Case: 24-year-old Caucasian woman with a rare variety of type 2M VWD

DiseaseAssertion: 2M VWD

FamilyInfo: family history was negative for easy bruisability, bleeding, or clotting disorder but maternal grandmother had lung cancer.

CaseNOTHPOFreeText: Von Willebrand factor antigen 45% on 9/12/17 and 37% on 9/19/17 with the ratio of VWF activity to the antigen is less than 0.7

ParentalGenotype(s):Unknown

CasePresentingHPOs: HP:0003010 (Prolonged bleeding time), HP:0000978 (Bruising susceptibility).

**CaseHPOFreeText: ** loss of weight over the last six months, The complete blood count, comprehensive metabolic panel, factor VIII, prothrombin time and partial thromboplastin time, D-Dimer, and antithrombin activity were normal. Her von Willebrand factor activity was much lower compared to the antigen.

CasePreviousTesting: None

GenotypingMethod: Patient have not been genotyped

PreviouslyPublished: N/A

Variant: N/A

ClinVarID: N/A

gnomAD: N/A

**Gene: ** VWF Inheritance mode autosomal dominant variety with normal, high molecular weight multimers

Disease: N/A, variant present in F12 gene

Patient: 36 yo, Female, Saudi descent

Variant:F12 NC_000005.9:g.176,830,269 G>A; p.Gly506Asp Homozygous mutation, exon 12 Located in peptidase S1 domain of F12

Family:

Consanguineous family history (parents first-degree cousins)

No family history of bleeding or thrombosis

Phenotypes:

Significantly high activated partial thromboplastin time

No history of bleeding during deliveries or tooth extractions

No history of thrombosis or skin manifestations

On no medications, physical examination unremarkable

Factor assays and VWF tests within normal ranges except Factor XII (Severely deficient)

variant is proposed to be deleterious but there is insufficient evidence to support this claim.

Disease: mild haemophilia A, influencing VWF levels

Patient: 20 yo, Female

Variant1: F8 NM_000132.3: c.1127T>G: p. Val376Gly (Exon 8, current clinvar interpretation not available)

Variant 2: F8 NM_000132.3: c.3780C>G: p. Asp1260Glu (Exon 14, current ClinVar interpretation is benign)

Variant 3: VWF NM_000552.5: c.1415A>G:p.His484Arg (Exon 13, current ClinVar interpretation is Benign/likely Benign)

Variant 4: VWF NM_000552.5: c.2365A>G:p.Thr789Ala (Exon 18, current ClinVar interpretation is Benign/ likely Benign)

Variant 5: VWF NM_000552.5: c.2771G>A:p.Arg924Gln (Exon 21, current ClinVar interpretation is conflicting interpretations of pathogenicity (VUS-3)(Benign-4)(Likely benign-1))

Variant 6: VWF NM_000552.5: c.4141A>G:p.Thr1381Ala (Exon 28, current ClinVar interpretation is Benign/ Likely Benign)

Variant 7: VWF NM_000552.5: c.6532G>T:p.Ala2178Ser (Exon 37, Conflicting interpretations of pathogenicity: (VUS-1) (Likely Benign-1))

Variant 8: F5 NM_000130.5: c.2773A>G:p.Lys925Glu (Exon 13, current ClinVar interpretation is Benign/Likely Benign)

Variant 9: F5 NM_000130.5: c.2594A>G:p.His865Arg (Exon 13, current ClinVar interpretation is Benign/Likely Benign)

Variant 10: F5 NM_000130.5: c.2573A>G:p.Lys858Arg (Exon 13, Conflicting interpretations of pathogenicity: (VUS-1) (Benign-2)(Likely Benign-1))

Variant 11: F5 NM_000130.5: c.5290A>G:p.Met1764Val (Exon 16, Conflicting interpretations of pathogenicity: (VUS-1) (Benign-2)(Likely Benign-1))

Variant 12: F13A1 NM_000129.4: c.103G>T:p.Val35Leu (Exon 2, Conflicting interpretations of pathogenicity: (VUS-1) (Benign-3))

Variant notes: All are heterozygous

Both variants in F8 are linked to reports associated with haemophilia, though second variant is considered benign.

Phenotypes: History of bleeding (Heavy mentrual bleeding since menarche)(Treated with transdermal oestrogen and Levonorgestel), iron deficiency anaemia. High Janssen score for pictorial blood assessment. Gum bleeding lasting longer than 10 minutes(Treated with local application of tranexamic acid), recurrent nosebleeds, high score for ISTH and BAT assessments. Decrease in VWF:Ag ratio, VWF:CB ratio decreased, VWF: GPIbR ratio decreased

Family: Maternal grandfather possibly haemophiliac, mother asymptomatic