Case#: a 2‐year‐old white girl who was found to have RCM following an evaluation precipitated by the sudden death of her older brother.

DiseaseAssertion: Restrictive cardiomyopathy

FamilyInfo: 4‐year‐old brother presented with a sudden cardiac arrest while running on a soccer field and could not be resuscitated. Her father had restrictive physiology and arrhythmias. The TNNT2 variant was found in the father and two children

ParentalTesting: Father carried the variant. For both paternal grandparents tested negative and the proband inherited the variant from her father.

CasePresentingHPOs: HP:0001723, HP:0001639, HP:0031295, HP:0030718, HP:0001695

CaseHPOFreeText: "Her ECG demonstrated criteria for right and left atrial enlargement with marked repolarization abnormality. Echocardiogram revealed mild right atrial and severe left atrial enlargement (left atrial volume, 61.5 cc/m2; normal, 16–28), with mildly increased left ventricular mass and otherwise normal ventricular dimensions. Right and left ventricular systolic function was preserved. "

CaseNotHPOs: not reported

CaseNotHPOFreeText: Ventricular dimensions and biventricular systolic function were reported as normal.

CasePreviousTesting: Cardiomyopathy‐based panel testing (Familion; Transgenomic, Inc., New Haven, CT) was conducted on the proband, demonstrating a single, heterozygous, variant TNNT2‐R94C (c.280C>T).

Genotyping Method: Clinical genetic testing was performed on family members using the same HCM panel test.

FunctionalAnalysis: Biophysical experiments using recombinant human TNNT2‐R94C demonstrated impaired cardiac regulation at the molecular level attributed to reduced calcium‐dependent blocking of myosin's interaction with the thin filament.

Variant: c.835C>T, p.Gln279Ter

ClinVar: 165549

CAID: CA004288

gnomAD: not reported

AdditionalInfo: not reported

Case1: 11 year old female

DiseaseAssertion: hypertrophic cardiomyopathy, restrictive cardiomyopathy

FamilyInfo: twin sister carrier identical mutation, both sisters expired, no family history of cardiomyopathy

ParentalTesting: sanger sequencing

CasePresentingHPOs:HP:0001629, HP:0001640, HP:0034314,HP:0002098, HP:0001723

CaseHPOFreeText:bilateral atrial dilation with mid ventricular hypertrophy, accelerated cardiac sound, liver palpable 2cm below costal margin, cold extremities, cardiac condition was New York Heart Association class (NYHA) III.

CaseNotHPOs: NR

CaseNotHPOFreeText: no gallop rhythm, no murmur, no blood test abnormalities, no metabolic disorders

CasePreviousTesting: cardiac catheterization, cardiac magnetic resonance, echocardiography, Chest Xray, electrocardiography,

Genotyping Method: sanger sequencing

FunctionalAnalysis: NR

Variant: TNNI3 c.574 C>T p.Arg192Cys

ClinVar: 165510

CAID: CA021951

gnomAD:NR

Case 2: 15 year old female

DiseaseAssertion: restrictive cardiomyopathy, hypertrophic cardiomyopathy

FamilyInfo: twin sister carrier identical mutation, both sisters expired, no family history of cardiomyopathy

ParentalTesting: Sanger Sequencing

CasePresentingHPOs:HP:0002875, HP:0001723

CaseHPOFreeText: Abnormal ECG, LV hypertrophy, enlargement of both atria, high LVEF levels, accelerated cardiac sound, liver was palpable 3 cm, extremities were warm, and cardiac condition was NYHA II.

CaseNotHPOs:NR

CaseNotHPOFreeText: no gallop rhythm, no murmur, no blood test abnormalities, no metabolic disorders

CasePreviousTesting: cardiac catheterization, cardiac auscultation, myocardial disarray with myocyte hypertrophy

Genotyping Method: Sanger sequencing

FunctionalAnalysis: NR

Variant: TNNI3 c.574 C>T p.Arg192Cys

ClinVar: 165510

CAID: CA021951

gnomAD:NR

Case#:7-year-old boy

DiseaseAssertion: restrictive cardiomyopathy

FamilyInfo: his parents were in generally good health and other family members denied a history of syncope, sudden death or cardiomyopathy

ParentalTesting: sanger sequencing

CasePresentingHPOs:HP:0007185, HP:0001695, HP:0005943, HP:0002516, HP:0001663

CaseHPOFreeText:electrocardiogram (ECG) revealed Ptf-V 1 < –0.04 mm⋅s and biphasic P waves, indicating left atrial enlargement and the chest X-ray revealed an enlarged heart shadow. The echocardiogram showed biatrial enlargement, especially in the left atrium (LA: 32 mm, RA: 30 mm), decreased diastolic function (E/A = 2.6; E Peak deceleration time 130 ms; Constant volume diastolic time 49 ms), moderate mitral valve regurgitation and left ventricular ejection fraction of 51.8%.

CaseNotHPOs:HP:0000969

CaseNotHPOFreeText:Except for bilateral enlargement, cardiac magnetic resonance (CMR) indicated no abnormalities

CasePreviousTesting: brain MRI, video electrocephalogram, electrocardiogram

Genotyping Method: sanger sequencing

FunctionalAnalysis:

Variant: TNNI3 c.611(exon8)G>A,p.R204H

ClinVar:177679

CAID:CA022060

gnomAD:chr19-55151856-C-T

Case#: A 50-year-old man diagnosed with HCM at age 41, with asymmetric septal hypertrophy and exertional chest discomfort and pain

DiseaseAssertion: Hypertrophic cardiomyopathy

FamilyInfo: His third elder sister, niece and daughter were also clinically affected by HCM. The proband's mother and eldest sister had suffered from sudden cardiac death. The proband's father, second elder sister (HCM1 in Fig. 1A), nephew (HCM5 in Fig. 1A) and son (HCM7 in Fig. 1A) were 87, 65, 35, and 14 years old, respectively, and had normal echocardiographic measurements.

ParentalTesting: The mother had died suddenly; the 87-year-old father had normal echocardiographic measurements. There was no testing reported.

CasePresentingHPOs: HP:0001639, HP:0005144, HP:0100749, HP:0011712

CaseHPOFreeText: chest distress and chest pain during exercise for 9 years. He presented with an asymmetric hypertrophic interventricular septum and a maximum interventricular septum thickness of 18.04 mm

CaseNotHPOs: not reported

CaseNotHPOFreeText: no findings found in the proband

CasePreviousTesting: nothing reported in the article

Genotyping Method: hole exome sequencing (WES) Exons were captured using Sure Select Human All Exon V5 kit. Sequenced by Illumina HiSeq 4000 sequencer.

FunctionalAnalysis: not reported

Variant: rs796925245 (g.1:201359630G>A, c.835C>T, p.Gln279Ter) (c.835C>T, p.Gln279Ter)

ClinVar: 1175037

CAID: CA088451

gnomAD: not reported

AdditionalInfo: n/r

Case#: Male half-brother with mild left ventricular dilation from early childhood and mild left ventricular impairment; latest reported ejection fraction was 51%.

DiseaseAssertion: DCM

FamilyInfo: several of the siblings DCM, two died at age of 12, father had DCM, and heart transplant for an individual who later died

ParentalTesting: father was an obligate carrier

CasePresentingHPOs: HP:0001644

CaseHPOFreeText: Mild left ventricular dilation and mildly increased LV volumes

CaseNotHPOs: not reported

CaseNotHPOFreeText: not reported

CasePreviousTesting: panel-based genetic test was conducted in the index patient.

Genotyping Method: panel-based genetic test was conducted in the index patient. sanger confirmation

FunctionalAnalysis: not reported

Variant: c.659_661del p.(Lys220del)

ClinVar: 43659

CAID: CA006429

gnomAD: not reported

AdditionalInfo: not reported

Case#: A 2-year-old girl with dilated cardiomyopathy (DCM) and left ventricular noncompaction, who received a heart transplant at 26 months.

DiseaseAssertion: DCM with left ventricular noncompaction

FamilyInfo: Family history revealed that three of the father’s (A.II.2) sisters (A.II.4-A.II.6) died in infancy due to cardiac failure.

ParentalTesting: The father and paternal grandmother tested positive for the same TNNT2 variant

CasePresentingHPOs: HP:0001644, HP:0030682, HP:0001635

CaseHPOFreeText: The heart failure signs began at 2 months and got worse. Then got a heart transplant at 26 months.

CaseNotHPOs: not reported

CaseNotHPOFreeText: nothing found

CasePreviousTesting: a genetic panel test, including the genes LDB3, LMNA, MYH7, MYBPC3, and TNNT2, was performed.

Genotyping Method: Variants were confirmed in first-degree family members by Sanger sequencing.

FunctionalAnalysis: not reported

Variant: c.316G>A (p.Glu106Lys)

ClinVar: 224775

CAID: CA088557

gnomAD: not reported

AdditionalInfo: not reported

Case#: 19-year-old boy with coarctation of the aorta who complained of mild exertional dyspnea.

DiseaseAssertion: dilated cardiomyopathy (DCMP). LV systolic dysfunction.

FamilyInfo: The family history was positive to sudden death (his cousin died, aged 3 months) and to DCMP and heart transplant (HT): a maternal aunt and her son who then died at 42 and 24 years old. Cascade family screening revealed a TNNT2 variant in the mother (II.1) and his cousin (IV.3).

ParentalTesting: The 19 year old brother's was tested and carried the TNNT2 variant. She was also affected by DCM. The father’s testing status was not reported.

CasePresentingHPOs: HP:0001680, HP:0002875, HP:0025169, HP:4000141

CaseHPOFreeText: surgically repaired coarctation of the aorta who complained of mild exertional dyspnea repaired at birth (NYHA class II–III). Cardiac MRI showed a moderately dilated, hypokinetic LV with an ejection fraction of 45%; echocardiography showed an ejection fraction around 42%.

CaseNotHPOs: not reported

CaseNotHPOFreeText: Nothing was found that was correlated.

CasePreviousTesting: genetic investigations through next generation sequencing (NGS) with a panel of 325 genes, known to be associated with cardiomyopathies

Genotyping Method: targeted next generation sequencing

FunctionalAnalysis: not reported

Variant: c.518G>A (p. Arg173Gln)

ClinVar: 43649

CAID: CA004727

gnomAD: not reported

AdditionalInfo: not reported

Case#: 1, age 36, age 30 (report)

DiseaseAssertion: Pompe Disease

FamilyInfo: Family 1, no further information

CasePresenting HPOs:HP:0002878, HP:0012378, HP:0003546, HP:0001324 (Respiratory failure, fatigue, exercise intolerance, muscle weakness)

CaseHPOFreeText: myopathy with vacuoles, biopsy with vacuolar myopathy with PAS +

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: single gene sequencing/analysis, 48.47 NaG/AaGIA, 89.61% inhibition of GAA; NaG/AaGIA above 40 and %INH above 87 are in the affected range

Variants:

Variant 1:NM_000152.5(GAA):c.1941C>G (p.Cys647Trp)

ClinVar: 550327

Variant 2: Not reported

ParentalGenotypes: N/A

PreviouslyPublished: N/A

Case#: 2/b, age 11, age 5 (report)

DiseaseAssertion: Pompe Disease

FamilyInfo: Family 2, no further information

CasePresenting HPOs:HP:0002878, HP:0012378, HP:0003546, HP:0001324 (Respiratory failure, fatigue, exercise intolerance, muscle weakness)

CaseHPOFreeText: valvular myopathy, biopsy with vacuolar myopathy with PAS +

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: single gene sequencing/analysis, 105.01 NaG/AaGIA, 90.98% inhibition of GAA; NaG/AaGIA above 40 and %INH above 87 are in the affected range

Variants:

Variant 1:NM_000152.5(GAA):c.377G>A (p.Trp126Ter)

ClinVar: 932904

Variant 2: NM_000152.5(GAA):c.1655T>C (p.Leu552Pro)

ClinVar: 279811

ParentalGenotypes: N/A

PreviouslyPublished: N/A

Case#: 6/b, age 40, age 36 (report)

DiseaseAssertion: gray zone (Pompe Disease)

FamilyInfo: Family 6, no further information

CasePresenting HPOs: HP:0001288 (Impaired gait)

CaseHPOFreeText: Progressive worsening muscle weakness, vacuolar myopathy biopsy PAS +

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: single gene sequencing/analysis, the results of (NaG/AaGIA > 40 and %INH < 87) or (NaG/AaGIA < 40 and %INH > 87) are considered to be within a gray zone.

Variants:

Variant 1: NM_000152.5(GAA):c.1941C>G (p.Cys647Trp)

ClinVar: 550327

Variant 2:NM_000152.5(GAA):c.-32-13T>G

ClinVar: 4027

ParentalGenotypes: N/A

PreviouslyPublished: N/A

Case#: 4, age 24, age 18 (report)

DiseaseAssertion: Pompe Disease

FamilyInfo: Family 4, no further information

CasePresenting HPOs:HP:0012378, HP:0003546, HP:0001324 (fatigue, exercise intolerance, muscle weakness)

CaseHPOFreeText: vacuolar myopathy biopsy PAS +

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: single gene sequencing/analysis, 40.54 NaG/AaGIA, 90.54% inhibition of GAA; NaG/AaGIA above 40 and %INH above 87 are in the affected range

Variants:

Variant 1:NM_000152.5(GAA):c.2608C>T (p.Arg870Ter)

ClinVar: 189009

Variant 2: not reported

ParentalGenotypes: N/A

PreviouslyPublished: N/A

Case#: 2/a, age 20, age 14 (report)

DiseaseAssertion: Pompe Disease

FamilyInfo: Family 2, no further information

CasePresenting HPOs:HP:0002878, HP:0012378, HP:0003546, HP:0001324 (Respiratory failure, fatigue, exercise intolerance, muscle weakness)

CaseHPOFreeText: valvular myopathy, biopsy with vacuolar myopathy with PAS +

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: single gene sequencing/analysis, 64.47 NaG/AaGIA, 92.28% inhibition of GAA; NaG/AaGIA above 40 and %INH above 87 are in the affected range

Variants:

Variant 1:NM_000152.5(GAA):c.377G>A (p.Trp126Ter)

ClinVar: 932904

Variant 2: NM_000152.5(GAA):c.1655T>C (p.Leu552Pro)

ClinVar: 279811

ParentalGenotypes: N/A

PreviouslyPublished: N/A

Case: Patient 6 (Family C), male, 53yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0030129, HP:0030130, HP:0011871, HP:0012147

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

CaseHPOFreeText: blood group O, Platelet count x103/μl = 193, PFA 100 sec = 199, SPA % = 5.2, MADR mg/mL = 0.75, VWF:Ag U/dL = 47.1, VWF:CB U/dL = 44.6, VWF:CB ratio = 0.94, VWF:RCo U/dL = 38.0, VWF:RCo ratio = 0.80, Platelet VWF U/dL = 47.4, FVIII U/dL = 43.8, BAT F/M = 0

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

Variant: c.4135C>T (p.Arg1379Cys)

HGVS: NM_000552.4(VWF):c.4135C>T (p.Arg1379Cys)

ClinVarID: 100333; https://www.ncbi.nlm.nih.gov/clinvar/variation/100333/

CAID: NA

gnomAD: MAF = 0.00003891 (5/128500 alleles) in the European (non-Finnish) population; https://gnomad.broadinstitute.org/variant/12-6128449-G-A?dataset=gnomad_r2_1

Case: Patient 10 (Family D), female, 24yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0030129, HP:0030130, HP:0011871, HP:0012147

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

CaseHPOFreeText: blood group AB, Platelet count x103/μl = 231, PFA 100 sec = 223, SPA % = 6, MADR mg/mL = 0.75, VWF:Ag U/dL = 46.0, VWF:CB U/dL = 49.1, VWF:CB ratio = 1.07, VWF:RCo U/dL = 40.5, VWF:RCo ratio = 0.83, Platelet VWF U/dL = 55.6, FVIII U/dL = 64.8, BAT F/M = NA

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

Variant: c.4135C>T (p.Arg1379Cys)

HGVS: NM_000552.4(VWF):c.4135C>T (p.Arg1379Cys)

ClinVarID: 100333; https://www.ncbi.nlm.nih.gov/clinvar/variation/100333/

CAID: NA

gnomAD: MAF = 0.00003891 (5/128500 alleles) in the European (non-Finnish) population; https://gnomad.broadinstitute.org/variant/12-6128449-G-A?dataset=gnomad_r2_1

Case: Patient 11 (Family E), male, 11yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0030129, HP:0030130, HP:0011871, HP:0012147

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

CaseHPOFreeText: blood group O, Platelet count x103/μl = 220, PFA 100 sec = >300, SPA % = 11.3, MADR mg/mL = 0.3, VWF:Ag U/dL = 28.8, VWF:CB U/dL = 28.4, VWF:CB ratio = 0.98, VWF:RCo U/dL = 23.0, VWF:RCo ratio = 0.80, Platelet VWF U/dL = 54.1, FVIII U/dL = 51.5, BAT F/M = 5

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

Variant: c.4021C>T (p.Arg1341Trp)

HGVS: NM_000552.4(VWF):c.4021C>T (p.Arg1341Trp)

ClinVarID: 100316; https://www.ncbi.nlm.nih.gov/clinvar/variation/100316/

CAID: NA

gnomAD: MAF = 0.00008674 (3/34586 alleles) in the Latino/Admixed American population; https://gnomad.broadinstitute.org/variant/12-6128563-G-A?dataset=gnomad_r2_1

Case: Patient 12 (Family F), female, 50yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0030129, HP:0030130, HP:0011871, HP:0012147

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

CaseHPOFreeText: blood group A, Platelet count x103/μl = 204, PFA 100 sec = 91, SPA % = 10, MADR mg/mL = 0.45, VWF:Ag U/dL = 108, VWF:CB U/dL = 101.9, VWF:CB ratio = 0.94, VWF:RCo U/dL = 97.7, VWF:RCo ratio = 0.91, Platelet VWF U/dL = 136.4, FVIII U/dL = 107.5, BAT F/M = 16

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

Variant: c.3797C>A (p.Pro1266Gln)

HGVS: NM_000552.4(VWF):c.3797C>A (p.Pro1266Gln)

ClinVarID: 100279; https://www.ncbi.nlm.nih.gov/clinvar/variation/100279/

CAID: NA

gnomAD: MAF = 0.001346 (41/30468 alleles; 2 homozygotes) in the South Asian population; https://gnomad.broadinstitute.org/variant/12-6128787-G-T?dataset=gnomad_r2_1

Case: Patient 5 (Family C), female, 50yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0030129, HP:0030130, HP:0011871, HP:0012147

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

CaseHPOFreeText: blood group O, Platelet count x103/μl = 211, PFA 100 sec = 210, SPA % = 10, MADR mg/mL = 0.6, VWF:Ag U/dL = 40.6, VWF:CB U/dL = 42.8, VWF:CB ratio = 1.1, VWF:RCo U/dL = NA, VWF:RCo ratio = NA, Platelet VWF U/dL = 41.2, FVIII U/dL = 62.8, BAT F/M = 8

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

Variant: c.4135C>T (p.Arg1379Cys)

HGVS: NM_000552.4(VWF):c.4135C>T (p.Arg1379Cys)

ClinVarID: 100333; https://www.ncbi.nlm.nih.gov/clinvar/variation/100333/

CAID: NA

gnomAD: MAF = 0.00003891 (5/128500 alleles) in the European (non-Finnish) population; https://gnomad.broadinstitute.org/variant/12-6128449-G-A?dataset=gnomad_r2_1

Case: Patient 7 (Family C), female, 21yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0030129, HP:0030130, HP:0011871, HP:0012147

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

CaseHPOFreeText: blood group O, Platelet count x103/μl = 293, PFA 100 sec = >300, SPA % = 6, MADR mg/mL = 0.6, VWF:Ag U/dL = 26.7, VWF:CB U/dL = 27.2, VWF:CB ratio = 1.01, VWF:RCo U/dL = 25.8, VWF:RCo ratio = 0.92, Platelet VWF U/dL = 59.1, FVIII U/dL = 40.9, BAT F/M = 6

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

Variant: c.4135C>T (p.Arg1379Cys)

HGVS: NM_000552.4(VWF):c.4135C>T (p.Arg1379Cys)

ClinVarID: 100333; https://www.ncbi.nlm.nih.gov/clinvar/variation/100333/

CAID: NA

gnomAD: MAF = 0.00003891 (5/128500 alleles) in the European (non-Finnish) population; https://gnomad.broadinstitute.org/variant/12-6128449-G-A?dataset=gnomad_r2_1

Case: Patient 9 (Family D), male, 18yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0030129, HP:0030130, HP:0011871, HP:0012147

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

CaseHPOFreeText: blood group A, Platelet count x103/μl = 231, PFA 100 sec = 95, SPA % = 0, MADR mg/mL = 0.75, VWF:Ag U/dL = 151.1, VWF:CB U/dL = 175.5, VWF:CB ratio = 1.16, VWF:RCo U/dL = 153.5, VWF:RCo ratio = 0.87, Platelet VWF U/dL = 95.2, FVIII U/dL = 148.2, BAT F/M = NA

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

Variant: c.3797C>A (p.Pro1266Gln)

HGVS: NM_000552.4(VWF):c.3797C>A (p.Pro1266Gln)

ClinVarID: 100279; https://www.ncbi.nlm.nih.gov/clinvar/variation/100279/

CAID: NA

gnomAD: MAF = 0.001346 (41/30468 alleles; 2 homozygotes) in the South Asian population; https://gnomad.broadinstitute.org/variant/12-6128787-G-T?dataset=gnomad_r2_1

Case: Patient 4 (Family C), female, 76yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0030129, HP:0030130, HP:0011871, HP:0012147

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

CaseHPOFreeText: blood group O, Platelet count x103/μl = 236, PFA 100 sec = >300, SPA % = 8.4, MADR mg/mL = 0.75, VWF:Ag U/dL = 35.4, VWF:CB U/dL = 37.3, VWF:CB ratio = 1.05, VWF:RCo U/dL = 25.4, VWF:RCo ratio = 0.72, Platelet VWF U/dL = 66.8, FVIII U/dL = 32.0, BAT F/M = 16

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

Variant: c.4135C>T (p.Arg1379Cys)

HGVS: NM_000552.4(VWF):c.4135C>T (p.Arg1379Cys)

ClinVarID: 100333; https://www.ncbi.nlm.nih.gov/clinvar/variation/100333/

CAID: NA

gnomAD: MAF = 0.00003891 (5/128500 alleles) in the European (non-Finnish) population; https://gnomad.broadinstitute.org/variant/12-6128449-G-A?dataset=gnomad_r2_1

Case: P53, Chinese, female, 70yo

DiseaseAssertion: VWD2A

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeText: HP:0012147

(Reduced quantity of VWF)

CaseNOTHPOs: type O blood, bleeding score = 9; VWF:Ag (%) = 32.1, VWF:RCo (%) = 6.0, FVIII:C (%) = 50.8, VWF:CB (%) = 14.7, VWFpp (%) = 56.9, VWF:RCo/VWF:Ag = 0.2, VWF:CB/VWF:Ag = 0.5, VWFpp/VWF:Ag = 1.8, FVIII:C/VWF:Ag = 1.6

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4790G>T (p.Arg1597Leu)

HGVS: NM_000552.4(VWF):c.4790G>T (p.Arg1597Leu)

ClinVarID: 100392; https://www.ncbi.nlm.nih.gov/clinvar/variation/100392/

CAID: NA

gnomAD: absent

Case: P19, Chinese, male, 35yo

DiseaseAssertion: VWD2M

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 4; VWF:Ag (%) = 17.5, VWF:RCo (%) = 5.1, FVIII:C (%) = 35.9, VWF:CB (%) = 16.9, VWFpp (%) = 45.3, VWF:RCo/VWF:Ag = 0.3, VWF:CB/VWF:Ag = 1.0, VWFpp/VWF:Ag = 2.6, FVIII:C/VWF:Ag = 2.1

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4120C>T (p.Arg1374Cys)

HGVS: NM_000552.4(VWF):c.4120C>T (p.Arg1374Cys)

ClinVarID: 100329; https://www.ncbi.nlm.nih.gov/clinvar/variation/100329/

CAID: NA

gnomAD: MAF = 0.000008824 (1/113322 alleles) in the European (non-Finnish) population; https://gnomad.broadinstitute.org/variant/12-6128464-G-A?dataset=gnomad_r2_1

Case: P60, Chinese, female, 8yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 3; VWF:Ag (%) = 37.8, VWF:RCo (%) = 35.2, FVIII:C (%) = 56.6, VWF:CB (%) = 38.6, VWFpp (%) = 41.1, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 1.0, VWFpp/VWF:Ag = 1.1, FVIII:C/VWF:Ag = 1.5

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.5546T>C (p.Ile1849Thr)

HGVS: NM_000038.6(APC):c.5546T>C (p.Ile1849Thr)

ClinVarID: 654506; https://www.ncbi.nlm.nih.gov/clinvar/variation/654506/

CAID: NA

gnomAD: absent

Case: P46, Chinese, female, 55yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 14; VWF:Ag (%) = 45.4, VWF:RCo (%) = 44.5, FVIII:C (%) = 76.9, VWF:CB (%) = 54.9, VWFpp (%) = 43.2, VWF:RCo/VWF:Ag = 1.0, VWF:CB/VWF:Ag = 1.2, VWFpp/VWF:Ag = 1.0, FVIII:C/VWF:Ag = 1.7

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4414G>C (p.Asp1472His)

HGVS: NM_000552.4(VWF):c.4414G>C (p.Asp1472His)

ClinVarID: 256679; https://www.ncbi.nlm.nih.gov/clinvar/variation/256679/

CAID: NA

gnomAD: MAF = 0.5077 (12039/23712 alleles; 3078 homozygotes) in African/African-American population; https://gnomad.broadinstitute.org/variant/12-6128170-C-G?dataset=gnomad_r2_1

Case: P12, Chinese, Male, 11yo

DiseaseAssertion: VWD2A

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 6; VWF:Ag (%) = 15.8, VWF:RCo (%) = 7.3, FVIII:C (%) = 45.5, VWF:CB (%) = 4.1, VWFpp (%) = 50.3, VWF:RCo/VWF:Ag = 0.5, VWF:CB/VWF:Ag = 0.3, VWFpp/VWF:Ag = 3.2, FVIII:C/VWF:Ag = 2.9

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4517C>T (p.Ser1506Leu)

HGVS: NM_000552.4(VWF):c.4517C>T (p.Ser1506Leu)

ClinVarID: 100369; https://www.ncbi.nlm.nih.gov/clinvar/variation/100369/

CAID: NA

gnomAD: absent

Case: P70, Chinese, female, 51yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 2; VWF:Ag (%) = 28.3, VWF:RCo (%) = 36.6, FVIII:C (%) = 61.3, VWF:CB (%) = 34.6, VWFpp (%) = 64.5, VWF:RCo/VWF:Ag = 1.3, VWF:CB/VWF:Ag = 1.2, VWFpp/VWF:Ag = 2.3, FVIII:C/VWF:Ag = 2.2

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.6554G>A (p.Arg2185Gln)

HGVS: NM_000552.4(VWF):c.6554G>A (p.Arg2185Gln)

ClinVarID: 100443; https://www.ncbi.nlm.nih.gov/clinvar/variation/100443/

CAID: NA

gnomAD: MAF = 0.1899 (4712/24810 alleles; 465 homozygotes) in the African/African-American population; https://gnomad.broadinstitute.org/variant/12-6103072-C-T?dataset=gnomad_r2_1

Case: P56, Chinese, male, 6yo

DiseaseAssertion: VWD2A

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type B blood, bleeding score = 13; VWF:Ag (%) = 15.4, VWF:RCo (%) = 7.1, FVIII:C (%) = 43.3, VWF:CB (%) = 2.4, VWFpp (%) = 43.8, VWF:RCo/VWF:Ag = 0.5, VWF:CB/VWF:Ag = 0.2, VWFpp/VWF:Ag = 2.8, FVIII:C/VWF:Ag = 2.8

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4517C>T (p.Ser1506Leu)

HGVS: NM_000552.4(VWF):c.4517C>T (p.Ser1506Leu)

ClinVarID: 100369; https://www.ncbi.nlm.nih.gov/clinvar/variation/100369/

CAID: NA

gnomAD: absent

Case: P25, Chinese, female, 23yo

DiseaseAssertion: VWD2M

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type B blood, bleeding score = 5; VWF:Ag (%) = 15.6, VWF:RCo (%) = 4.4, FVIII:C (%) = 31.0, VWF:CB (%) = 14.2, VWFpp (%) = 47.7, VWF:RCo/VWF:Ag = 0.3, VWF:CB/VWF:Ag = 0.9, VWFpp/VWF:Ag = 3.1, FVIII:C/VWF:Ag = 2.0

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4121G>A (p.Arg1374His)

HGVS: NM_000552.4(VWF):c.4121G>A (p.Arg1374His)

ClinVarID: 100330; https://www.ncbi.nlm.nih.gov/clinvar/variation/100330/

CAID: NA

gnomAD: absent

Case: P14, Chinese, female, 3yo

DiseaseAssertion: VWD2M

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 5; VWF:Ag (%) = 18.2, VWF:RCo (%) = 7.6, FVIII:C (%) = 29.1, VWF:CB (%) = 17.5, VWFpp (%) = 45.6, VWF:RCo/VWF:Ag = 0.4, VWF:CB/VWF:Ag = 1.0, VWFpp/VWF:Ag = 2.5, FVIII:C/VWF:Ag = 1.6

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4121G>A (p.Arg1374His)

HGVS: NM_000552.4(VWF):c.4121G>A (p.Arg1374His)

ClinVarID: 100330; https://www.ncbi.nlm.nih.gov/clinvar/variation/100330/

CAID: NA

gnomAD: absent

Case: P84, Chinese, female, 36yo

DiseaseAssertion: VWD2M

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type B blood, bleeding score = 5; VWF:Ag (%) = 26.6, VWF:RCo (%) = 3.3, FVIII:C (%) = 41.7, VWF:CB (%) = 25.2, VWFpp (%) = 41.1, VWF:RCo/VWF:Ag = 0.1, VWF:CB/VWF:Ag = 1.0, VWFpp/VWF:Ag = 1.6, FVIII:C/VWF:Ag = 1.6

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4121G>A (p.Arg1374His)

HGVS: NM_000552.4(VWF):c.4121G>A (p.Arg1374His)

ClinVarID: 100330; https://www.ncbi.nlm.nih.gov/clinvar/variation/100330/

CAID: NA

gnomAD: absent

Case: P13, Chinese, male, 8yo

DiseaseAssertion: VWD2A

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 5; VWF:Ag (%) = 21.6, VWF:RCo (%) = 9.4, FVIII:C (%) = 53.2, VWF:CB (%) = 5.7, VWFpp (%) = 56.1, VWF:RCo/VWF:Ag = 0.4, VWF:CB/VWF:Ag = 0.3, VWFpp/VWF:Ag = 2.6, FVIII:C/VWF:Ag = 2.5

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4517C>T (p.Ser1506Leu)

HGVS: NM_000552.4(VWF):c.4517C>T (p.Ser1506Leu)

ClinVarID: 100369; https://www.ncbi.nlm.nih.gov/clinvar/variation/100369/

CAID: NA

gnomAD: absent

Case: P65, Chinese, female, 24yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 3; VWF:Ag (%) = 55.7, VWF:RCo (%) = 51.2, FVIII:C (%) = 72.7, VWF:CB (%) = 57.1, VWFpp (%) = 61.7, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 1.0, VWFpp/VWF:Ag = 1.1, FVIII:C/VWF:Ag = 1.3

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4499C>T (p.Ala1500Val)

HGVS: NM_000552.4(VWF):c.4499C>T (p.Ala1500Val)

ClinVarID: 439339; https://www.ncbi.nlm.nih.gov/clinvar/variation/439339/

CAID: NA

gnomAD: MAF = 0.003511 (70/19938 alleles) in the East Asain population; https://gnomad.broadinstitute.org/variant/12-6128085-G-A?dataset=gnomad_r2_1

Case: P4, Chinese, male, 35yo

DiseaseAssertion: VWD2M

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type A blood, bleeding score = 6; VWF:Ag (%) = 22.6, VWF:RCo (%) = 5.0, FVIII:C (%) = 36.6, VWF:CB (%) = 25.4, VWFpp (%) = 43.0, VWF:RCo/VWF:Ag = 0.2, VWF:CB/VWF:Ag = 1.1, VWFpp/VWF:Ag = 1.9, FVIII:C/VWF:Ag = 1.6

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4121G>A (p.Arg1374His)

HGVS: NM_000552.4(VWF):c.4121G>A (p.Arg1374His)

ClinVarID: 100330; https://www.ncbi.nlm.nih.gov/clinvar/variation/100330/

CAID: NA

gnomAD: absent

Case: P45, Chinese, female, 8yo

DiseaseAssertion: VWD2A

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type A blood, bleeding score = 4; VWF:Ag (%) = 23.5, VWF:RCo (%) = 6.5, FVIII:C (%) = 40.0, VWF:CB (%) = 15.2, VWFpp (%) = 44.5, VWF:RCo/VWF:Ag = 0.3, VWF:CB/VWF:Ag = 0.6, VWFpp/VWF:Ag = 1.9, FVIII:C/VWF:Ag = 1.7

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4628C>T (p.Ser1543Phe)

HGVS: NM_000552.4(VWF):c.4628C>T (p.Ser1543Phe)

ClinVarID: 100376; https://www.ncbi.nlm.nih.gov/clinvar/variation/100376/

CAID: NA

gnomAD: absent

Case: P52, Chinese, female, 55yo

DiseaseAssertion: VWD2M

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 9; VWF:Ag (%) = 19.1, VWF:RCo (%) = 3.1, FVIII:C (%) = 35.8, VWF:CB (%) = 22.7, VWFpp (%) = 50.3, VWF:RCo/VWF:Ag = 0.2, VWF:CB/VWF:Ag = 1.2, VWFpp/VWF:Ag = 2.6, FVIII:C/VWF:Ag = 1.9

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4120C>A (p.Arg1374Ser)

HGVS: NM_000552.4(VWF):c.4120C>A (p.Arg1374Ser)

ClinVarID: 100328; https://www.ncbi.nlm.nih.gov/clinvar/variation/100328/

CAID: NA

gnomAD: absent

Case: P26, Chinese, female, 30yo

DiseaseAssertion: VWD2A

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type AB blood, bleeding score = 14; VWF:Ag (%) = 11.3, VWF:RCo (%) = 3.7, FVIII:C (%) = 45.0, VWF:CB (%) = 4.0, VWFpp (%) = 41.7, VWF:RCo/VWF:Ag = 0.3, VWF:CB/VWF:Ag = 0.4, VWFpp/VWF:Ag = 3.7, FVIII:C/VWF:Ag = 4.0

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4517C>T (p.Ser1506Leu)

HGVS: NM_000552.4(VWF):c.4517C>T (p.Ser1506Leu)

ClinVarID: 100369; https://www.ncbi.nlm.nih.gov/clinvar/variation/100369/

CAID: NA

gnomAD: absent

Case: P3, Chinese, male, 7yo

DiseaseAssertion: VWD2A

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type B blood, bleeding score = 5; VWF:Ag (%) = 13.0, VWF:RCo (%) = 5.0, FVIII:C (%) = 39.1, VWF:CB (%) = 3.5, VWFpp (%) = 46.8, VWF:RCo/VWF:Ag = 0.4, VWF:CB/VWF:Ag = 0.3, VWFpp/VWF:Ag = 3.6, FVIII:C/VWF:Ag = 3.0

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4517C>T (p.Ser1506Leu)

HGVS: NM_000552.4(VWF):c.4517C>T (p.Ser1506Leu)

ClinVarID: 100369; https://www.ncbi.nlm.nih.gov/clinvar/variation/100369/

CAID: NA

gnomAD: absent

Case: P58, Chinese, female, 27yo

DiseaseAssertion: VWD2A

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs:

CaseHPOFreeText: HP:0012147

(Reduced quantity of VWF)

CaseNOTHPOs: type O blood, bleeding score = 8; VWF:Ag (%) = 17.1, VWF:RCo (%) = 2.3, FVIII:C (%) = 44.3, VWF:CB (%) = 3.7, VWFpp (%) = 41.1, VWF:RCo/VWF:Ag = 0.1, VWF:CB/VWF:Ag = 0.2, VWFpp/VWF:Ag = 2.4, FVIII:C/VWF:Ag = 2.6

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4790G>T (p.Arg1597Leu)

HGVS: NM_000552.4(VWF):c.4790G>T (p.Arg1597Leu)

ClinVarID: 100392; https://www.ncbi.nlm.nih.gov/clinvar/variation/100392/

CAID: NA

gnomAD: absent

Case: P17, Chinese, female, 20yo

DiseaseAssertion: VWD2M

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type B blood, bleeding score = 10; VWF:Ag (%) = 17.6, VWF:RCo (%) = 7.3, FVIII:C (%) = 35.8, VWF:CB (%) = 15.8, VWFpp (%) = 51.9, VWF:RCo/VWF:Ag = 0.4, VWF:CB/VWF:Ag = 0.9, VWFpp/VWF:Ag = 2.9, FVIII:C/VWF:Ag = 2.0

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.3389G>T (p.Cys1130Phe)

HGVS: NM_000552.4(VWF):c.3389G>T (p.Cys1130Phe)

ClinVarID: 100261; https://www.ncbi.nlm.nih.gov/clinvar/variation/100261/

CAID: NA

gnomAD: absent

Case: P66, Chinese, male, 27yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 1; VWF:Ag (%) = 56.0, VWF:RCo (%) = 43.4, FVIII:C (%) = 70.0, VWF:CB (%) = 58.9, VWFpp (%) = 53.6, VWF:RCo/VWF:Ag = 0.8, VWF:CB/VWF:Ag = 1.1, VWFpp/VWF:Ag = 1.0, FVIII:C/VWF:Ag = 1.3

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4414G>C (p.Asp1472His)

HGVS: NM_000552.4(VWF):c.4414G>C (p.Asp1472His)

ClinVarID: 256679; https://www.ncbi.nlm.nih.gov/clinvar/variation/256679/

CAID: NA

gnomAD: MAF = 0.5077 (12039/23712 alleles; 3078 homozygotes) in African/African-American population; https://gnomad.broadinstitute.org/variant/12-6128170-C-G?dataset=gnomad_r2_1

Case: P32, Chinese, male, 3yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: patient coexisting with severe haemophilia A; type O blood, bleeding score = 3; VWF:Ag (%) = 51.3, VWF:RCo (%) = 50.7, FVIII:C (%) = 1.0, VWF:CB (%) = 50.3, VWFpp (%) = 49.2, VWF:RCo/VWF:Ag = 1.0, VWF:CB/VWF:Ag = 1.0, VWFpp/VWF:Ag = 1.0, FVIII:C/VWF:Ag = 0.0

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.646G>A (p.Glu216Lys)

HGVS: NM_000552.5(VWF):c.646G>A (p.Glu216Lys)

ClinVarID: 870925; https://www.ncbi.nlm.nih.gov/clinvar/variation/870925/

CAID: NA

gnomAD: 0.001353 (27/19952 alleles) in East Asian population; https://gnomad.broadinstitute.org/variant/12-6204637-C-T?dataset=gnomad_r2_1

MultipleGeneVariants

Gene: F8

Variant: p.Arg446Ter - Unregistered Variant

Case: IP #28 (also in row 14 table 6)

DiseaseAssertion: type 2A VWF

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 39; VWF:Ac [IU/dL] = 7; FVIII:C [IU/dL] = 61

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4078G>T p.Val1360Phe

HGVS:

ClinVarID: 1809581

CAID:

gnomAD: absent

Case: IP #9

DiseaseAssertion: type 2A VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 17; VWF:Ac [IU/dL] = 10; FVIII:C [IU/dL] = 51

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.2771G>A p.Arg924Gln

HGVS:

ClinVarID: 100240

CAID:

gnomAD: 0.01774 (28642 in 1614096) 297 homozygotes https://gnomad.broadinstitute.org/variant/12-6031493-C-T?dataset=gnomad_r4

Case: IP #34

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 55; VWF:Ac [IU/dL] = 35; FVIII:C [IU/dL] = 60

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4517C>T p.Ser1506Leu

HGVS:

ClinVarID: 100369

CAID:

gnomAD: absent

Case: IP #26 in type 2N VWD sub-cohort

DiseaseAssertion: type 2N VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 50; VWF:Ac [IU/dL] = 29; FVIII:C [IU/dL] = 40

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3673T>G p.Cys1225Gly

HGVS:

ClinVarID: 100272

CAID:

gnomAD: absent

Case: IP #15 in type 2M VWD sub-cohort

DiseaseAssertion: type 2M VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = n/a; VWF:Ac [IU/dL] = 50; FVIII:C [IU/dL] = n/a; VWF:CB (IU/dL) = 25

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.5191T>A p.Ser1731Thr

HGVS:

ClinVarID: 100420

CAID:

gnomAD: 0.001158 (1870 in 1614210) 5 homozygotes https://gnomad.broadinstitute.org/variant/12-6016636-A-T?dataset=gnomad_r4

Case: IP #33 in type U VWD sub-cohort

DiseaseAssertion: unclassified VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 11; VWF:Ac [IU/dL] = 4; FVIII:C [IU/dL] = 10

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4120C>A p.Arg1374Ser

HGVS:

ClinVarID: 100328

CAID:

gnomAD: absent

Case: IP #55

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 71; VWF:Ac [IU/dL] = 17; FVIII:C [IU/dL] = n/a

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4825G>A p.Gly1609Arg

HGVS:

ClinVarID: 100395

CAID:

gnomAD: 0.000003098 (5 in 1614130) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018593-C-T?dataset=gnomad_r4

Case: IP #29 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/2M/1C) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 21; VWF:Ac [IU/dL] = 9; FVIII:C [IU/dL] = 42

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4120C>T p.Arg1374Cys

HGVS:

ClinVarID: 100329

CAID:

gnomAD: absent

Case: IP #12 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2M/2B/1) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 7; VWF:Ac [IU/dL] = n/a; FVIII:C [IU/dL] = 8

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3835G>A p.Val1279Ile

HGVS:

ClinVarID: 100288

CAID:

gnomAD: 0.0003751 (605 in 1612942) 1 homozygote https://gnomad.broadinstitute.org/variant/12-6019583-C-T?dataset=gnomad_r4

Case: IP #25 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/2M/1C) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 22; VWF:Ac [IU/dL] = 8; FVIII:C [IU/dL] = 26

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4120C>T p.Arg1374Cys

HGVS:

ClinVarID: 100329

CAID:

gnomAD: absent

Case: IP #9 in type 2M VWD sub-cohort

DiseaseAssertion: type 2M VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032440 - blood group B

CaseHPOFreeRext: VWF:Ag [IU/dL] = 91; VWF:Ac [IU/dL] = 28; FVIII:C [IU/dL] = 105; VWF:CB (IU/dL) = 88

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4195C>T p.Arg1399Cys

HGVS:

ClinVarID: 100337

CAID:

gnomAD: 0.00005143 (83 in 1613776) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019223-G-A?dataset=gnomad_r4

Case: IP #11 in type 2M VWD sub-cohort

DiseaseAssertion: type 2M VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 21; VWF:Ac [IU/dL] = 9; FVIII:C [IU/dL] = 32; VWF:CB (IU/dL) = 14

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4225G>T p.Val1409Phe

HGVS:

ClinVarID: 3393378

CAID:

gnomAD: absent

Case: IP #36 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/2M) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 42; VWF:Ac [IU/dL] = 15; FVIII:C [IU/dL] = 53

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4241T>G p.Val1414Gly

HGVS:

ClinVarID: 619752

CAID:

gnomAD: absent

Case: IP #14 in type 2M VWD sub-cohort

DiseaseAssertion: type 2M VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 94; VWF:Ac [IU/dL] = 89; FVIII:C [IU/dL] = 126; VWF:CB (IU/dL) = 49

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.5191T>A p.Ser1731Thr

HGVS:

ClinVarID: 100420

CAID:

gnomAD: 0.001158 (1870 in 1614210) 5 homozygotes https://gnomad.broadinstitute.org/variant/12-6016636-A-T?dataset=gnomad_r4

Case: IP #64

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 34; VWF:Ac [IU/dL] = 9; FVIII:C [IU/dL] = 42

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4892G>A p.Gly1631Asp

HGVS:

ClinVarID: 1342155

CAID:

gnomAD: absent

Case: IP #32 in type U VWD sub-cohort

DiseaseAssertion: unclassified VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 11; VWF:Ac [IU/dL] = 9; FVIII:C [IU/dL] = 17

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4120C>A p.Arg1374Ser

HGVS:

ClinVarID: 100328

CAID:

gnomAD: absent

Case: IP #4 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/1) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 14; VWF:Ac [IU/dL] = 14; FVIII:C [IU/dL] = 23

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3389G>A p.Cys1130Tyr

HGVS:

ClinVarID: 1684001

CAID:

gnomAD: absent

Case: IP #24 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/2M/1C) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 22; VWF:Ac [IU/dL] = 10; FVIII:C [IU/dL] = 40

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4120C>T p.Arg1374Cys

HGVS:

ClinVarID: 100329

CAID:

gnomAD: absent

Case: IP #35 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/2M) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032441 - blood group AB

CaseHPOFreeRext: VWF:Ag [IU/dL] = 14; VWF:Ac [IU/dL] = 9; FVIII:C [IU/dL] = 30

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4241T>G p.Val1414Gly

HGVS:

ClinVarID: 619752

CAID:

gnomAD: absent

Case: IP #12 in type 2M VWD sub-cohort

DiseaseAssertion: type 2M VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 23; VWF:Ac [IU/dL] = 21; FVIII:C [IU/dL] = 52; VWF:CB (IU/dL) = n/a

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.5191T>A p.Ser1731Thr

HGVS:

ClinVarID: 100420

CAID:

gnomAD: 0.001158 (1870 in 1614210) 5 homozygotes https://gnomad.broadinstitute.org/variant/12-6016636-A-T?dataset=gnomad_r4

Case: IP #28 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/2M/1C) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 11; VWF:Ac [IU/dL] = 4; FVIII:C [IU/dL] = 11

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4120C>T p.Arg1374Cys

HGVS:

ClinVarID: 100329

CAID:

gnomAD: absent

Case: IP #1

DiseaseAssertion: type 2A (IIC) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 11.4; VWF:Ac [IU/dL] = 4; FVIII:C [IU/dL] = n/a

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.421G>A p.Asp141Asn

HGVS:

ClinVarID: 100338

CAID:

gnomAD: absent

Case: IP #3 (also in row 1 splice variants table 6)

DiseaseAssertion: Type 2A (IIC) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 49; VWF:Ac [IU/dL] = n/a; FVIII:C [IU/dL] = n/a

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.1110-6_1110-5insC

HGVS: NM_000552.5:c.1110-6dup p.?

ClinVarID: 507028

CAID:

gnomAD: absent

Case: IP #4

DiseaseAssertion: type 2A (IIC) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 117; VWF:Ac [IU/dL] = 52; FVIII:C [IU/dL] = 104

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.1309_1326del p.Asp437_Arg442del

HGVS:

ClinVarID: 100179

CAID:

gnomAD: 0.000001239 (2 in 1614154) no homozygotes https://gnomad.broadinstitute.org/variant/12-6064351-AGCGGGTGCACACAGCGTC-A?dataset=gnomad_r4

Case: IP #15

DiseaseAssertion: type 2A (IIE) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 41; VWF:Ac [IU/dL] = n/a; FVIII:C [IU/dL] = 82

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3390C>T p.Cys1130Cys

HGVS:

ClinVarID: 627186

CAID:

gnomAD: 0.000006021 (3 in 498246) no homozygotes https://gnomad.broadinstitute.org/variant/12-6022888-G-A?dataset=gnomad_r4

Case: IP #39

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 110; VWF:Ac [IU/dL] = 14; FVIII:C [IU/dL] = 103

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4645G>A p.Glu1549Lys

HGVS:

ClinVarID: 100379

CAID:

gnomAD: absent

Case: IP #13 in type 2M VWD sub-cohort

DiseaseAssertion: type 2M VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 47; VWF:Ac [IU/dL] = 46; FVIII:C [IU/dL] = 86; VWF:CB (IU/dL) = n/a

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.5191T>A p.Ser1731Thr

HGVS:

ClinVarID: 100420

CAID:

gnomAD: 0.001158 (1870 in 1614210) 5 homozygotes https://gnomad.broadinstitute.org/variant/12-6016636-A-T?dataset=gnomad_r4

Case: IP #57

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 53; VWF:Ac [IU/dL] = 15; FVIII:C [IU/dL] = 46

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4825G>A p.Gly1609Arg

HGVS:

ClinVarID: 100395

CAID:

gnomAD: 0.000003098 (5 in 1614130) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018593-C-T?dataset=gnomad_r4

Case: IP #24 in type 2B VWD sub-cohort

DiseaseAssertion: type 2B VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 19; VWF:Ac [IU/dL] = 8; FVIII:C [IU/dL] = n/a

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4120C>T p.Arg1374Cys

HGVS:

ClinVarID: 100329

CAID:

gnomAD: 0.000003098 (5 in 1613796) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019298-G-A?dataset=gnomad_r4

Case: IP #2 in type U VWD sub-cohort

DiseaseAssertion: unclassified VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 17; VWF:Ac [IU/dL] = 15; FVIII:C [IU/dL] = 18

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.2625C>T p.Tyr875=

HGVS:

ClinVarID: 439330

CAID:

gnomAD: 0.000003717 (6 in 1614106) no homozygotes https://gnomad.broadinstitute.org/variant/12-6034748-G-A?dataset=gnomad_r4

Case: IP #2

DiseaseAssertion: type 2A (IIC) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 201; VWF:Ac [IU/dL] = 124; FVIII:C [IU/dL] = 244

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.1309_1326del p.Asp437_Arg442del

HGVS:

ClinVarID: 100179

CAID:

gnomAD: 0.000001239 (2 in 1614154) no homozygotes https://gnomad.broadinstitute.org/variant/12-6064351-AGCGGGTGCACACAGCGTC-A?dataset=gnomad_r4

Case: IP #11 in type U VWD sub-cohort

DiseaseAssertion: unclassified VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 18; VWF:Ac [IU/dL] = 12; FVIII:C [IU/dL] = 27

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3586T>C p.Cys1196Arg

HGVS:

ClinVarID: 100270

CAID:

gnomAD: 0.000001239 (2 in 1614220) no homozygotes https://gnomad.broadinstitute.org/variant/12-6021988-A-G?dataset=gnomad_r4

Case: IP #63

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032440 - blood group B

CaseHPOFreeRext: VWF:Ag [IU/dL] = 45; VWF:Ac [IU/dL] = 8; FVIII:C [IU/dL] = 36

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4885G>A p.Gly1629Arg

HGVS:

ClinVarID: 100398

CAID:

gnomAD: absent

Case: IP #8 in type 2M VWD sub-cohort

DiseaseAssertion: type 2M VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 30; VWF:Ac [IU/dL] = 16; FVIII:C [IU/dL] = 61; VWF:CB (IU/dL) = 43

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4105T>A p.Phe1369Ile

HGVS:

ClinVarID: 100326

CAID:

gnomAD: 0.000006197 (10 in 1613726) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019313-A-T?dataset=gnomad_r4

Case: IP #38 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/2B) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 19; VWF:Ac [IU/dL] = 1; FVIII:C [IU/dL] = 27

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4373G>A p.Cys1458Tyr

HGVS:

ClinVarID: 100351

CAID:

gnomAD: absent

Case: IP #31 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/2M/1C) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 32; VWF:Ac [IU/dL] = 14; FVIII:C [IU/dL] = 43

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4120C>T p.Arg1374Cys

HGVS:

ClinVarID: 100329

CAID:

gnomAD: absent

Case: IP #34 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/2M/1C) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 19; VWF:Ac [IU/dL] = 6; FVIII:C [IU/dL] = 38

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4121G>A p.Arg1374His

HGVS:

ClinVarID: 100330

CAID:

gnomAD: 0.000001239 (2 in 1613878) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019297-C-T?dataset=gnomad_r4

Case: IP #27 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/2M/1C) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 18; VWF:Ac [IU/dL] = 12; FVIII:C [IU/dL] = 22

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4120C>T p.Arg1374Cys

HGVS:

ClinVarID: 100329

CAID:

gnomAD: absent

Case: IP #35

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 65; VWF:Ac [IU/dL] = 10; FVIII:C [IU/dL] = 24

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4517C>T p.Ser1506Leu

HGVS:

ClinVarID: 100369

CAID:

gnomAD: absent

Case: IP #56

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032440 - blood group B

CaseHPOFreeRext: VWF:Ag [IU/dL] = 46; VWF:Ac [IU/dL] = 12; FVIII:C [IU/dL] = 60

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4825G>A p.Gly1609Arg

HGVS:

ClinVarID: 100395

CAID:

gnomAD: 0.000003098 (5 in 1614130) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018593-C-T?dataset=gnomad_r4

Case: IP #27 in type 2N VWD sub-cohort

DiseaseAssertion: type 2N VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 42; VWF:Ac [IU/dL] = 44; FVIII:C [IU/dL] = 69

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3673T>G p.Cys1225Gly

HGVS:

ClinVarID: 100272

CAID:

gnomAD: absent

Case: IP #40

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 46; VWF:Ac [IU/dL] = 31; FVIII:C [IU/dL] = 57

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4690C>T p.Arg1564Trp

HGVS:

ClinVarID: 811702

CAID:

gnomAD: 0.000006818 (11 in 1613330) no homozygotes https://gnomad.broadinstitute.org/variant/12-6018728-G-A?dataset=gnomad_r4

Case: IP #26 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/2M/1C) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 23; VWF:Ac [IU/dL] = 6; FVIII:C [IU/dL] = 23

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4120C>T p.Arg1374Cys

HGVS:

ClinVarID: 100329

CAID:

gnomAD: absent

Case: IP #30 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/2M/1C) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 20; VWF:Ac [IU/dL] = 11; FVIII:C [IU/dL] = 27

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4120C>T p.Arg1374Cys

HGVS:

ClinVarID: 100329

CAID:

gnomAD: absent

Case: IP #13 (also in row 7 table 6)

DiseaseAssertion: type 2A (IIE) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 23; VWF:Ac [IU/dL] = n/a; FVIII:C [IU/dL] = 45

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3314C>A p.Ala1105Asp

HGVS:

ClinVarID: 626953

CAID:

gnomAD: absent

Case: IP #67

DiseaseAssertion: type 2A VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 9,3; VWF:Ac [IU/dL] = 4; FVIII:C [IU/dL] = 41

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.7988G>C p.Arg2663Pro

HGVS:

ClinVarID: 372760

CAID:

gnomAD: 0.001352 (2181 in 1613616) 4 homozygotes https://gnomad.broadinstitute.org/variant/12-5952518-C-G?dataset=gnomad_r4

Case: IP #65

DiseaseAssertion: type 2A (IIA) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: VWF:Ag [IU/dL] = 33; VWF:Ac [IU/dL] = 15; FVIII:C [IU/dL] = n/a

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4912G>A p.Glu1638Lys

HGVS:

ClinVarID: 100403

CAID:

gnomAD: absent

Case: IP #37 in type U VWD sub-cohort

DiseaseAssertion: unclassified (2A/2M) VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032442 - blood group O

CaseHPOFreeRext: VWF:Ag [IU/dL] = 15; VWF:Ac [IU/dL] = 7; FVIII:C [IU/dL] = 25

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4241T>G p.Val1414Gly

HGVS:

ClinVarID: 619752

CAID:

gnomAD: absent

Case: IP #10 in type 2M VWD sub-cohort

DiseaseAssertion: type 2M VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032440 - blood group B

CaseHPOFreeRext: VWF:Ag [IU/dL] = 73; VWF:Ac [IU/dL] = 23; FVIII:C [IU/dL] = 79; VWF:CB (IU/dL) = 57

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.4195C>T p.Arg1399Cys

HGVS:

ClinVarID: 100337

CAID:

gnomAD: 0.00005143 (83 in 1613776) no homozygotes https://gnomad.broadinstitute.org/variant/12-6019223-G-A?dataset=gnomad_r4

Case: IP #10 in type U VWD sub-cohort

DiseaseAssertion: unclassified VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: HP:0032370 - blood group A

CaseHPOFreeRext: VWF:Ag [IU/dL] = 21; VWF:Ac [IU/dL] = 18; FVIII:C [IU/dL] = 55

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Sequence variations in the VWF were identified through direct sequencing, while the detection of large rearrangements utilized the multiplex ligation-dependent probe amplification (MLPA) technique or assessed copy number variations (CNVs). Sanger sequencing methodology was applied for VWF analysis in patients investigated prior to 2016 (approximately 14% of IPs), whereas next-generation sequencing (NGS) was employed for the analysis of VWF in patients inspected from 2017 onwards (about 86% of IPs). In both strategies, the entire VWF, encompassing all 52 exons, intron/exon boundaries, and promoter regions, was analyzed.

PreviouslyPublished:

Gene: VWF

Variant: c.3586T>C p.Cys1196Arg

HGVS:

ClinVarID: 100270

CAID:

gnomAD: 0.000001239 (2 in 1614220) no homozygotes https://gnomad.broadinstitute.org/variant/12-6021988-A-G?dataset=gnomad_r4

Case: Row 1 Supplemental Table 1.

DiseaseAssertion: type 1 VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: FVIII:C/VWF:Ag ratio = 1.5; VWFpp/ VWF:Ag = 2.0

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Ion semiconductor sequencing (Ion-Torrent) was used to analyze the VWF gene from peripheral blood obtained in EDTA tubes or from saliva samples. The 52 exons of VWF gene were analyzed including ±20 bp exon-intron boundaries. If no VWF gene variant was detected, multiplex ligation-dependent probe amplification (MLPA) analysis was performed to find large deletions or duplications. Thus, MLPA was performed in 183 patients (46.9%). All variants were confirmed with Sanger sequencing.

PreviouslyPublished:

Gene: VWF

Variant: 55G>A G19R

HGVS: c.55G>A p.G19R

ClinVarID: 100432

CAID:

gnomAD: 0.00007062 (114 in 1614206) no homozygotes https://gnomad.broadinstitute.org/variant/12-6123142-C-T?dataset=gnomad_r4

Case: Row 3 in Supplemental Table 1. Represents 2 patients in 2 families.

DiseaseAssertion: type 1 VWD

FamilyInfo:

ParentalGenotype(s): Both patients also had R2313C (novel)

CasePresentingHPOs:

CaseHPOFreeRext: FVIII:C/VWF:Ag = 2.5 (2.4-2.5); VWFpp/VWF:Ag = 1.8 (1.3-2.3)

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Genetic analysis was performed at the laboratory of hematology of the Radboud University Medical Center in Nijmegen. Ion semiconductor sequencing (Ion-Torrent) was used to analyze the VWF gene from peripheral blood obtained in EDTA tubes or from saliva samples. The 52 exons of VWF gene were analyzed including ±20 bp exon-intron boundaries. If no VWF gene variant was detected, multiplex ligation-dependent probe amplification (MLPA) analysis was performed to find large deletions or duplications. Thus, MLPA was performed in 183 patients (46.9%). All variants were confirmed with Sanger sequencing.

PreviouslyPublished:

Gene: VWF

Variant: 421G>A D141N

HGVS: c.421G>A p.Asp141Asn

ClinVarID: 100338

CAID:

gnomAD: absent

Case: Row 12 in Supplemental Table 1.

DiseaseAssertion: type 2A VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: FVIII:C/VWF:Ag = 3.3; VWFpp/VWF:Ag = 1.9

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Genetic analysis was performed at the laboratory of hematology of the Radboud University Medical Center in Nijmegen. Ion semiconductor sequencing (Ion-Torrent) was used to analyze the VWF gene from peripheral blood obtained in EDTA tubes or from saliva samples. The 52 exons of VWF gene were analyzed including ±20 bp exon-intron boundaries. If no VWF gene variant was detected, multiplex ligation-dependent probe amplification (MLPA) analysis was performed to find large deletions or duplications. Thus, MLPA was performed in 183 patients (46.9%). All variants were confirmed with Sanger sequencing.

PreviouslyPublished:

Gene: VWF

Variant: 1708T>C C570R

HGVS: VWF:c.1708T>C (p.Cys570Arg)

ClinVarID: 1695347

CAID:

gnomAD: absent

Case: Row 10 in Supplemental Table 1. Data represents 2 patients from the same family.

DiseaseAssertion: type 2A VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: FVIII:C/VWF:Ag = 1.8 (1.2-2.3); VWFpp/VWF:Ag = 0.8 (0.7-0.8)

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Genetic analysis was performed at the laboratory of hematology of the Radboud University Medical Center in Nijmegen. Ion semiconductor sequencing (Ion-Torrent) was used to analyze the VWF gene from peripheral blood obtained in EDTA tubes or from saliva samples. The 52 exons of VWF gene were analyzed including ±20 bp exon-intron boundaries. If no VWF gene variant was detected, multiplex ligation-dependent probe amplification (MLPA) analysis was performed to find large deletions or duplications. Thus, MLPA was performed in 183 patients (46.9%). All variants were confirmed with Sanger sequencing.

PreviouslyPublished:

Gene: VWF

Variant: 1607T>C L536P

HGVS: VWF:c.1607T>C p.Leu536Pro

ClinVarID: 627250

CAID:

gnomAD: 0.000003718 (6 in 1613592) no homozygotes https://gnomad.broadinstitute.org/variant/12-6057971-A-G?dataset=gnomad_r4

MultipleGeneVariants:

Gene: VWF

Variant: H1419M fs*22

Case: Row 5 in Supplemental Table 1.

DiseaseAssertion: type 1 VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: FVIII:C/VWF:Ag = 2.5; VWFpp/VWF:Ag = 2.0

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Genetic analysis was performed at the laboratory of hematology of the Radboud University Medical Center in Nijmegen. Ion semiconductor sequencing (Ion-Torrent) was used to analyze the VWF gene from peripheral blood obtained in EDTA tubes or from saliva samples. The 52 exons of VWF gene were analyzed including ±20 bp exon-intron boundaries. If no VWF gene variant was detected, multiplex ligation-dependent probe amplification (MLPA) analysis was performed to find large deletions or duplications. Thus, MLPA was performed in 183 patients (46.9%). All variants were confirmed with Sanger sequencing.

PreviouslyPublished:

Gene: VWF

Variant: 722T>G V241G

HGVS: c.722T>G (p.Val241Gly)

ClinVarID: 1695353

CAID:

gnomAD: absent

Case: Row 4 in Supplemental Table 1.

DiseaseAssertion: type 1 VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: FVIII:C/VWF:Ag = 1.3; VWFpp/VWF:Ag = 1.3

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Genetic analysis was performed at the laboratory of hematology of the Radboud University Medical Center in Nijmegen. Ion semiconductor sequencing (Ion-Torrent) was used to analyze the VWF gene from peripheral blood obtained in EDTA tubes or from saliva samples. The 52 exons of VWF gene were analyzed including ±20 bp exon-intron boundaries. If no VWF gene variant was detected, multiplex ligation-dependent probe amplification (MLPA) analysis was performed to find large deletions or duplications. Thus, MLPA was performed in 183 patients (46.9%). All variants were confirmed with Sanger sequencing.

PreviouslyPublished:

Gene: VWF

Variant: 706C>T R236C

HGVS: c.706C>T p.Arg236Cys

ClinVarID: 1695352

CAID:

gnomAD: absent

Case: Row 9 in Supplemental Table 1.

DiseaseAssertion: type 1 VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: FVIII:C/VWF:Ag = 3.0; VWFpp/VWF:Ag = 1.6

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Genetic analysis was performed at the laboratory of hematology of the Radboud University Medical Center in Nijmegen. Ion semiconductor sequencing (Ion-Torrent) was used to analyze the VWF gene from peripheral blood obtained in EDTA tubes or from saliva samples. The 52 exons of VWF gene were analyzed including ±20 bp exon-intron boundaries. If no VWF gene variant was detected, multiplex ligation-dependent probe amplification (MLPA) analysis was performed to find large deletions or duplications. Thus, MLPA was performed in 183 patients (46.9%). All variants were confirmed with Sanger sequencing.

PreviouslyPublished:

Gene: VWF

Variant: 1600G>A D534N

HGVS: c.1600G>A (p.Asp534Asn)

ClinVarID: 1695364

CAID:

gnomAD: absent

Case: Row 18 in Supplemental Table 1.

DiseaseAssertion: type 1 VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: FVIII:C/VWF:Ag = 1.8; VWFpp/VWF:Ag = 1.3

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Genetic analysis was performed at the laboratory of hematology of the Radboud University Medical Center in Nijmegen. Ion semiconductor sequencing (Ion-Torrent) was used to analyze the VWF gene from peripheral blood obtained in EDTA tubes or from saliva samples. The 52 exons of VWF gene were analyzed including ±20 bp exon-intron boundaries. If no VWF gene variant was detected, multiplex ligation-dependent probe amplification (MLPA) analysis was performed to find large deletions or duplications. Thus, MLPA was performed in 183 patients (46.9%). All variants were confirmed with Sanger sequencing.

PreviouslyPublished:

Gene: VWF

Variant: 2442+4A>G

HGVS: VWF:c.2442+4A>G

ClinVarID: 1695350

CAID:

gnomAD: absent

Case: Row 7 in Supplemental Table 1.

DiseaseAssertion: type 1 VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: FVIII:C/VWF:Ag = 1.1; VWFpp/VWF:Ag = 1.4

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Genetic analysis was performed at the laboratory of hematology of the Radboud University Medical Center in Nijmegen. Ion semiconductor sequencing (Ion-Torrent) was used to analyze the VWF gene from peripheral blood obtained in EDTA tubes or from saliva samples. The 52 exons of VWF gene were analyzed including ±20 bp exon-intron boundaries. If no VWF gene variant was detected, multiplex ligation-dependent probe amplification (MLPA) analysis was performed to find large deletions or duplications. Thus, MLPA was performed in 183 patients (46.9%). All variants were confirmed with Sanger sequencing.

PreviouslyPublished:

Gene: VWF

Variant: 1318delT C440A fs*17

HGVS: c.1318del (p.Cys440Alafs*17)

ClinVarID: 1695356

CAID:

gnomAD: absent

Case: Row 13 in Supplemental Table 1.

DiseaseAssertion: type 1 VWD

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: FVIII:C/VWF:Ag = 2.5; VWFpp/VWF:Ag = 1.9

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Genetic analysis was performed at the laboratory of hematology of the Radboud University Medical Center in Nijmegen. Ion semiconductor sequencing (Ion-Torrent) was used to analyze the VWF gene from peripheral blood obtained in EDTA tubes or from saliva samples. The 52 exons of VWF gene were analyzed including ±20 bp exon-intron boundaries. If no VWF gene variant was detected, multiplex ligation-dependent probe amplification (MLPA) analysis was performed to find large deletions or duplications. Thus, MLPA was performed in 183 patients (46.9%). All variants were confirmed with Sanger sequencing.

PreviouslyPublished:

Gene: VWF

Variant: 1955G>T C652F

HGVS: VWF:c.1955G>T (p.Cys652Phe)

ClinVarID: 1695348

CAID:

gnomAD: absent

Case: Row 22 in Supplemental Table 1.

DiseaseAssertion: VWD type 1

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs:

CaseHPOFreeRext: FVIII:C/VWF:Ag = 1.6; VWFpp/VWF:Ag = 1.5

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: Genetic analysis was performed at the laboratory of hematology of the Radboud University Medical Center in Nijmegen. Ion semiconductor sequencing (Ion-Torrent) was used to analyze the VWF gene from peripheral blood obtained in EDTA tubes or from saliva samples. The 52 exons of VWF gene were analyzed including ±20 bp exon-intron boundaries. If no VWF gene variant was detected, multiplex ligation-dependent probe amplification (MLPA) analysis was performed to find large deletions or duplications. Thus, MLPA was performed in 183 patients (46.9%). All variants were confirmed with Sanger sequencing.

PreviouslyPublished:

Gene: VWF

Variant: 2878C>T R960W

HGVS: VWF:c.2878C>T p.Arg960Trp

ClinVarID: 1033091

CAID:

gnomAD: 0.0001295 (209 in 1614054) no homozygotes https://gnomad.broadinstitute.org/variant/12-6029431-G-A?dataset=gnomad_r4

Case: P6, female, 31yo

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 = 3; VWF:Ag (%) = 23, VWF:RCo(%) = 4, VWF:RCo/VWF:Ag ratio = 0.17, VWF:CIIIB (%) = 9.4, VWF:CIIIB/VWF:Ag ratio = 0.4, VWF:CVIB (%) = 4, VWF:CVIB/VWF:Ag ratio = 0.17

CaseNOTHPOs: HP:0030132

(Absence of large von Willebrand factor multimers)

CaseNOTHPOFreeText: NA

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4121G>A (p.Arg1374His)

HGVS: NM_000552.4(VWF):c.4121G>A (p.Arg1374His)

ClinVarID: 100330; https://www.ncbi.nlm.nih.gov/clinvar/variation/100330/

CAID:

gnomAD: absent

Case: P3, female, 48yo

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 = 9; VWF:Ag (%) = 35, VWF:RCo(%) = 19, VWF:RCo/VWF:Ag ratio = 0.54, VWF:CIIIB (%) = 25, VWF:CIIIB/VWF:Ag ratio = 0.71, VWF:CVIB (%) = 31, VWF:CVIB/VWF:Ag ratio = 0.89

CaseNOTHPOs: HP:0030132

(Absence of large von Willebrand factor multimers)

CaseNOTHPOFreeText: NA

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4120C>T (p.Arg1374Cys)

HGVS: NM_000552.4(VWF):c.4120C>T (p.Arg1374Cys)

ClinVarID: 100329; https://www.ncbi.nlm.nih.gov/clinvar/variation/100329/

CAID:

gnomAD: MAF = 0.000008824 (1/113322 alleles) in the European (Non-Finnish) population; https://gnomad.broadinstitute.org/variant/12-6128464-G-A?dataset=gnomad_r2_1

Case: P4, female, 76yo

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 = 1; VWF:Ag (%) = 36, VWF:RCo(%) = 16, VWF:RCo/VWF:Ag ratio = 0.44, VWF:CIIIB (%) = 32, VWF:CIIIB/VWF:Ag ratio = 0.89, VWF:CVIB (%) = 26, VWF:CVIB/VWF:Ag ratio = 0.72

CaseNOTHPOs: HP:0030132

(Absence of large von Willebrand factor multimers)

CaseNOTHPOFreeText: NA

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4120C>T (p.Arg1374Cys)

HGVS: NM_000552.4(VWF):c.4120C>T (p.Arg1374Cys)

ClinVarID: 100329; https://www.ncbi.nlm.nih.gov/clinvar/variation/100329/

CAID:

gnomAD: MAF = 0.000008824 (1/113322 alleles) in the European (Non-Finnish) population; https://gnomad.broadinstitute.org/variant/12-6128464-G-A?dataset=gnomad_r2_1

Case: P5, male, 73yo

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 = 8; VWF:Ag (%) = 46, VWF:RCo(%) = 8.5, VWF:RCo/VWF:Ag ratio = 0.18, VWF:CIIIB (%) = 19.5, VWF:CIIIB/VWF:Ag ratio = 0.4, VWF:CVIB (%) = 15, VWF:CVIB/VWF:Ag ratio = 0.33

CaseNOTHPOs: HP:0030132

(Absence of large von Willebrand factor multimers)

CaseNOTHPOFreeText: NA

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4121G>A (p.Arg1374His)

HGVS: NM_000552.4(VWF):c.4121G>A (p.Arg1374His)

ClinVarID: 100330; https://www.ncbi.nlm.nih.gov/clinvar/variation/100330/

CAID:

gnomAD: absent

Case: P7, 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 = 7; VWF:Ag (%) = 56, VWF:RCo(%) = 32, VWF:RCo/VWF:Ag ratio = 0.58, VWF:CIIIB (%) = 37, VWF:CIIIB/VWF:Ag ratio = 0.67, VWF:CVIB (%) = 17.4, VWF:CVIB/VWF:Ag ratio = 0.31

CaseNOTHPOs: HP:0030132

(Absence of large von Willebrand factor multimers)

CaseNOTHPOFreeText: NA

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant: c.4195C>T (p.Arg1399Cys)

HGVS: NM_000552.4(VWF):c.4195C>T (p.Arg1399Cys)

ClinVarID: 100337; https://www.ncbi.nlm.nih.gov/clinvar/variation/100337/

CAID:

gnomAD: MAF = 0.0001386 (1/7214 alleles) in the Other population; https://gnomad.broadinstitute.org/variant/12-6128389-G-A?dataset=gnomad_r2_1

Case: Patient 2, female, 9.6yo

DiseaseAssertion: VWD2A

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147, HP:0030129, HP:0030130, HP:0030132

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

CaseHPOFreeText: VWF:Ag = 27%, undetectable VWF:RCo and VWF:CB; Platelets (*109/L) = 274, Mean Platelet Volume (fL) = 10, FVIII:C (\%) = 34, VWF:CB (\%) <5, VWF:RCo (\%) = <5, aPTT (sec) = 51.6, PT (\%) =724

CaseNOTHPOs: HP:0001873

(Thrombocytopenia)

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: sequencing of exon 28 of the VWF

PreviouslyPublished: NA

Gene: VWF

Variant: c.4373G>A (p.Cys1458Tyr)

HGVS: NM_000552.4(VWF):c.4373G>A (p.Cys1458Tyr)

ClinVarID: 100351; https://www.ncbi.nlm.nih.gov/clinvar/variation/100351/

CAID: NA

gnomAD: absent

Case: Proband 1 (Family 1)

DiseaseAssertion: VWD1

FamilyInfo: 2 family members diagnosed with VWD1

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147, HP:0001892, HP:0030130

(Reduced quantity of Von Willebrand factor, Abnormal bleeding, Impaired von Willibrand factor collagen binding activity)

CaseHPOFreeText: normal to slightly prolonged Ivy BT, FVIII:C % = 28, VWF:Ag % = 12, VWF:RCo % = 14, VIII C/vWF:AG ratio = 2.3, vWF:Rco/vWF:AG ratio = 1.2

CaseNOTHPOs: HP:0011871, HP:0030132

(Impaired ristocetin-induced platelet aggregation, Absence of large von Willibrand factor multimers)

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NA

PreviouslyPublished: PMID: 11992235

Gene: VWF

Variant: c.6536C>T (p.Ser2179Phe)

HGVS: NM_000552.4(VWF):c.6536C>T (p.Ser2179Phe)

ClinVarID: 100442; https://www.ncbi.nlm.nih.gov/clinvar/variation/100442/

CAID:

gnomAD: absent

Case: Dutch Family Proband (II-1), male

DiseaseAssertion: VWD2A

FamilyInfo: 10 additional affected family members (phenotypic details in Table 4)

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0030132, HP:0011871, HP:0012147, HP:0030129

(Absence of large von Willebrand factor multimers, Impaired RIPA, Reduced quantity of VWF, Impaired ristocetin cofactor assay activity)

CaseHPOFreeText: FVIII:C = 63, vWF:Ag = 59, vWF:pp = 76, pp/Ag = 1.3, vWF:RCo = <15, Rco/Ag = 0.30, RIPA = N; minor or poor response to DDAVP of functional vWF:RCo and vWF:CB with no correction of vWF multimers and BT directly after DDAVP

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NA

PreviouslyPublished: PMID: 19346881

Gene: VWF

Variant: c.4496T>A (p.Val1499Glu)

HGVS: NM_000552.4(VWF):c.4496T>A (p.Val1499Glu)

ClinVarID: 440408; https://www.ncbi.nlm.nih.gov/clinvar/variation/440408/

CAID:

gnomAD: absent

Case: Proband 3 (S2179F)

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147, HP:0001892, HP:0030130

(Reduced quantity of Von Willebrand factor, Abnormal bleeding, Impaired von Willibrand factor collagen binding activity)

CaseHPOFreeText: normal to slightly prolonged Ivy BT, FVIII:C % = 26, VWF:Ag % = 6, VWF:RCo % = 6, VIII C/vWF:AG ratio = 4.3, vWF:Rco/vWF:AG ratio = 1.0

CaseNOTHPOs: HP:0011871, HP:0030132

(Impaired ristocetin-induced platelet aggregation, Absence of large von Willibrand factor multimers)

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NA

PreviouslyPublished: PMID: 11992235

Gene: VWF

Variant: c.6536C>T (p.Ser2179Phe)

HGVS: NM_000552.4(VWF):c.6536C>T (p.Ser2179Phe)

ClinVarID: 100442; https://www.ncbi.nlm.nih.gov/clinvar/variation/100442/

CAID:

gnomAD: absent

Case: Proband 2 (Family 2)

DiseaseAssertion: VWD1

FamilyInfo: 2 family members diagnosed with VWD1

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147, HP:0001892, HP:0030130, HP:0011871

(Reduced quantity of Von Willebrand factor, Abnormal bleeding, Impaired von Willibrand factor collagen binding activity)

CaseHPOFreeText: normal to slightly prolonged Ivy BT, FVIII:C % = 19, VWF:Ag % = 13, VWF:RCo % = 12, VIII C/vWF:AG ratio = 1.5, vWF:Rco/vWF:AG ratio = 0.9

CaseNOTHPOs: HP:0030132

(Absence of large von Willibrand factor multimers)

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NA

PreviouslyPublished: PMID: 11992235

Gene: VWF

Variant: c.6536C>T (p.Ser2179Phe)

HGVS: NM_000552.4(VWF):c.6536C>T (p.Ser2179Phe)

ClinVarID: 100442; https://www.ncbi.nlm.nih.gov/clinvar/variation/100442/

CAID:

gnomAD: absent