Case#: Zahari_HA24

Demographics:

CasePresentingHPOs: HP:0003125 severe hemophiliac FVIII:C:<1%

CaseNotHPOs:

CasePreviousTesting: No

CaseMethod1:

CaseMethod2:

CaseGenotypingMethod: F8 coding regions (26 exons) including the intron/exon boundaries and the promoter regions were amplified using 26 sets of primers and subsequently sequenced.

Variant: NM_000132.3:c.3625C>T(p.Gln1209Ter)

ClinVar:

CAID: CA414895516

gnomAD: Not Found

VariantEvidence: The variant introduces a stop codon in exon 14 and premature truncation of the protein product. The variant is awarded default points

CaseAddInfo:

CasePMIDs:

Case#: Zahari_HA24

Demographics:

CasePresentingHPOs: HP:0003125 severe hemophiliac FVIII:C:<1%

CaseNotHPOs:

CasePreviousTesting: No

CaseMethod1:

CaseMethod2:

CaseGenotypingMethod: F8 coding regions (26 exons) including the intron/exon boundaries and the promoter regions were amplified using 26 sets of primers and subsequently sequenced.

Variant: NM_000132.3:c.3625C>T(p.Gln1209Ter)

ClinVar:

CAID: CA414895516

gnomAD: Not Found

VariantEvidence: The variant introduces a stop codon in exon 14 and premature truncation of the protein product. The variant is awarded default points

CaseAddInfo:

CasePMIDs:

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