6 Matching Annotations
  1. Dec 2024
    1. Disease: Von-willebrand Disorder Type 3

      Patient: 26 yo, female

      Variant: VWF NM_000552.5 c:997+118 T>G g.(6073501 A>C), homozygous, intronic

      Phenotypes: No detectable VWF in plasma, early onset bleeding complications, epistaxis, easy bruising, bleeding following injury, menorrhagia, iron-deficient anemia

      Note: underwent prophylaxis replacement therapy, on-demand antihemorrhagic treatments, oral contraceptives, and replacement therapy.

      Family: not mentioned

      Predictions:

      VEP SpliceAI tool predicted variant likely deleterious (delta score 0.95)

      Used Polyphen-2 and SIFT which determined pathogenic likelihood.

      Neural Network Splicing, Alternative Splice Site Predictor, plug-in MaxEnt(For 5' donor site) of Human Splicing Finder all concur this variant can create a new donor splice site in intron 8. Contains premature stop codon and susceptible to NMD.

      Functional work:

      qRT-PCR performed to identify levels of VWF in IP-derived endothelial cells.

      histochemical immunostaining for IP-derived endothelial cells confirm no VWF production, only a residual amount present. Suggests leaky mutation.

      performed RNA sequencing to assess co-regulated gene networks

  2. Nov 2024
    1. 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.

  3. 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

    1. Disease: Von-willebrand Disorder, type 1

      Patient 1 Variant: VWF NM_000552.5: c.4135C>T p.(Arg1379Cys) Exon 28

      Family: History not mentioned

      Patient 1 phenotype: near normal VWF:Ag and WVF:RCo levels RIPA within normal range Platelet VWF levels were normal normal pattern for multimeric analysis of plasma Slightly reduced VWF levels

      In silico predictions available:

      I-Mutant 3.0 value = -1.36 PYMOL prediction = substitution of ARG 1379 with a cysteine results in the loss of hydrogen bonds with Lys1407 and Lys1408, predicted change in secondary structure of A1 domain

  4. Sep 2018