4 Matching Annotations
  1. Nov 2024
    1. Disease: Platelet-type Von-willebrand Disorder (PT-VWD)

      Patient: 17 yo, male, adopted

      Variant: GP1BA NM_000173.7: c:580C>T p.(P.Leu194Phe), Heterozygous, gain-of-function

      Phenotypes: moderate bleeding phenotype, ISTH-BAT bleeding score of 3, recurrent epistaxis, easy bruising, mild thrombocytopenia

      Family: Adopted, no other family history mentioned, segregation studies not performed.

      Genetic analysis performed: found variant in GP1BA, results obtained by sanger sequencing.

      Variant present in gnomAD(rs368111193): low allele frequency, contradictory classifications

      Variant is not present in ClinVar, LOVD, or HGMD databases

      According to this paper, ACMG guidelines classified this variant as a VUS.

      This paper entered it into Clinvar (var ID 1693270)

  2. Oct 2024
    1. Disease: Von Willebrand Disease (VWD) Type 2A

      Patient: 31 yo, Female

      Variant1: VWF NC_000012.12: c.875-5T>Gdel, p.(Ser292_Glu333delinsLys) Causes complete exon 8 skipping

      Variant2: VWF NM_000552.5: c.813C>G, p.(Tyr271*)

      Phenotypes: History of bleeding (epistaxis, uncontrollable by conventional hemostatic treatment), Easy bruising, gum bleeding, excessive menstrual bleeding, mild decrease in plasma VWF:Ag, severe impairment in VWF function, VWF:Ab/VWF:Ag ratio decreased, VWF:CB/VWF:Ag ratio decreased, FVIII:C lvs slighly below normal range

      Family: Son had bleeding diathesis and spontaneous epistaxis (less severe than proband), normal parents

      In silico data available: SpliceAI delta score of 0.51 for loss of splice acceptor caused by variant 1

      Alamut showed small to moderate effects of the variant on normal splicing of VWF

      NetGene2 showed weak strength of 3' splice sites in exon 8

      SpliceAid2 showed TIA-1 and TIAL 1, which bind to U-rich motifs and facilitate 5' splice site recognition where destroyed in the mutated sequence

  3. Sep 2024
    1. Disease: Von-willebrand Disorder

      Patient: 21 yo, female, Italian descent

      Variant: VWF NM_000552.5 c:C3379 > T p.(P1127S), homozygous

      Heterozygous and Homozygous polymorphic variant in exon 25

      Phenotypes: Bleeding Score System (BSS) = 3 minor bruising normal menstrual bleeding

      Family: (father paternity confirmed) Father suffered from rectorrhagia for rectal polyps Mother (same variant, heterozygous) has heavy menstrual bleeding, epistaxis events up to age 30, BBS= 2

      Present in dbSNP (rs139579968) MAF in European pop = 0.0001-0.0004

      Present in gnomAD, said to be present in 2 transcripts in VWF 40 alleles are present

      Predictions: listed with PolyPhen-2 and SIFT = probably damaging to protein expression/function

      CADD (score =33) and REVEL(score = 0.748) suggest deleterious effect of pathogenic variant

      I-TASSER showed large difference in 3D configuration of sequences differing by a single amino acid.

    1. Disease: Von Willebrand Disease (VWD)

      Patient: 18 yo, Male, heterozygote

      Variant: VWF NM_000552.5: c.5456_5842del p.(R1819_C1948delinsS)

      Was not present in gnomAD when searched

      Dominant negative effect

      Phenotypes:

      lower collagen-binding capacity

      History of bleeding (epistaxis)

      gum bleeding

      cutaneous bruises

      ADAMTS13 resistant

      Family: Mother, father, sister are asymptomatic

      Suggested as de novo, no picture found in patient's relative of the deletion, loss of A3 loop