Case1: 13 year old female

DiseaseAssertion: LVNC

FamilyInfo: No family history of cardiac disease

ParentalTesting:NR

CasePresentingHPOs: HP:0011664. HP:0002094. HP:0001279. HP:0031295

CaseHPOFreeText:Left Ventricular noncompaction, Dyspnea (shortness of breath), Fainting, Left atrial enlargement

CaseNotHPOs:HP:0000929. HP:0001712

CaseNotHPOFreeText:Abnormal skull morphology, left ventricular hypertrophy

CasePreviousTesting:

Genotyping Method:Next-Generation Sequencing (NGS)

FunctionalAnalysis:NR

Variant:c.575G>A

ClinVar:12424

CAID:CA021957

gnomAD:NR

AdditionalInfo:NR

Case1:Male, 46 years old

DiseaseAssertion:NR

FamilyInfo: 3 generations of asymptomatic carriers

ParentalTesting:NR

CasePresentingHPOs:NR

CaseHPOFreeText:

CaseNotHPOs:HP:0001712

CaseNotHPOFreeText:Left Ventricular hypertrophy

CasePreviousTesting:NR

Genotyping Method: NR

FunctionalAnalysis:

Variant: c.170C>A VUS

ClinVar:43121

CAID:CA013575

gnomAD: NR

AdditionalInfo:

Case#1: Female

DiseaseAssertion: Left ventricular noncompaction cardiomyopathy, congenital adrenal hyperplasia

FamilyInfo: Clinical evaluation of proband’s parents, wife, 18 year old son, and 14 year old daughter were showed them as asymptomatic

ParentalTesting: variants found in both mother and father

CasePresentingHPOs: N/A

CaseHPOFreeText: Hypertension, Hypokalemia, disorders of sex development, delayed puberty

CaseNotHPOs: N/A

CaseNotHPOFreeText:Adrenal volume was normal

CasePreviousTesting: Targeted gene panel for pathogenic variants in MYBPC3

Genotyping Method: Whole exome Sequencing

Variant: NM_000256.3 c.1000G>A, p.E334K

ClinVar:177902

CAID: CA009667

gnomAD:chr11-47346297-C-T

Case1: Female, four years five months

DiseaseAssertion: RCM

FamilyInfo: “ No family history of RCM or other cardiovascular diseases was reported.”

ParentalTesting: NA

CasePresentingHPOs:HP:0002094, HP:0002875,

CaseHPOFreeText: “congestive hepatomegaly” “lower extremity edema” “increased heart shadow without calcification of the pericardium” “bi-atrial enlargement without calcification of the pericardium, thickened pericardium, or endocardium” “‘eft and right atria were enlarged, the right ventricle was slightly enlarged”

CaseNotHPOs:

CaseNotHPOFreeText: “the left ventricle was normal in size, without calcification of the pericardium, thickened pericardium, or endocardium”

CasePreviousTesting: Chest X-ray, Abdominal ultrasonography, MRI, Two-dimensional echocardiography

Genotyping Method: Sanger Sequencing

FunctionalAnalysis: NA

Variant:c.508C>T p.Arg170Trp

ClinVar: 4188245

CAID:

gnomAD:

AdditionalInfo:

Case3: Four month, 21 day old male

DiseaseAssertion: RCM

FamilyInfo: “No family history of RCM or other cardiovascular diseases was reported.”

ParentalTesting:

CasePresentingHPOs: HP:0000961

CaseHPOFreeText: “late hoarseness” “ dilation of the left and right atria”

CaseNotHPOs:

CaseNotHPOFreeText: “normal ventricular sizes, without calcification of the pericardium, thickened pericardium, or endocardium”

CasePreviousTesting: echocardiography

Genotyping Method: Sanger Sequencing

FunctionalAnalysis:

Variant: c.517C>T p.Leu173Phe

ClinVar: Not found

CAID: CA407440287

gnomAD:

AdditionalInfo: “Unfortunately, tissue velocity images were not obtained and the TTE images of this case were lost.”

Case2: Five year old female

DiseaseAssertion: RCM

FamilyInfo: “No family history of RCM or other cardiovascular diseases was reported.”

ParentalTesting:

CasePresentingHPOs:HP:0002875, HP:0002094

CaseHPOFreeText: “lower extremity edema” “congestive hepatomegaly” “ increased heart shadow without calcification of the pericardium” “bi-atrial enlargement without calcification of the pericardium, thickened pericardium, or endocardium”

CaseNotHPOs:

CaseNotHPOFreeText:

CasePreviousTesting: Abdominal ultrasonography, ECG, Chest X-ray, MRI, Two-dimensional echocardiography

Genotyping Method: Sanger Sequencing

FunctionalAnalysis:

Variant: NM_006757.4(TNNT3):c.575G>A (p.Gly192Asp)

ClinVar: 4633351

CAID:

gnomAD:

AdditionalInfo:

Patient7: Male

CasePresentingHPOs: HP:0002194

HPOsFreeText: ERT dosage = 20 mg/kg/2 w, CRIM positive

CaseNotHPOs: HP:0004887

NotHPOsFreeText: no reversal of HCM

CaseAddInfo: Symptom onset and diagnosis at 3mo, ERT at 4mo, ERT lasted for 24mo, died at 28mo

CasePMIDs: 22644586, 14695532

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.4(GAA):c.655G>A (p.Gly219Arg)

ClinVar: 189065, https://www.ncbi.nlm.nih.gov/clinvar/variation/189065/

gnomAD: 1.666e-05, http://exac.broadinstitute.org/variant/17-78079656-G-A

Patient11: Female

CasePresentingHPOs: HP:0004887, HP:0002100, HP:0006597, HP:0200136, HP:0011471

HPOsFreeText: ERT dosage = 40mg/kg/w, HCM reversal, CRIM positive, able to run, diaphragmatic paralysis required plication at 3yo

CaseNotHPOs: HP:0009046

NotHPOsFreeText:

CaseAddInfo: Symptom onset at 2mo, diagnosis at 4mo, ERT at 5mo, ERT lasted for 67mo, ventilation required at 62mo, currently 6yo

CasePMIDs: 14695532, 14972326

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.4(GAA):c.1064T>C (p.Leu355Pro)

ClinVar: 284093, https://www.ncbi.nlm.nih.gov/clinvar/variation/284093/

gnomAD: 8.304e-06, http://exac.broadinstitute.org/variant/17-78082197-T-C

CaseOPTPD-5: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 1.27 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

Variant2: NM_000152.4:c.1222A>G (p.Met408Val)

ClinVar: 371235 https://www.ncbi.nlm.nih.gov/clinvar/variation/371235/

gnomAD: European (Non-Finnish) 1.790e-5, Overall 8.058e-6 http://gnomad.broadinstitute.org/variant/17-78082523-A-G

CaseAddInfo: One Pompe Mutation allele and Two Pseudodeficency Mutation alleles, Nomenclature indicates patient is homozygous for Variant 1 and Variant 2 is in cis with one copy

CaseLP2-12: Male, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 0.43 umol/hr/L, Serum CK at 29 U/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.1935C>A (p.Asp645Glu)

ClinVar: 4029 https://www.ncbi.nlm.nih.gov/clinvar/variation/4029/

gnomAD: East Asian 1.729e-3, Overall 1.240e-4 http://gnomad.broadinstitute.org/variant/17-78086721-C-A

Variant2: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

Variant3: NM_000152.4:c.2482-5T>C

ClinVar: 558320 https://www.ncbi.nlm.nih.gov/clinvar/variation/558320/

gnomAD: Not in gnomAD

CaseAddInfo: Late Onset Pompe Disease, Nomenclature indicates Variants 1 and 2 are in cis one one allele and Variants 2 and 3 are in cis on the other

CaseOPOPD-52: Male, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 1.05 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

Variant2: NM_000152.4:c.1843G>A (p.Gly615Arg)

ClinVar: 188786 https://www.ncbi.nlm.nih.gov/clinvar/variation/188786/

gnomAD: East Asian 2.223e-4, Overall 1.640e-5 http://gnomad.broadinstitute.org/variant/17-78086465-G-A

CaseAddInfo: One Pompe Mutation allele and One Pseudodeficency Mutation allele, 1 other patient has the same genotype

CaseOPOPD-45: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 1.46 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.1411_1414delGAGA (p.Glu471Profs)

ClinVar: 188874 https://www.ncbi.nlm.nih.gov/clinvar/variation/188874/

gnomAD: East Asian 2.513e-4, Overall 1.781e-5 http://gnomad.broadinstitute.org/variant/17-78083827-CGAGA-C

Variant2: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

CaseAddInfo: One Pompe Mutation allele and One Pseudodeficency Mutation allele, 1 other has the same genotype

CaseOPOPD-4: Female, Taiwan, Birth diagnosis

HPOsFreeText: GAA (MS/MS) enzyme activity at 1.16 umol/hr/L

GenotypingMethod: GAA Gene Sequencing and PCR Amplification

Variant1: NM_000152.4:c.460_465del (p.Arg154_Thr155del)

ClinVar: 551306 https://www.ncbi.nlm.nih.gov/clinvar/variation/551306/

gnomAD: Not in gnomAD

Variant2: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

CaseAddInfo: One Pompe Mutation and One Pseudodeficency Mutation

Case59

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.1441T>C (p.Trp481Arg)

ClinVar: 189007 https://www.ncbi.nlm.nih.gov/clinvar/variation/189007/

gnomAD: African 8.031e-5, Overall 2.126e-5 http://gnomad.broadinstitute.org/variant/17-78084529-T-C

Variant2: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

CaseAddInfo: Adult Late Onset Pompe Disease

Case90

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.925G>A (p.Gly309Arg)

ClinVar: 188797 https://www.ncbi.nlm.nih.gov/clinvar/variation/188797/

gnomAD: Ashkenazi Jewish 1.010e-4, Overall 2.860e-5 http://gnomad.broadinstitute.org/variant/17-78081665-G-A

Variant2: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

CaseAddInfo: Adult Late Onset Pompe Disease, 1 other patient has the same genotype

Case69

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.2238G>A (p.Trp746*)

ClinVar: 370904 https://www.ncbi.nlm.nih.gov/clinvar/variation/370904/

gnomAD: African 4.011e-5, Overall 1.063e-5 http://gnomad.broadinstitute.org/variant/17-78090815-G-A

Variant2: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

CaseAddInfo: Adult Late Onset Pompe Disease, 1 other patient has the same genotype

Case35

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.2238G>A (p.Trp746*)

ClinVar: 370904 https://www.ncbi.nlm.nih.gov/clinvar/variation/370904/

gnomAD: African 4.011e-5, Overall 1.063e-5 http://gnomad.broadinstitute.org/variant/17-78090815-G-A

Variant2: NM_000152.4:c.1843G>A (p.Gly615Arg)

ClinVar: 188786 https://www.ncbi.nlm.nih.gov/clinvar/variation/188786/

gnomAD: East Asian 2.223e-4, Overall 1.640e-5 http://gnomad.broadinstitute.org/variant/17-78086465-G-A

CaseAddInfo: Infantile Onset Pompe Disease

Case38

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.2481+102_2646+31del (p.Gly828_Asn882del) (exon 18 del)

ClinVar: 4031 https://www.ncbi.nlm.nih.gov/clinvar/variation/4031/

gnomAD: Not in gnomAD

Variant2: NM_000152.4:c.1912G>T (p.Gly638Trp)

CAID: 280954 https://www.ncbi.nlm.nih.gov/clinvar/variation/280954/

gnomAD: African 6.752e-5, Overall 1.239e-5 http://gnomad.broadinstitute.org/variant/17-78086698-G-T

CaseAddInfo: Infantile Onset Pompe Disease

Case24

HPOsFreeText: See Group Phenotypes

CasePreviousTesting: Sanger sequencing

CaseMethod1: Sanger sequencing and PCR Amplification

CaseMethod2: Whole Exome Sequencing (WES)

CaseGenotypingMethod: Patients were previously confirmed with Pompe disease by Sanger sequencing to capture the pathogenic variants. The process was repeated as part of the study taking care to amplify the coding regions and exon/intron boundaries to compare with the WES results afterwards.

Variant1: NM_000152.4:c.2560C>T (p.Arg854*)

ClinVar: 4034 https://www.ncbi.nlm.nih.gov/clinvar/variation/4034/

gnomAD: African 1.891e-3, Overall 2.090e-4 http://gnomad.broadinstitute.org/variant/17-78092070-C-T

Variant2: NM_000152.4:c.2459_2461delCTG (p.Ala820del)

ClinVar: 456404 https://www.ncbi.nlm.nih.gov/clinvar/variation/456404/

gnomAD: European (Non-Finnish) 6.492e-5, Overall 3.190e-5 http://gnomad.broadinstitute.org/variant/17-78091524-GGCT-G

CaseAddInfo: Infantile Onset Pompe Disease

Patient30: Female, 1 year onset

CasePresentingHPOs: HP:0001324, HP:0001263 (Muscle weakness, Developmental delay)

HPOsFreeText: GAA activity 3% from leukocyte

CaseNotHPOs: HP:0002098, HP:0002240, HP:0001640 (Respiratory distress, Hepatomegaly, Cardiomegaly)

NotHPOsFreeText: No wheelchair needed, Respiratory Assistance not needed

CaseAddInfo: LOPD

Patient19: Male, 21 years report, 14 year onset

CasePresentingHPOs: HP:0001324, HP:0002098 (Muscle weakness, Respiratory distress)

HPOsFreeText: GAA activity 9.3% from leukocyte, Respiratory Assistance needed

CaseNotHPOs: HP:0001640, HP:0002240 (Cardiomegaly, Hepatomegaly)

NotHPOsFreeText: Wheelchair not needed

CaseAddInfo: LOPD

Patient14: Male, 59 years report, 40 year onset

CasePresentingHPOs: HP:0001324, HP:0002098 (Muscle weakness, Respiratory distress)

HPOsFreeText: GAA activity 6.9% from dried blood spot, Respiratory Assistance needed

CaseNotHPOs: HP:0001640, HP:0002240 (Cardiomegaly, Hepatomegaly)

NotHPOsFreeText: Wheelchair not needed

CaseAddInfo: LOPD

Patient20: Male, 22 years report, 12 year onset

CasePresentingHPOs: HP:0001324, HP:0002098 (Muscle weakness, Respiratory distress)

HPOsFreeText: GAA activity 11.6% from leukocyte, Respiratory Assistance needed

CaseNotHPOs: HP:0001640, HP:0002240 (Cardiomegaly, Hepatomegaly)

NotHPOsFreeText: Wheelchair not needed

CaseAddInfo: LOPD

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

Patient1: 7yo

CasePresentingHPOs: HP:0001638

HPOsFreeText: rhGAA dosage = 20QW, independent walker

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 17days old at ERT start

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1935C>A (p.Asp645Glu)

ClinVar: 4029, https://www.ncbi.nlm.nih.gov/clinvar/variation/4029/

gnomAD: 0.0001721, http://exac.broadinstitute.org/variant/17-78086721-C-A

Variant2: NM_000152.4(GAA):c.784G>A (p.Glu262Lys)

ClinVar: 188806, https://www.ncbi.nlm.nih.gov/clinvar/variation/188806/

gnomAD: 1.66e-05, http://exac.broadinstitute.org/variant/17-78081447-G-A

Patient2: Female, 37yo

CasePresentingHPOs: HP:0003077, HP:0001513

HPOsFreeText: LOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 10yr disease duration, ERT lasted for 33mo

CasePMIDs: PMID: 25614309

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1655T>C (p.Leu552Pro)

ClinVar: 279811, https://www.ncbi.nlm.nih.gov/clinvar/variation/279811/

gnomAD: n/a

Variant2: NM_000152.4(GAA):c.1478C>T (p.Pro493Leu)

ClinVar: 379593, https://www.ncbi.nlm.nih.gov/clinvar/variation/379593/

gnomAD: 0.00001416, http://gnomad.broadinstitute.org/variant/17-78084566-C-T

Case7: Female, 3 years onset, 3 years diagnosis, 27 years report, France

CasePresentingHPOs: HP:0002540, HP:0002878, HP:0004887 (Inability to walk, Respiratory failure, Respiratory failure requiring assisted ventilation)

HPOsFreeText: Lost ambulation at 11 years, Started invasive ventilation at 11 years, Started ERT given every other week at a dose of 20 mg/kg at 18 years for 114 months, Peak Anti-rhGAA antibodies at 1:102,400, FVC at 0.22/6 (L / % expected), MIP at 10 (cm H2O), MEP at 10 (cm H2O), Time off ventilation stayed constant at 0 min, Total Motor Function Measure from 23 to 19, 6MWT stayed constant at 0 meters

CaseNotHPOs: HP:0030148 (Heart murmur)

NotHPOsFreeText: No adverse reaction to ERT was recorded

CaseAddInfo: Late Onset Pompe Disease

Patient25: Male, Southern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: c.971dupC (p.Ser325GlufsX5) no ClinVar or CAID

Variant2: NM_000152.4(GAA):c.1802C>T (p.Ser601Leu)

ClinVar: 194154, https://www.ncbi.nlm.nih.gov/clinvar/variation/194154/

gnomAD: n/a

Patient10: Male, Southern China

CasePresentingHPOs:

HPOsFreeText: IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.2105G>A (p.Arg702His)

ClinVar: 426278, https://www.ncbi.nlm.nih.gov/clinvar/variation/426278/

gnomAD: 6.695e-05, http://exac.broadinstitute.org/variant/17-78087081-G-A

Variant2: NM_000152.4(GAA):c.2297A>C (p.Tyr766Ser)

ClinVar: 420102, https://www.ncbi.nlm.nih.gov/clinvar/variation/420102/

gnomAD: 8.35e-06, http://exac.broadinstitute.org/variant/17-78090874-A-C

Case: Female, 59yo, Japanese, non-consanguineous family

CasePresentingHPOs: HP:0002515, HP:0001290, HP:0009055, HP:0002015, HP:0002098, HP:0002315, HP:0007340, HP:0004944, HP:0002138, HP:0001297, HP:0000822, HP:0001288, HP:0002788, HP:0003236, HP:0002119, HP:0002415, HP:0012444, HP:0001922, HP:0012529

HPOsFreeText: 3mm aneurysm in left middle cerebral artery, underwent cerebral arterial clipping, muscle atrophy more significant in proximal muscles of lower limbs, hypotonia more significant in right thigh, CPK = 327mg/dL, alanine aminotransferase = 44mg/dL, aspartate aminotransferase = 42mg/dL, lactic dehydrogenase = 266mg/dL, low-density lipoprotein = 162mg/dL, flattened diaphragm, left atrial ventricular enlargement with mass = 156g, left ventricular index = 106g/m^2, extensor muscle atrophy, diffuse fibrosis in thighs, multiple infractions, bilateral tortuous irregular cerebral arteries, GAA activity = 1.3 pmol hour^-1 punch^-1, vacuolated platelets, glycogen accumulation, large lysosomes filled with membrane bound deposition in fibroblasts

CaseNotHPOs: HP:0003691, HP:0012195, HP:0030850, HP:0010535, HP:0000365, HP:0000505, HP:0002111

NotHPOsFreeText: regurgitation

CaseAddInfo: Hypertension developed at 40yo and was treated with antihypertensive drugs. Cerebral stroke at 57yo. Father died at 82yo due to cardiac aneurism and arterial thrombosis. Mother had left ventricular hypertrophy and died at 62yo due to colon carcinoma. Sister had psychiatric illness. Her 2 sons were healthy.

CasePreviousTesting: CT scan, chest x-ray, echocardiogram, MRI, DBS, electron microscopy of blood cells, skin biopsy

CaseGenotypingMethod: PCR and direct DNA sequencing of GAA gene, cDNA-sequencing analysis

Variant: NM_000152.4(GAA):c.546G>T (p.Thr182=), homozygous

ClinVar: 370637, https://www.ncbi.nlm.nih.gov/clinvar/variation/370637/

gnomAD: n/a

PatientF3P1: Female, 3 months diagnosis, Multiracial (maternal European and Native American and paternal Czechoslovakian, German, and Australian)

CasePresentingHPOs: HP:0004755, HP:0001290 (Supraventricular tachycardia, Generalized hypotonia)

CaseAddInfo: Proband

Patient7: Male, 3.8mo at ERT start, 3.3yo at study end

CasePresentingHPOs:

HPOsFreeText: treated with 40mg/kg/wk, patient had 10 infusion associated reactions

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo:

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NC_000017.11:g.(?80118193)(80118357_?)del (c.2481 + 102_2646 + 31del)

ClinVar: 456368, https://www.ncbi.nlm.nih.gov/clinvar/variation/456368/

gnomAD: n/a

Variant2: NM_000152.4(GAA):c.525delT (p.Glu176Argfs)

ClinVar: 4033, https://www.ncbi.nlm.nih.gov/clinvar/variation/4033/

gnomAD: 0.00009959, http://gnomad.broadinstitute.org/variant/17-78078909-CT-C

Patient4: 19yo

CasePresentingHPOs:

HPOsFreeText: hyperCKemia, GAA = 24%, BMI = 26.1, normal CTA and CT

CaseNotHPOs:

NotHPOsFreeText: No cardiovascular risk

CaseAddInfo: 12yr disease duration

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.4(GAA):c.1771C>T (p.Arg591Trp)

ClinVar: 551782, https://www.ncbi.nlm.nih.gov/clinvar/variation/551782/

gnomAD: 8.662e-06, http://exac.broadinstitute.org/variant/17-78086393-C-T

CasePD/Pathogenic-9: 3 weeks diagnosis

HPOsFreeText: GAA activity 8.4 (nmol · h−1 · mg−1), Mean percentage of normal 11.7%

GenotypingMethod: Newborn Screening Panels

Variant1: NM_000152.4:c.1726G>A (p.Gly576Ser)

ClinVar: 92467 https://www.ncbi.nlm.nih.gov/clinvar/variation/92467/

gnomAD: East Asian 0.1427, Overall 0.01700 http://gnomad.broadinstitute.org/variant/17-78085871-G-A

Variant2: NM_000152.4:c.2065G>A (p.Glu689Lys)

ClinVar: 4030 https://www.ncbi.nlm.nih.gov/clinvar/variation/4030/

gnomAD: East Asian 0.2355, Overall 0.05524 http://gnomad.broadinstitute.org/variant/17-78087041-G-A

Variant3: NM_000152.4:c.2662G>T (p.Glu888Ter)

ClinVar: 578595 https://www.ncbi.nlm.nih.gov/clinvar/variation/578595/

gnomAD: East Asian 2.719e-4, Overall 1.998e-5 http://gnomad.broadinstitute.org/variant/17-78092467-G-T

CaseAddInfo: Patient has one pseudodeficency allele and one pathogenic allele, Nomenclature claims Variant 1 and 2 are in cis

CaseLOPD-16: 2.5 weeks diagnosis

HPOsFreeText: GAA activity 2.5 (nmol · h−1 · mg−1), Mean percentage of normal 3.6%

GenotypingMethod: Newborn Screening Panels

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 http://www.ncbi.nlm.nih.gov/clinvar/variation/4027

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.2065G>A (p.Glu689Lys)

ClinVar: 4030 https://www.ncbi.nlm.nih.gov/clinvar/variation/4030/

gnomAD: East Asian 0.2355, Overall 0.05524 http://gnomad.broadinstitute.org/variant/17-78087041-G-A

Multiple interpretations of p.W746C possible, below is considered the most likely

Variant3: NM_000152.4:c.2238G>C (p.Trp746Cys)

ClinVar: 265160 https://www.ncbi.nlm.nih.gov/clinvar/variation/265160/

gnomAD: European (Non-Finnish) 5.673e-4, Overall 3.083e-4 http://gnomad.broadinstitute.org/variant/17-78090815-G-C

CaseAddInfo: Late Onset Pompe Disease, Nomenclature claims Variant 2 and 3 are in cis

Case10HPOsFreeText: 20 mg/kg GAA treatment, GAA activity at 0.2 pmol/punch/hr, GAA activity at 33% lower limit of normal

CaseAddInfo: Late Onset Pompe Disease

CaseGenotypingMethod: Method not described, only that the diagnosis was "confirmed … based on 2 GAA gene mutations"

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 https://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.1548G>A (p.Trp516Ter)

ClinVar: 189025 https://www.ncbi.nlm.nih.gov/clinvar/variation/189025/

gnomAD: European (Non-Finnish) 1.552e-5, Overall 7.079e-6 https://gnomad.broadinstitute.org/variant/17-78084636-G-A

CaseAddInfo: Patient is compound heterozygous for this variant

Case3: Female, 18 years onset, 19 years diagnosis, 26 years report

CasePresentingHPOs: HP:0003325, HP:0003327, HP:0003236, HP:0002747 (Limb-girdle muscle weakness, Axial muscle weakness, Increased serum CK, Respiratory muscle weakness)

CaseAddInfo: Late-Onset Pompe Disease

Case6: Female, 22 years onset, 23 years diagnosis, 37 years report

CasePresentingHPOs: HP:0003325, HP:0003327, HP:0003236, HP:0002747 (Limb-girdle muscle weakness, Axial muscle weakness, Increased serum CK, Respiratory muscle weakness)

CaseAddInfo: Late-Onset Pompe Disease

Patient25: Female

CasePresentingHPOs: HP:0004887

HPOsFreeText: CRIM positive, Anti-rh GGA antibodies maximum titer = ≤ 1:400, tracheostomy, able to sit independently

CaseNotHPOs: HP:0025156, HP:0002546, HP:0000365

NotHPOsFreeText: infusion associated reaction

CaseAddInfo: variants in trans, symptom onset at 2yo, diagnosis at 3yo, ERT at 4yo

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.784G>A (p.Glu262Lys)

ClinVar: 188806, https://www.ncbi.nlm.nih.gov/clinvar/variation/188806/

gnomAD: 0.00001417, http://gnomad.broadinstitute.org/variant/17-78081447-G-A

Patient7: Male, 4.5mo at diagnosis and ERT

CasePresentingHPOs:

HPOsFreeText: classic IOPD, moderate response to ERT, Pompe muscle pathology score = 3.5, Glycogen = 31.4 Vv(PAS + /mf)%, larger empty vacuoles = 38.1 Vv (LEV/mf)%, Autophagic vacuoles = 0,06 %/mf

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: homozygous, biopsy taken from  musculus vastus lateralis

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_000152.5(GAA):c.2078dup(p.Ala694Glyfs)

ClinVar: 180143, https://www.ncbi.nlm.nih.gov/clinvar/variation/180143/

gnomAD: n/a

CaseVI,2: Adult onset, 61 years diagnosis

CasePresentingHPOs: HP:0003701, HP:0002795, HP:0003388, HP:0003236, HP:0003198 (Proximal muscle weakness, Abnormal respiration, Easy fatiguability, Increased serum CK, Myopathy)

HPOsFreeText: GAA activity from dried blood spot: 0.22%, Forced Vital Capacity Seated: 2040 (46%), 6-Minute Walking Test: 418 min, Plasma CK 2.5-5x Normal

CaseAddInfo: Late-Onset Pompe Disease

Patient1: Italian

CasePresentingHPOs:

HPOsFreeText: non-classic IOPD

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: homozygous

CasePMIDs:

CasePreviousTesting:

CaseGenotypingMethod: method not described

Variant: NM_000152.4(GAA):c.1655T>C (p.Leu552Pro)

ClinVar: 278911, https://www.ncbi.nlm.nih.gov/clinvar/variation/279811/

gnomAD: 0.00003188, https://gnomad.broadinstitute.org/variant/17-78085800-T-C

Case7: Female, 37 years onset, 38 years diagnosis, Italy

HPOsFreeText: See Group Phenotypes, ERT started at 40, GAA Activity at ~4.5 pmol/min/mg before ERT and ~5.5 after

GroupGenotypingMethod: PCR Amplification and GAA Gene Sequencing

Variant1: NM_000152.4:c.-32-13T>G

ClinVar: 4027 https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: Ashkenazi Jewish 5.541e-3, Overall 3.401e-3 http://gnomad.broadinstitute.org/variant/17-78078341-T-G

Variant2: NM_000152.4:c.2237G>A (p.Trp746Ter)

ClinVar: 280063 https://www.ncbi.nlm.nih.gov/clinvar/variation/280063/

gnomAD: European (Non-Finnish) 8.834e-6, Overall 3.988e-6 http://gnomad.broadinstitute.org/variant/17-78090814-G-A

CaseAddInfo: Late Onset Pompe Disease

Case#: Patient 16, female

CasePresentingHPOs: HP:0003325

CaseAddInfo: onset and diagnosis at 32yo

VariantAllele1: NM_000152.4(GAA):c.-32-13T>G

ClinVar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

VariantAllele2: NC_000017.11:g.(?80118193)(80118357_?)del

ClinVar: 456368, https://www.ncbi.nlm.nih.gov/clinvar/variation/456368/

gnomAD: n/a

Patient11: Female, 39yo at diagnosis, 53yo at ERT

CasePresentingHPOs:

HPOsFreeText: anti rh-GAA antibodies titre = 1:400, enzyme (μmol/g/h) = 0.41 (3-20), NIV required only after ERT began, mobility aid required before and after ERT

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 21yr disease duration, variants in trans

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_000152.4(GAA):c.1548G>A (p.Trp516Ter)

ClinVar: 189025, https://www.ncbi.nlm.nih.gov/clinvar/variation/189025/

gnomAD: n/a

Variant2: NM_000152.4(GAA):c.2799+4A>G

ClinVar: 286228, https://www.ncbi.nlm.nih.gov/clinvar/variation/286228/

gnomAD: 8.319e-06, http://exac.broadinstitute.org/variant/17-78092608-A-G

Patient7: female, Serbian

CasePresentingHPOs: HP:0003677, HP:0003236, HP:0003325

HPOsFreeText: CK < 10x increase

CaseNotHPOs: HP:0002093

CaseAddInfo: onset in middle age

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant 1: NM_000152.4(GAA):c.2269C>T (p.Gln757Ter)

ClinVar: 429727, https://www.ncbi.nlm.nih.gov/clinvar/variation/429727/

gnomAD: n/a

Variant2: NM_000152.4(GAA):c.-32-13T>G

Clinvar: 4027, https://www.ncbi.nlm.nih.gov/clinvar/variation/4027/

gnomAD: 0.003582, http://exac.broadinstitute.org/variant/17-78078341-T-G

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 8 (Family D), male, 49yo

DiseaseAssertion: VWD2B

FamilyInfo: NA

ParentalGenotype(s): NA

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

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

CaseHPOFreeText: blood group A, Platelet count x103/μl = 252, PFA 100 sec = 175, SPA % = 0, MADR mg/mL = 0.6, VWF:Ag U/dL = 54.3, VWF:CB U/dL = 55.1, VWF:CB ratio = 1.01, VWF:RCo U/dL = 51.6, VWF:RCo ratio = 0.94, Platelet VWF U/dL = 60.3, FVIII U/dL = 62.2, BAT F/M = NA

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 28 of VWF

PreviouslyPublished: NA

Gene: VWF

Variant 1: c.4135C>T (p.Arg1379Cys)

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

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

CAID: NA

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

Variant 2: c.3797C>A (p.Pro1266Gln)

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

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

CAID: NA

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

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: P44, Chinese, male, 6yo

DiseaseAssertion: VWD2A

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type A blood, bleeding score = 6; VWF:Ag (%) = 43.6, VWF:RCo (%) = 18.3, FVIII:C (%) = 38.7, VWF:CB (%) = 16.7, VWFpp (%) = 64.8, VWF:RCo/VWF:Ag = 0.4, VWF:CB/VWF:Ag = 0.4, VWFpp/VWF:Ag = 1.5, FVIII:C/VWF:Ag = 0.9

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant 1: c.1870G>A (p.Gly624Ser)

HGVS: NM_000552.4(VWF):c.1870G>A (p.Gly624Ser)

ClinVarID: 619737; https://www.ncbi.nlm.nih.gov/clinvar/variation/619737/

CAID: NA

gnomAD: MAF = 0.004886 (59/12076 alleles; 1 homozygote) in the East Asian population; https://gnomad.broadinstitute.org/variant/12-6166098-C-T?dataset=gnomad_r2_1

Variant 2: c.4883T>C (p.Ile1628Thr)

HGVS: NM_000552.4(VWF):c.4883T>C (p.Ile1628Thr)

ClinVarID: 284; https://www.ncbi.nlm.nih.gov/clinvar/variation/284/

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: P63, Chinese, female, 23yo

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type A blood, bleeding score = 15; VWF:Ag (%) = 1.2, VWF:RCo (%) = 0.5, FVIII:C (%) = 5.9, VWF:CB (%) = 0.6, VWFpp (%) = 0.5, VWF:RCo/VWF:Ag = 0.4, VWF:CB/VWF:Ag = 0.5, VWFpp/VWF:Ag = 0.4, FVIII:C/VWF:Ag = 4.9

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant 1: c.817C>T (p.Arg273Trp)

HGVS: NM_000552.4(VWF):c.817C>T (p.Arg273Trp)

ClinVarID: 100493; https://www.ncbi.nlm.nih.gov/clinvar/variation/100493/

CAID: NA

gnomAD: MAF = 0.00005288 (6/113462 alleles) in the European (non-Finnish) population; https://gnomad.broadinstitute.org/variant/12-6184558-G-A?dataset=gnomad_r2_1

Variant 2: c.5335C>T (p.Arg1779Ter)

HGVS: NM_000552.4(VWF):c.5335C>T (p.Arg1779Ter)

ClinVarID: 100425; https://www.ncbi.nlm.nih.gov/clinvar/variation/100425/

CAID: NA

gnomAD: absent

Case: P76, Chinese, male, 21yo

DiseaseAssertion: VWD1

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type A blood, bleeding score = 3; VWF:Ag (%) = 4.7, VWF:RCo (%) = 5.4, FVIII:C (%) = 27.2, VWF:CB (%) = 5.5, VWFpp (%) = 4.3, VWF:RCo/VWF:Ag = 1.1, VWF:CB/VWF:Ag = 1.2, VWFpp/VWF:Ag = 0.9, FVIII:C/VWF:Ag = 5.8, RIPA (1.2 mg/ml, %) = 73.4

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant 1: Exon1-exon5 del - Unregistered Variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Variant 2: c.7464C>T (p.Gly2488=) - reported to be a splice site variant

HGVS: NM_000552.4(VWF):c.7464C>T (p.Gly2488=)

ClinVarID: 619755; https://www.ncbi.nlm.nih.gov/clinvar/variation/619755/

CAID: NA

gnomAD: MAF = 0.000008799 (1/113644 alleles) in the European (non-Finnish) population; https://gnomad.broadinstitute.org/variant/12-6080849-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: P16, Chinese, female, 25yo

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 15; VWF:Ag (%) = 2.1, VWF:RCo (%) = 1.9, FVIII:C (%) = 4.3, VWF:CB (%) = 1.7, VWFpp (%) = 1.5, VWF:RCo/VWF:Ag = 0.9, VWF:CB/VWF:Ag = 0.8, VWFpp/VWF:Ag = 0.7, FVIII:C/VWF:Ag = 2.0

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant 1: c.1093C>T (p.Arg365Ter)

HGVS: NM_000552.4(VWF):c.1093C>T (p.Arg365Ter)

ClinVarID: 100172; https://www.ncbi.nlm.nih.gov/clinvar/variation/100172/

CAID: NA

gnomAD: absent

Variant 2: c.8116–2delA - Unregistered variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

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: P79, Chinese, female, 24yo

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type B blood, bleeding score = 9; VWF:Ag (%) = 0.5, VWF:RCo (%) = <0.5, FVIII:C (%) = 5.7, VWF:CB (%) = <0.5, VWFpp (%) = <0.5, VWF:RCo/VWF:Ag = NA, VWF:CB/VWF:Ag = NA, VWFpp/VWF:Ag = NA, FVIII:C/VWF:Ag = 11.4

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant 1: c.1093C>T (p.Arg365Ter)

HGVS: NM_000552.4(VWF):c.1093C>T (p.Arg365Ter)

ClinVarID: 100172; https://www.ncbi.nlm.nih.gov/clinvar/variation/100172/

CAID: NA

gnomAD: absent

Variant 2: c.4975C>T (p.Arg1659Ter)

HGVS: NM_000552.4(VWF):c.4975C>T (p.Arg1659Ter)

ClinVarID: 297; https://www.ncbi.nlm.nih.gov/clinvar/variation/297/

CAID: NA

gnomAD: MAF = 0.0004007 (10/24958 alleles) in the European (Finnish) population; https://gnomad.broadinstitute.org/variant/12-6127609-G-A?dataset=gnomad_r2_1

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: P31, Chinese, female, 21yo

DiseaseAssertion: VWD3

FamilyInfo: NA

ParentalGenotype(s): NA

CasePresentingHPOs: HP:0012147

(Reduced quantity of VWF)

CaseHPOFreeText: type O blood, bleeding score = 15; VWF:Ag (%) = 1.0, VWF:RCo (%) = 0.7, FVIII:C (%) = 4.1, VWF:CB (%) = 0.8, VWFpp (%) = 0.8, VWF:RCo/VWF:Ag = 0.7, VWF:CB/VWF:Ag = 0.8, VWFpp/VWF:Ag = 0.8, FVIII:C/VWF:Ag = 4.1

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting: NA

GenotypingMethod: NGS

PreviouslyPublished: NA

Gene: VWF

Variant 1: c.953_954insG - Unregistered Variant

HGVS: NA

ClinVarID: NA

CAID: NA

gnomAD: NA

Variant 2: c.4368C>G (p.Tyr1456Ter)

HGVS: NM_000552.4(VWF):c.4368C>G (p.Tyr1456Ter)

ClinVarID: 100350; https://www.ncbi.nlm.nih.gov/clinvar/variation/100350/

CAID: NA

gnomAD: absent

Case: 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: Case 2, male, newborn

DiseaseAssertion: VWD2B

FamilyInfo: First child of consanguineous parents (first cousins), no family history of bleeding, search of maternal platelet autoantibodies was negative; parents had VWF measurements showed decreased VWF:RCo, ratio FVIII:C/VWF:Ag < 0.5, and enhanced RIPA

ParentalGenotype(s): both parents heterozygous for both variants

CasePresentingHPOs: HP:0012330, HP:0001873, HP:0000967, HP:0030129

(Pyelonephritis, thrombocytopenia, petechiae, impaired ristocetin cofactor assay activity)

CaseHPOFreeText: born at 40wks, thrombocytopenia: 5 GL−1 at birth, platelets clumps in citrate tube, normal platelet morphology, no platelet incompatibility between the mother and the child in HPA groups 1, 3, 5, and 15, Allo- and autoantibodies on the mother and child and cross-match between father and mother serum were negative; bone marrow aspiration showed hyperplasia of megakaryocyte line, with all stages of maturation, consistent with peripheral origin, normal development; VWF:RCo = 13 IU dL−1, VWF:Ag = 47 IU dL−1, VWF:RCo /VWF:Ag= 0.3, FVIII:C = 22 IU dL−1, FVIII/VWF:Ag= 0.6, VWF:FVIII = 10 IU dL−1< RIPA analysis could not be performed

CaseNOTHPOs: HP:0032169, HP:0001892

(infection, abnormal bleeding)

CaseNOTHPOFreeText: DIC

CasePreviousTesting: NA

GenotypingMethod: Sequencing of exon 20 and 28 of VWF gene

PreviouslyPublished: NA

Gene: VWF

Variant 1: c.4010C>T (p.Pro1337Leu); exon 28, homozygous

HGVS: NM_000552.4(VWF):c.4010C>T (p.Pro1337Leu)

ClinVarID: 100314; https://www.ncbi.nlm.nih.gov/clinvar/variation/100314/

CAID: NA

gnomAD: MAF = 0.00005440 (1/18384 alleles) in East Asian population; https://gnomad.broadinstitute.org/variant/12-6128574-G-A?dataset=gnomad_r2_1

Variant 2: c.2561G>A (p.Arg854Gln); exon 20; homozygous

HGVS: NM_000552.4(VWF):c.2561G>A (p.Arg854Gln)

ClinVarID: 296; https://www.ncbi.nlm.nih.gov/clinvar/variation/296/

CAID: NA

gnomAD: MAF = 0.005692 (143/25122 alleles, 4 homozygotes) in European (non-Finnish) population; https://gnomad.broadinstitute.org/variant/12-6143978-C-T?dataset=gnomad_r2_1

Case: Patient A, male, 14 years old at WIL-29 study entry; ethnicity not reported.

DiseaseAssertion: VWD3. The patient was initially suspected to have VWD2A based on the family history but was reclassified as VWD3 after next-generation sequencing.

FamilyInfo: Patient A and Patient B are brothers from a consanguineous family. Both parents were diagnosed with VWD. Figure 2 shows both parents as heterozygous and Patient A and Patient B as homozygous for the familial VWF variant. The pedigree also includes another brother affected with VWD whose genetic testing was underway and a sister whose VWD diagnosis and genetic testing were pending.

ParentalGenotype: Both parents were heterozygous for the familial VWF variant, as shown in Figure 2.

CasePresentingHPOs: HP:0000421, HP:0030129, HP:0012147 (Epistaxis, Impaired ristocetin cofactor assay activity, Reduced quantity of VWF)

CaseHPOFreeText: Recurrent spontaneous epistaxis. Historical VWF:RCo 1% and VWF:Ag 10%. VWF:RCo 1 IU/dL at WIL-31 screening. At the month 0 pharmacokinetic visit, pre-injection FVIII 12 IU/dL and VWF:RCo <5 IU/dL; after 60 IU/kg wilate, virtually no rise in VWF activity (maximum VWF:RCo 9 IU/dL, in vivo recovery 0.07 kg/dL). VWF inhibitors were confirmed present at WIL-31 study entry, and the patient remained inhibitor-positive at the 12-month visit.

CaseNotHPOs: NA

CaseNotHPOFreeText: No anaphylactic reactions or severe treatment-related adverse events were reported.

CasePreviousTesting: Diagnosed with VWD shortly after birth and initially suspected to have VWD2A based on family history. Historical VWF activity and antigen testing, and subsequent pharmacokinetic and VWF inhibitor testing, were performed. No earlier molecular genetic testing was reported.

GenotypingMethod: Next-generation sequencing performed in Bonn, Germany. Additional technical details regarding the sequencing assay or panel were not provided.

Gene: VWF

Variant: c.4094T>C p.Leu1365Pro, homozygous

HGVS: NM_000552.5:c.4094T>C (p.Leu1365Pro)

ClinVar: 2438545

CAID: NA

gnomAD: Absent (not reported in gnomAD; 0/251040 control chromosomes)

Case: Patient B, male, 11 years old at WIL-29 study entry; ethnicity not reported.

DiseaseAssertion: VWD3. The patient was initially suspected to have VWD2A based on the family history but was reclassified as VWD3 after next-generation sequencing.

FamilyInfo: Patient B and Patient A are brothers from a consanguineous family. Both parents were diagnosed with VWD. Figure 2 shows both parents as heterozygous and Patient A and Patient B as homozygous for the familial VWF variant. The pedigree also includes another brother affected with VWD whose genetic testing was underway and a sister whose VWD diagnosis and genetic testing were pending.

ParentalGenotype: Both parents were heterozygous for the familial VWF variant, as shown in Figure 2.

CasePresentingHPOs: HP:0000421, HP:0030129 (Epistaxis, Impaired ristocetin cofactor assay activity)

CaseHPOFreeText: Recurrent spontaneous epistaxis. Historical VWF:RCo 1%; historical VWF:Ag not measured. VWF:RCo 1 IU/dL at WIL-31 screening. At the month 0 pharmacokinetic visit, pre-injection FVIII 16 IU/dL and VWF:RCo <5 IU/dL; after 60 IU/kg wilate, maximum VWF:RCo 65 IU/dL and in vivo recovery 1.02 kg/dL. VWF inhibitors were confirmed present at WIL-31 study entry; no VWF inhibitor was detectable at the 12-month visit.

CaseNotHPOs: NA

CaseNotHPOFreeText: No anaphylactic reactions or severe treatment-related adverse events were reported.

CasePreviousTesting: Diagnosed with VWD shortly after birth and initially suspected to have VWD2A based on family history. Historical VWF activity testing, and subsequent pharmacokinetic and VWF inhibitor testing, were performed. Historical VWF antigen was not measured. No earlier molecular genetic testing was reported.

GenotypingMethod: Next-generation sequencing performed in Bonn, Germany. Additional technical details regarding the sequencing assay or panel were not provided.

Gene: VWF

Variant: c.4094T>C p.Leu1365Pro, homozygous

HGVS: NM_000552.5:c.4094T>C (p.Leu1365Pro)

ClinVar: 2438545

CAID: NA

gnomAD: Absent (not reported in gnomAD; 0/251040 control chromosomes)

Case: 2B-4

DiseaseAssertion: VWD2B

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.55; AcuStar CB/Ag = 0.44; ELISA CB/Ag = 0.44

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: 1373334

Gene: VWF

Variant: c.4010C>T (p.Pro1337Leu)

HGVS: NM_000552.5(VWF):c.4010C>T (p.Pro1337Leu)

ClinVarID: 100314; https://www.ncbi.nlm.nih.gov/clinvar/variation/100314/?new_evidence=false

CAID:

gnomAD: MAF = 0.00005440 in East Asian population; https://gnomad.broadinstitute.org/variant/12-6128574-G-A

Case: 2B-10

DiseaseAssertion: VWD2B

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.74; AcuStar CB/Ag = 0.97; ELISA CB/Ag = 1.13

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: 11325649

Gene: VWF

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

HGVS: NM_000552.5(VWF):c.4135C>T (p.Arg1379Cys)

ClinVarID: 100333; https://www.ncbi.nlm.nih.gov/clinvar/variation/100333/?new_evidence=false

CAID:

gnomAD: MAF (European, non-Finnish) = 0.00003891; 0 homozygotes; https://gnomad.broadinstitute.org/variant/12-6128449-G-A

Case: 2A-5

DiseaseAssertion: VWD2A

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.37; AcuStar CB/Ag = 0.12; ELISA CB/Ag = 0.28

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: PMIDs: 1537829, 22431572

Gene: VWF

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

HGVS: NM_000552.5(VWF):c.4517C>T (p.Ser1506Leu)

ClinVarID: 100369; https://www.ncbi.nlm.nih.gov/clinvar/variation/100369/?new_evidence=false

CAID:

gnomAD: absent

Case: 2B-9

DiseaseAssertion: VWD2B

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.73; AcuStar CB/Ag = 1.09; ELISA CB/Ag = 1.18

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: 11325649

Gene: VWF

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

HGVS: NM_000552.5(VWF):c.4135C>T (p.Arg1379Cys)

ClinVarID: 100333; https://www.ncbi.nlm.nih.gov/clinvar/variation/100333/?new_evidence=false

CAID:

gnomAD: MAF (European, non-Finnish) = 0.00003891; 0 homozygotes; https://gnomad.broadinstitute.org/variant/12-6128449-G-A

Case: 2B-3

DiseaseAssertion: VWD2B

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.12; AcuStar CB/Ag = 0.09; ELISA CB/Ag = 0.56

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: 1373334

Gene: VWF

Variant: c.4010C>T (p.Pro1337Leu)

HGVS: NM_000552.5(VWF):c.4010C>T (p.Pro1337Leu)

ClinVarID: 100314; https://www.ncbi.nlm.nih.gov/clinvar/variation/100314/?new_evidence=false

CAID:

gnomAD: MAF = 0.00005440 in East Asian population; https://gnomad.broadinstitute.org/variant/12-6128574-G-A

Case: 2M-4

DiseaseAssertion: VWD2M

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.44; AcuStar CB/Ag = 0.51; ELISA CB/Ag = 0.73

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: 7620154

Gene: VWF

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

HGVS: NM_000552.5(VWF):c.4121G>A (p.Arg1374His)

ClinVarID: 100330; https://www.ncbi.nlm.nih.gov/clinvar/variation/100330/?new_evidence=false

CAID:

gnomAD: absent

Case: 2A-6

DiseaseAssertion: VWD2A

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.36; AcuStar CB/Ag = 0.15; ELISA CB/Ag = 0.42

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: PMIDs: 1537829, 16322474

Gene: VWF

Variant: c.4513G>C (p.Gly1505Arg)

HGVS: NM_000552.5(VWF):c.4513G>C (p.Gly1505Arg)

ClinVarID: 100367; https://www.ncbi.nlm.nih.gov/clinvar/variation/100367/?oq=p.Gly1505Arg[varname]+&m=NM_000552.5(VWF):c.4513G%3EC%20(p.Gly1505Arg)

CAID:

gnomAD: absent

Case: 2B-1

DiseaseAssertion: VWD2B

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.41; AcuStar CB/Ag = 0.49; ELISA CB/Ag = 0.40

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: 1373334

Gene: VWF

Variant: c.4010C>T (p.Pro1337Leu)

HGVS: NM_000552.5(VWF):c.4010C>T (p.Pro1337Leu)

ClinVarID: 100314; https://www.ncbi.nlm.nih.gov/clinvar/variation/100314/?new_evidence=false

CAID:

gnomAD: MAF = 0.00005440 in East Asian population; https://gnomad.broadinstitute.org/variant/12-6128574-G-A

Case: 2M-7

DiseaseAssertion: VWD2M

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.40; AcuStar CB/Ag = 0.55; ELISA CB/Ag = 0.87

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: 7620154, 16247740

Gene: VWF

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

HGVS: NM_000552.5(VWF):c.4120C>T (p.Arg1374Cys)

ClinVarID: 100329; https://www.ncbi.nlm.nih.gov/clinvar/variation/100329/?new_evidence=false

CAID:

gnomAD: MAF = 0.000008824 in European (Non-Finnish) population; https://gnomad.broadinstitute.org/variant/12-6128464-G-A

Case: 2M-6

DiseaseAssertion: VWD2M

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.36; AcuStar CB/Ag = 0.54; ELISA CB/Ag = 0.66

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: 7620154

Gene: VWF

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

HGVS: NM_000552.5(VWF):c.4121G>A (p.Arg1374His)

ClinVarID: 100330; https://www.ncbi.nlm.nih.gov/clinvar/variation/100330/?new_evidence=false

CAID:

gnomAD: absent

Case: 2M-3

DiseaseAssertion: VWD2M

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.50; AcuStar CB/Ag = 0.63; ELISA CB/Ag = 0.94

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: 7620154

Gene: VWF

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

HGVS: NM_000552.5(VWF):c.4121G>A (p.Arg1374His)

ClinVarID: 100330; https://www.ncbi.nlm.nih.gov/clinvar/variation/100330/?new_evidence=false

CAID:

gnomAD: absent

Case: 2M-5

DiseaseAssertion: VWD2M

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.37; AcuStar CB/Ag = 0.41; ELISA CB/Ag = 0.62

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: 7620154

Gene: VWF

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

HGVS: NM_000552.5(VWF):c.4121G>A (p.Arg1374His)

ClinVarID: 100330; https://www.ncbi.nlm.nih.gov/clinvar/variation/100330/?new_evidence=false

CAID:

gnomAD: absent

Case: 2B-11

DiseaseAssertion: VWD2B

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.70; AcuStar CB/Ag = 0.83; ELISA CB/Ag = 1.07

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: 11325649

Gene: VWF

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

HGVS: NM_000552.5(VWF):c.4135C>T (p.Arg1379Cys)

ClinVarID: 100333; https://www.ncbi.nlm.nih.gov/clinvar/variation/100333/?new_evidence=false

CAID:

gnomAD: MAF (European, non-Finnish) = 0.00003891; 0 homozygotes; https://gnomad.broadinstitute.org/variant/12-6128449-G-A

Case: 2B-6

DiseaseAssertion: VWD2B

FamilyInfo:

ParentalGenotype(s):

CasePresentingHPOs: AcuStar RCo/Ag = 0.66; AcuStar CB/Ag = 0.69; ELISA CB/Ag = 0.71

CaseHPOFreeText:

CaseNOTHPOs:

CaseNOTHPOFreeText:

CasePreviousTesting:

GenotypingMethod: not described

PreviouslyPublished: 1373334

Gene: VWF

Variant: c.4010C>T (p.Pro1337Leu)

HGVS: NM_000552.5(VWF):c.4010C>T (p.Pro1337Leu)

ClinVarID: 100314; https://www.ncbi.nlm.nih.gov/clinvar/variation/100314/?new_evidence=false

CAID:

gnomAD: MAF = 0.00005440 in East Asian population; https://gnomad.broadinstitute.org/variant/12-6128574-G-A