- Dec 2024
-
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
-
- Mar 2021
-
www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Cells reconstituted with WT-PALB2 showed substantially less sensitivity to olaparib than cells expressing p.A1025R and p.I944N (Fig. 4a). Similar results were observed for cisplatin treatment, although the difference in sensitivity was less pronounced (Fig. 4b). p.L24S, p.L1070P, and p.L35P were also associated with greater sensitivity to olaparib (Fig. 4c) and cisplatin (Fig. 4d) than WT-PALB2.
AssayResult: 0.01 µM: 70; 0.08 µM: 50; 0.8 µM: 40; 8 µM: 15
AssayResultAssertion: Abnormal
Approximation: Exact Olaparib concentrations and assay result values not reported; values estimated from Figures 4a and 4c.
-
Cells reconstituted with WT-PALB2 showed substantially less sensitivity to olaparib than cells expressing p.A1025R and p.I944N (Fig. 4a). Similar results were observed for cisplatin treatment, although the difference in sensitivity was less pronounced (Fig. 4b). p.L24S, p.L1070P, and p.L35P were also associated with greater sensitivity to olaparib (Fig. 4c) and cisplatin (Fig. 4d) than WT-PALB2.
AssayResult: 0.01 µM: 50; 0.08 µM: 35; 0.8 µM: 25; 8 µM: 10
AssayResultAssertion: Abnormal
Approximation: Exact Olaparib concentrations and assay result values not reported; values estimated from Figures 4a and 4c.
-
Cells reconstituted with WT-PALB2 showed substantially less sensitivity to olaparib than cells expressing p.A1025R and p.I944N (Fig. 4a). Similar results were observed for cisplatin treatment, although the difference in sensitivity was less pronounced (Fig. 4b). p.L24S, p.L1070P, and p.L35P were also associated with greater sensitivity to olaparib (Fig. 4c) and cisplatin (Fig. 4d) than WT-PALB2.
AssayResult: 0.01 µM: 60; 0.08 µM: 55; 0.8 µM: 40; 8 µM: 15
AssayResultAssertion: Abnormal
Approximation: Exact Olaparib concentrations and assay result values not reported; values estimated from Figures 4a and 4c.
Comment: This variant was used as an abnormal control in other assays in this publication, but it was not specifically designated as a control in this assay.
-
Cells reconstituted with WT-PALB2 showed substantially less sensitivity to olaparib than cells expressing p.A1025R and p.I944N (Fig. 4a). Similar results were observed for cisplatin treatment, although the difference in sensitivity was less pronounced (Fig. 4b). p.L24S, p.L1070P, and p.L35P were also associated with greater sensitivity to olaparib (Fig. 4c) and cisplatin (Fig. 4d) than WT-PALB2.
AssayResult: 0.01 µM: 65; 0.08 µM: 50; 0.8 µM: 30; 8 µM: 20
AssayResultAssertion: Abnormal
Approximation: Exact Olaparib concentrations and assay result values not reported; values estimated from Figures 4a and 4c.
-
Cells reconstituted with WT-PALB2 showed substantially less sensitivity to olaparib than cells expressing p.A1025R and p.I944N (Fig. 4a). Similar results were observed for cisplatin treatment, although the difference in sensitivity was less pronounced (Fig. 4b). p.L24S, p.L1070P, and p.L35P were also associated with greater sensitivity to olaparib (Fig. 4c) and cisplatin (Fig. 4d) than WT-PALB2.
AssayResult: 0.01 µM: 50; 0.08 µM: 40; 0.8 µM: 20; 8 µM: 15
AssayResultAssertion: Abnormal
Approximation: Exact Olaparib concentrations and assay result values not reported; values estimated from Figures 4a and 4c.
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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: 5
AssayResultAssertion: Normal
StandardErrorMean: 0.58
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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.101G>A p.(Arg34His)
Tags
- CGType:FunctionalAssayResult
- CAID:CA339433
- ClinVarID:657328
- ClinVarID:230588
- ClinVarID:21675
- CAID:CA197176
- Variant:42
- CGType:Variant
- Variant:85
- FuncAssay:1
- CAID:CA164933
- Variant:92
- ClinVarID:187262
- Variant:3
- ClinVarID:141256
- CG:BulkAnnotation
- FuncAssay:3
- CAID:CA923726356
- CAID:CA279502031
- CAID:CA10580054
- Variant:56
- Variant:4
Annotators
URL
-
-
www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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SUPPLEMENTARY DATA
AssayResult: 34
AssayResultAssertion: Abnormal
PValue: < 0.0001
-
SUPPLEMENTARY DATA
AssayResult: 68
AssayResultAssertion: Indeterminate
PValue: < 0.0001
Approximation: Exact assay result value not reported; value estimated from Figure 6C.
-
SUPPLEMENTARY DATA
AssayResult: 90
AssayResultAssertion: Normal
PValue: Not reported
Approximation: Exact assay result value not reported; value estimated from Figure 6C.
-
SUPPLEMENTARY DATA
AssayResult: 46
AssayResultAssertion: Indeterminate
PValue: < 0.0001
Approximation: Exact assay result value not reported; value estimated from Figure 6C.
-
SUPPLEMENTARY DATA
AssayResult: 23.6
AssayResultAssertion: Abnormal
PValue: < 0.0001
-
SUPPLEMENTARY DATA
AssayResult: 82
AssayResultAssertion: Normal
PValue: Not reported
Approximation: Exact assay result value not reported; value estimated from Figure 6C.
-
SUPPLEMENTARY DATA
AssayResult: 53
AssayResultAssertion: Indeterminate
PValue: < 0.0001
Approximation: Exact assay result value not reported; value estimated from Figure 6C.
-
SUPPLEMENTARY DATA
AssayResult: 41
AssayResultAssertion: Indeterminate
PValue: < 0.0001
Approximation: Exact assay result value not reported; value estimated from Figure 6C.
-
SUPPLEMENTARY DATA
AssayResult: 95
AssayResultAssertion: Normal
PValue: Not reported
Approximation: Exact assay result value not reported; value estimated from Figure 6C.
-
SUPPLEMENTARY DATA
AssayResult: 90
AssayResultAssertion: Normal
PValue: Not reported
Approximation: Exact assay result value not reported; value estimated from Figure 6C.
-
SUPPLEMENTARY DATA
AssayResult: 83
AssayResultAssertion: Not reported
PValue: Not reported
Approximation: Exact assay result value not reported; value estimated from Figure 6C.
-
SUPPLEMENTARY DATA
AssayResult: 77
AssayResultAssertion: Indeterminate
PValue: < 0.01
Approximation: Exact assay result value not reported; value estimated from Figure 6C.
-
SUPPLEMENTARY DATA
AssayResult: 81
AssayResultAssertion: Not reported
PValue: Not reported
Approximation: Exact assay result value not reported; value estimated from Figure 6C.
-
SUPPLEMENTARY DATA
AssayResult: 38
AssayResultAssertion: Abnormal
PValue: < 0.0001
Approximation: Exact assay result value not reported; value estimated from Figure 6C.
-
SUPPLEMENTARY DATA
AssayResult: 5
AssayResultAssertion: Abnormal
PValue: < 0.0001
Approximation: Exact assay result value not reported; value estimated from Figure 6C.
-
SUPPLEMENTARY DATA
AssayResult: 36
AssayResultAssertion: Abnormal
PValue: < 0.0001
Approximation: Exact assay result value not reported; value estimated from Figure 6C.
-
SUPPLEMENTARY DATA
AssayResult: 85
AssayResultAssertion: Not reported
PValue: Not reported
Approximation: Exact assay result value not reported; value estimated from Figure 6C.
-
SUPPLEMENTARY DATA
AssayResult: 58
AssayResultAssertion: Indeterminate
PValue: < 0.0001
Approximation: Exact assay result value not reported; value estimated from Figure 6C.
-
SUPPLEMENTARY DATA
AssayResult: 86.74
AssayResultAssertion: Not reported
PValue: 0.1836
Comment: Exact values reported in Table S3.
-
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.11C>T p.(Pro4Leu)
Tags
- ClinVarID:126738
- CAID:CA186642
- Variant:22
- Variant:14
- CAID:CA7963465
- Variant:45
- CAID:CA10579934
- CAID:CA151233
- CGType:Variant
- CAID:CA288392
- ClinVarID:126774
- ClinVarID:126755
- Variant:3
- ClinVarID:126652
- ClinVarID:126699
- ClinVarID:241553
- FuncAssay:3
- ValidationControl:Benign
- ClinVarID:126758
- CAID:CA299799
- CAID:CA269654
- ClinVarID:126716
- ClinVarID:126590
- Variant:15
- ValidationControl:Pathogenic
- ClinVarID:126593
- Variant:11
- Variant:18
- Variant:10
- Variant:4
- CAID:CA288386
- Variant:32
- CAID:CA331796
- Variant:27
- CAID:CA299750
- ClinVarID:126669
- CGType:FunctionalAssayResult
- ClinVarID:126782
- Variant:2
- ClinVarID:657666
- ClinVarID:657328
- CAID:CA151236
- Variant:37
- CAID:CA395139336
- ClinVarID:232977
- Variant:1
- Variant:8
- ClinVarID:182774
- Variant:31
- Variant:38
- FuncAssay:1
- CAID:CA151242
- CG:BulkAnnotation
- CAID:CA279502031
- Variant:41
- CAID:CA269666
- CAID:CA168501
- CAID:CA395144524
- ClinVarID:126682
- CAID:CA269636
- ClinVarID:183828
- Variant:24
- CAID:CA161315
Annotators
URL
-
-
www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
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Source Data
AssayResult: 128.59
AssayResultAssertion: Not reported
ReplicateCount: 2
StandardErrorMean: 14.72
Comment: Exact values reported in “Source Data” file.
-
Source Data
AssayResult: 84.05
AssayResultAssertion: Not reported
ReplicateCount: 2
StandardErrorMean: 16.48
Comment: Exact values reported in “Source Data” file.
-
Source Data
AssayResult: 97.73
AssayResultAssertion: Not reported
ReplicateCount: 2
StandardErrorMean: 5.41
Comment: Exact values reported in “Source Data” file.
-
Source Data
AssayResult: 19.53
AssayResultAssertion: Not reported
ReplicateCount: 2
StandardErrorMean: 8.56
Comment: Exact values reported in “Source Data” file.
-
Source Data
AssayResult: 119.03
AssayResultAssertion: Not reported
ReplicateCount: 2
StandardErrorMean: 6.12
Comment: Exact values reported in “Source Data” file.
-
Source Data
AssayResult: 37.28
AssayResultAssertion: Not reported
ReplicateCount: 2
StandardErrorMean: 11.28
Comment: Exact values reported in “Source Data” file.
-
Source Data
AssayResult: 111.51
AssayResultAssertion: Not reported
ReplicateCount: 2
StandardErrorMean: 7.63
Comment: Exact values reported in “Source Data” file.
-
Source Data
AssayResult: 80.44
AssayResultAssertion: Not reported
ReplicateCount: 2
StandardErrorMean: 9.06
Comment: Exact values reported in “Source Data” file.
-
Source Data
AssayResult: 27.29
AssayResultAssertion: Not reported
ReplicateCount: 2
StandardErrorMean: 6.53
Comment: Exact values reported in “Source Data” file.
-
Source Data
AssayResult: 102.2
AssayResultAssertion: Not reported
ReplicateCount: 2
StandardErrorMean: 12.81
Comment: Exact values reported in “Source Data” file.
-
Source Data
AssayResult: 112.08
AssayResultAssertion: Not reported
ReplicateCount: 2
StandardErrorMean: 4.1
Comment: Exact values reported in “Source Data” file.
-
Source Data
AssayResult: 87.4
AssayResultAssertion: Not reported
ReplicateCount: 2
StandardErrorMean: 0.88
Comment: Exact values reported in “Source Data” file.
-
Source Data
AssayResult: 100.97
AssayResultAssertion: Not reported
ReplicateCount: 2
StandardErrorMean: 7.27
Comment: Exact values reported in “Source Data” file.
-
Source Data
AssayResult: 20.08
AssayResultAssertion: Not reported
ReplicateCount: 2
StandardErrorMean: 6.84
Comment: Exact values reported in “Source Data” file.
-
Source Data
AssayResult: 89.72
AssayResultAssertion: Not reported
ReplicateCount: 2
StandardErrorMean: 7.95
Comment: Exact values reported in “Source Data” file.
-
Source Data
AssayResult: 93.33
AssayResultAssertion: Not reported
ReplicateCount: 2
StandardErrorMean: 11
Comment: Exact values reported in “Source Data” file.
-
Source Data
AssayResult: 83.16
AssayResultAssertion: Not reported
ReplicateCount: 2
StandardErrorMean: 0.2
Comment: Exact values reported in “Source Data” file.
-
Source Data
AssayResult: 26.03
AssayResultAssertion: Not reported
ReplicateCount: 2
StandardErrorMean: 11.42
Comment: Exact values reported in “Source Data” file.
-
Source Data
AssayResult: 72.7
AssayResultAssertion: Not reported
ReplicateCount: 3
StandardErrorMean: 9.73
Comment: Exact values reported in “Source Data” file.
-
Source Data
AssayResult: 97.61
AssayResultAssertion: Not reported
ReplicateCount: 2
StandardDeviation: 0.97
StandardErrorMean: 0.68
Comment: Exact values reported in “Source Data” file.
-
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.10C>T p.(P4S)
Tags
- CAID:CA395139401
- CAID:CA16620118
- CAID:CA395141224
- Variant:28
- CAID:CA163622
- Variant:48
- CAID:CA279530867
- Variant:40
- ClinVarID:142468
- ClinVarID:182773
- CGType:Variant
- Variant:20
- Variant:30
- CAID:CA395125757
- ClinVarID:126683
- Variant:3
- ClinVarID:126699
- Variant:5
- FuncAssay:3
- ValidationControl:Benign
- ClinVarID:126758
- ValidationControl:Pathogenic
- ClinVarID:186840
- CAID:CA269551
- CAID:CA251717
- ClinVarID:126590
- Variant:4
- ClinVarID:420826
- CAID:CA288386
- CAID:CA294407
- FuncAssay:2
- Variant:49
- ClinVarID:530038
- ClinVarID:1245
- CGType:FunctionalAssayResult
- Variant:2
- ClinVarID:657328
- CAID:CA196017
- ClinVarID:922719
- CAID:CA151250
- Variant:24
- Variant:34
- Variant:38
- CAID:CA195974
- FuncAssay:1
- ClinVarID:126749
- CAID:CA299747
- Variant:65
- ClinVarID:126594
- CAID:CA151222
- CAID:CA151242
- Variant:7
- CG:BulkAnnotation
- ClinVarID:126670
- Variant:46
- Variant:13
- CAID:CA279502031
- Variant:63
- ClinVarID:1243
- CAID:CA151239
- CAID:CA161315
- Variant:62
- ClinVarID:186824
Annotators
URL
-
-
www.cell.com www.cell.com
-
Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function
AssayResult: 28.5
AssayResultAssertion: Abnormal
ReplicateCount: 21
StandardErrorMean: 7.6
Comment: This variant had partial loss of function of peak current (10-50% of wildtype) and a >10mV loss of function shift in Vhalf activation, therefore it was considered abnormal (in vitro features consistent with Brugada Syndrome Type 1). (Personal communication: A. Glazer)
-
we selected 73 previously unstudied variants: 63 suspected Brugada syndrome variants and 10 suspected benign variants
HGVS: NM_198056.2:c.1045G>A p.(Asp349Asn)
-
- Feb 2021
-
jmg.bmj.com jmg.bmj.com
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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: NM000546.5:c.(?-202)(29+1-28+1)del p.?
Comment: A CAID could not be generated for this deletion variant with uncertain breakpoints.
-
Supplemental material
AssayResult: 6.4
AssayResultAssertion: Abnormal
Comment: See Table S3 for details
-
Supplemental material
AssayResult: 3.1
AssayResultAssertion: Abnormal
Comment: See Table S3 for details; The blood sample used to test this variant was derived from an individual carrying the c.723del variant in combination with the c.*1175A>C variant in heterozygosity.
-
Supplemental material
AssayResult: 5.5, 5.7
AssayResultAssertion: Abnormal
Comment: See Table S3 for details; The blood sample used to test this variant was derived from an individual carrying the variant in homozygosity.
-
Supplemental material
AssayResult: 20.5
AssayResultAssertion: Normal
Comment: See Table S3 for details
-
Supplemental material
AssayResult: 3.4
AssayResultAssertion: Abnormal
Comment: See Table S3 for details
-
Supplemental material
AssayResult: 2.6, 4.8
AssayResultAssertion: Abnormal
Comment: See Table S3 for details
-
Supplemental material
AssayResult: 3.8
AssayResultAssertion: Abnormal
Comment: See Table S3 for details; This variant was reported as c.323_235del but assumed to be c.323_325del, which corresponds to the reported protein change (p.(Gly108_Phe109delinsVal)).
-
Supplemental material
AssayResult: 4, 5
AssayResultAssertion: Abnormal
Comment: See Table S3 for details
-
Supplemental material
AssayResult: 5.8, 6.1
AssayResultAssertion: Abnormal
Comment: See Table S3 for details
-
Supplemental material
AssayResult: 5.3
AssayResultAssertion: Abnormal
Comment: See Table S3 for details
-
Supplemental material
AssayResult: 5.1
AssayResultAssertion: Abnormal
Comment: See Table S3 for details
-
Supplemental material
AssayResult: 17.1
AssayResultAssertion: Normal
Comment: See Table S3 for details
-
Supplemental material
AssayResult: 3.2
AssayResultAssertion: Abnormal
Comment: See Table S3 for details
-
Supplemental material
AssayResult: 3.5
AssayResultAssertion: Abnormal
Comment: See Table S3 for details
-
Supplemental material
AssayResult: 4.1
AssayResultAssertion: Abnormal
Comment: See Table S3 for details
-
Supplemental material
AssayResult: 2.9
AssayResultAssertion: Abnormal
Comment: See Table S3 for details
-
Supplemental material
AssayResult: 6.1
AssayResultAssertion: Abnormal
Comment: See Table S3 for details
-
Supplemental material
AssayResult: 12.9
AssayResultAssertion: Normal
Comment: See Table S3 for details
-
Supplemental material
AssayResult: 4.7
AssayResultAssertion: Abnormal
Comment: See Table S3 for details
-
Supplemental material
AssayResult: 7.1, 6.0
AssayResultAssertion: Abnormal
Comment: See Table S3 for details
-
Supplemental material
AssayResult: 3.1
AssayResultAssertion: Abnormal
Comment: See Table S3 for details
-
Supplemental material
AssayResult: 5.4
AssayResultAssertion: Abnormal
Comment: See Table S3 for details
-
Supplemental material
AssayResult: 5
AssayResultAssertion: Abnormal
Comment: See Table S3 for details
-
Supplemental material
AssayResult: 4.8
AssayResultAssertion: Abnormal
Comment: See Table S3 for details
-
Supplemental material
AssayResult: 3.8
AssayResultAssertion: Abnormal
Comment: See Table S3 for details
-
Supplemental material
AssayResult: 3.2
AssayResultAssertion: Abnormal
Comment: See Table S3 for details
-
Supplemental material
AssayResult: 58
AssayResultAssertion: Normal
Comment: See Table S2 for details
-
Supplemental material
AssayResult: 5.8
AssayResultAssertion: Abnormal
Comment: See Table S2 for details
Tags
- Variant:6
- Variant:26
- Variant:45
- CAID:CA000225
- Variant:23
- CAID:CA1139768485
- ClinVarID:481148
- CAID:CA16603061
- ClinVarID:127816
- ClinVarID:177825
- Variant:42
- CGType:Variant
- Variant:48
- ClinVarID:127808
- CAID:CA000102
- CAID:CA000343
- Variant:35
- ClinVarID:376644
- Variant:20
- CAID:CA000013
- ClinVarID:127812
- Variant:3
- Variant:17
- CAID:CA000272
- Variant:5
- FuncAssay:3
- ValidationControl:Benign
- CAID:CA397832246
- ClinVarID:127821
- ClinVarID:246343
- ClinVarID:142320
- ValidationControl:Pathogenic
- Variant:15
- FuncAssay:2
- Variant:4
- Variant:18
- CAID:CA000123
- Variant:10
- CAID:CA000144
- CAID:CA000251
- Variant:36
- CGType:FunctionalAssayResult
- CAID:CA000259
- Variant:16
- CAID:CA497717451
- ClinVarID:35555
- ClinVarID:185120
- Variant:12
- CAID:CA645588451
- ClinVarID:127824
- CAID:CA000457
- ClinVarID:12364
- Variant:1
- CAID:CA397832401
- Variant:8
- FuncAssay:1
- CAID:CA000049
- CAID:CA000454
- CAID:CA000071
- CAID:CA1139768484
- Variant:7
- ClinVarID:12374
- CAID:CA397842793
- Variant:41
- ClinVarID:141114
- CAID:CA1139768486
- CAID:CA10584593
- ClinVarID:12379
- Variant:25
- Variant:46
Annotators
URL
-
- Jan 2020
-
www.sciencedirect.com www.sciencedirect.com
-
www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
-
variant id lookup result: https://www.ncbi.nlm.nih.gov/clinvar/variation/692266/
-
- Dec 2019
-
www.sciencedirect.com www.sciencedirect.com
-
variant id lookup result: https://www.ncbi.nlm.nih.gov/clinvar/variation/547947/
-
variant id lookup result: https://www.ncbi.nlm.nih.gov/clinvar/variation/599396/
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