- Nov 2024
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onlinelibrary.wiley.com onlinelibrary.wiley.com
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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)
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- Oct 2024
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www.sciencedirect.com www.sciencedirect.com
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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
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- Sep 2024
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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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.
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onlinelibrary.wiley.com onlinelibrary.wiley.com
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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
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