Case#: Tamura_Case (male, 49 y/o)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: No family history of stroke, thrombosis or bleeding episodes

ParentalTesting: N/A

CasePresentingHPOs: HP:0012233, HP:0011858

CaseHPOsFreeText: cerebral infarction, prolonged APTT (58.4 s), elevated diluted Russell viper venom time ratio (2.68), and anti-β2 glycoprotein I antibody (9.7 U/mL) and anticardiolipin antibody IgG (39 U/mL), antiphospholipid antibody syndrome (APS), intramuscular hemorrhage, reduced factor IX activity (<0.5%)

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.109G>A (p.Ala37Thr)

ClinVar: 804089

CAID: CA10529736

gnomAD: Allele Frequency in population where variant was found in the highest (South Asian population): 0.0001128

Case#: Pezeshkpoor_Patient_O (male, 36 y/o, from Switzerland)

DiseaseAssertion: Severe Hemophilia B

FamilyInfo: N/A

ParentalTesting: N/A

CasePresentingHPOs: HP:0002625, HP:0011858

CaseHPOsFreeText: deep vein thrombosis, low FIX:C levels (<1%), prolonged aPTT of 90 seconds, diffuse muscle bleeding

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.109G>A (p.Ala37Thr)

ClinVar: 804089

CAID: CA10529736

gnomAD: Allele Frequency in population where variant was found in the highest (South Asian population): 0.0001128

AdditionalCaseInfo: Sequencing of SERPINC1 revealed a splice site mutation located at c.1154-14G>A

Case#: Pezeshkpoor_Patient_M (male, 58 y/o, from Switzerland)

DiseaseAssertion: Hemophilia B

FamilyInfo: N/A

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: spontaneous bleeding symptoms from the blood, the mouth, the tongue, and epiglottis, low FIX:C levels

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.109G>A (p.Ala37Thr)

ClinVar: 804089

CAID: CA10529736

gnomAD: Allele Frequency in population where variant was found in the highest (South Asian population): 0.0001128

Case#: Pezeshkpoor_Patient_L (male,. 70 y/o, from Switzerland)

DiseaseAssertion: Hemophilia B

FamilyInfo: Mutation was identified in two brothers and six female relatives

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: bleeding episodes during VKA therapy, low FIX:C levels

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.109G>A (p.Ala37Thr)

ClinVar: 804089

CAID: CA10529736

gnomAD: allele Frequency in population where variant was found in the highest (South Asian population): 0.0001128

Case#: Pezeshkpoor_Patient_P (male, 68 y/o, from Switzerland)

DiseaseAssertion: Moderate Hemophilia B

FamilyInfo: N/A

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: diffuse subcutaneous bleeding, low FIX:C levels (3%), international normalized ratio (INR) of 3.3, a prolonged aPTT of 88 s, reduced vitamin K-dependent coagulation factors

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.109G>A (p.Ala37Thr)

ClinVar: 804089

CAID: CA10529736

gnomAD: Allele Frequency in population where variant was found in the highest (South Asian population): 0.0001128

Case#: Pezeshkpoor_Patient_N (male, 68 y/o, from Switzerland)

DiseaseAssertion: Hemophilia B

FamilyInfo: The daughter of the patient has the mutation, while the brother of the patient does not.

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: mechanical aoritc valve replacement, low FIX:C levels

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.109G>A (p.Ala37Thr)

ClinVar: 804089

CAID: CA10529736

gnomAD: Allele Frequency in population where variant was found in the highest (South Asian population): 0.0001128

Case#: Oldenburg Cases A, B and C (A: 66 y/o, B: 38 y/o, C: 30 y/o (all in Germany))

DiseaseAssertion: Mild Hemophilia B

FamilyInfo: No bleeding tendency noted in any of these patients family history

ParentalTesting: N/A

CasePresentingHPOs: HP:0011858

CaseHPOsFreeText: severe bleeding at each occasion of oral anticoagulation with phenoprocoumon, bleeding was located in the muscles of the upper leg (patients A and C) and scrotum, left calf and thigh musles (patient B), reduced factor IX levels

CaseNotHPOs: N/A

CasePreviousTesting: N/A

Gene: F9

Variant: NM_000133.4:c.109G>A (p.Ala37Thr)

LegacyVariant: p.Ala-10Thr

ClinVar: 804089

CAID: CA10529736

gnomAD: Allele Frequency in population where variant was found in the highest (South Asian population): 0.0001128

AdditionalCaseInfo: all patients were unrelated up to the third generation. However, the parents of patients A and C emigrated from the same region in North-Eastern Europe (North Poland)

Case#: Odnoczko_Case (male, 74 y/o, in Poland)

DiseaseAssertion: Severe Hemophilia B (only in patients who receive vitamin K antagnoists (VKAs). The authors believe that during VKA therapy, the FIX activity is much lower than that of other vitamin K-dependent clotting factors for cases with this variant.

FamilyInfo: Family history of bleeding diathesis was negative

ParentalTesting:

CasePresentingHPOs: HP:0012233, HP:0031364, HP:0001892

CaseHPOsFreeText: left thigh & buttock hematoma, ecchymosis on extremeties with no mucosal bleeding, bleeding diathesis

CasePreviousTesting: local labaratory blood tests revealed anemia (hemoglobin concentration 8 g/dl; ref. range 14–18 g/dl), prolongation of prothrombin time (PT) with International Normalized Ratio (INR) within the therapeutic range (between 2.0 and 3.0). The proband's activated partial thromboplastin time (APTT) was significantly (>2-folds) prolonged and FIX activity markedly decreased

Gene: F9

Variant: NM_000133.4:c.109G>A (p.Ala37Thr)

ClinVar: 804089

CAID: CA10529736

gnomAD: Allele Frequency in population where variant was found in the highest (South Asian population): 0.0001128