInfo:

ParentalGenotypes(s):

CasePresentingHPOs:

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText: bleeding score= 0, VWF:GPIbM (%)= 47.0, VWF:Ag (%)= 59.1, vWF:GPIbM/vWF:Ag ratio= 0.80, FVIII:C (%): 78, VWF: CBA (%)= 36.8

CasePreviousTesting:

Gene: VWF

Variant: c.3923G>A p.Arg1308His

HGVS: NM_000552.5:c.3923G>A

ClinVar: 100303

gnomAD: https://gnomad.broadinstitute.org/variant/12-6128661-C-T?dataset=gnomad_r2_1, frequency: 0.00004603

Case: Case 8, ages 2-17, Croatian

DiseaseAssertion: VWD2B

FamilyInfo:

ParentalGenotypes(s):

CasePresentingHPOs:

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText: bleeding score= 3, VWF:GPIbM (%)= 16.1, VWF:Ag (%)= 57.8, vWF:GPIbM/vWF:Ag ratio= 0.28, FVIII:C (%): 61, VWF: CBA (%)= 36.4

CasePreviousTesting:

Gene: VWF

Variant: c.3946G>A, p.Val1316Met

HGVS: NM_000552.5:c.3946G>A

ClinVar: 290

gnomAD: not in gnomad