- Dec 2024
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pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov
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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
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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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- Mar 2021
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Results for individual PALB2 variants were normalized relative to WT-PALB2 and the p.Tyr551ter (p.Y551X) truncating variant on a 1:5 scale with the fold change in GFP-positive cells for WT set at 5.0 and fold change GFP-positive cells for p.Y551X set at 1.0. The p.L24S (c.71T>C), p.L35P (c.104T>C), p.I944N (c.2831T>A), and p.L1070P (c.3209T>C) variants and all protein-truncating frame-shift and deletion variants tested were deficient in HDR activity, with normalized fold change <2.0 (approximately 40% activity) (Fig. 1a).
AssayResult: 7.3
AssayResultAssertion: Normal
StandardErrorMean: 0.08
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A total of 84 PALB2 patient-derived missense variants reported in ClinVar, COSMIC, and the PALB2 LOVD database were selected
HGVS: NM_024675.3:c.1145G>T p.(Ser382Ile)
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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SUPPLEMENTARY DATA
AssayResult: 58
AssayResultAssertion: Indeterminate
PValue: < 0.0001
Approximation: Exact assay result value not reported; value estimated from Figure 6C.
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SUPPLEMENTARY DATA
AssayResult: -32
AssayResultAssertion: Abnormal
PValue: < 0.0001
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SUPPLEMENTARY DATA
AssayResult: 76.45
AssayResultAssertion: Indeterminate
PValue: 0.0001
Comment: Exact values reported in Table S3.
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To this end, 44 missense variants found in breast cancer patients were identified in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar) and/or selected by literature curation based on their frequency of description or amino acid substitution position in the protein (Supplemental Table S1).
HGVS: NM_024675.3:c.23C>T p.(Pro8Leu)
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www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Source Data
AssayResult: 83.96
AssayResultAssertion: Not reported
ReplicateCount: 2
StandardErrorMean: 9.89
Comment: Exact values reported in “Source Data” file.
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Source Data
AssayResult: 66.19
AssayResultAssertion: Not reported
ReplicateCount: 2
StandardDeviation: 21.26
StandardErrorMean: 15.03
Comment: Exact values reported in “Source Data” file.
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We, therefore, analyzed the effect of 48 PALB2 VUS (Fig. 2a, blue) and one synthetic missense variant (p.A1025R) (Fig. 2a, purple)29 on PALB2 function in HR.
HGVS: NM_024675.3:c.1250C>A p.(S417Y)
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www.cell.com www.cell.com
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Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function
AssayResult: 1.2
AssayResultAssertion: Abnormal
ReplicateCount: 11
StandardErrorMean: 0.7
Comment: This variant had loss of function of peak current (<10% of wildtype), therefore it was considered abnormal (in vitro features consistent with Brugada Syndrome Type 1). (Personal communication: A. Glazer)
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we selected 73 previously unstudied variants: 63 suspected Brugada syndrome variants and 10 suspected benign variants
HGVS: NM_198056.2:c.1156G>A p.(Gly386Arg)
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- Feb 2021
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jmg.bmj.com jmg.bmj.com
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Supplemental material
AssayResult: 86
AssayResultAssertion: Normal
Comment: See Table S3 for details
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Supplemental material
AssayResult: 6.1
AssayResultAssertion: Abnormal
Comment: See Table S3 for details
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We analysed a total of 82 blood samples derived from 77 individuals (online supplemental table 3). These 77 individuals corresponded either to new index cases suspected to harbour a pathogenic TP53 variant or to relatives of index cases harbouring TP53 variants.
HGVS: NM_000546.5:c.215C>A p.(Pro72His)
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