10,000 Matching Annotations
  1. Mar 2021
  2. www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
    A global functional analysis of missense mutations reveals two major hotspots in the PALB2 tumor suppressor
    30
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    ncbi.nlm.nih.gov/pmc/articles/PMC6847799/
  3. www.biorxiv.org www.biorxiv.org
    A systematic CRISPR screen reveals an IL-20/IL20RA-mediated peritoneal immune crosstalk to prevent the ovarian cancer metastasis
    1
    1. samporteous 18 Mar 2021

      Reviewer #1 (Public Review):

      The authors used a CRISPR screen to investigate the basis of metastasis of ovarian cancer (OC) cells. Overall, they identified two key genes, IL20RA, one of which was studied in detail. They identify an IL20/IL20RA communication between ovarian cancer cells and peritoneal mesothelial cells to promote M1 macrophages and prevent dissemination of the cancer cells. IL-20 mediated crosstalk is blocked in metastasized OC cells by decreased expression of IL-20RA. Interestingly, IL20RA is also decreased in cells from OC patients with peritoneal metastasis, and reconstitution of IL20RA in metastatic OC cells suppresses metastasis. Moreover, OC cells induce mesothelial cells to produce IL20 and IL24.

      Overall, this is a nice study. It is well-written, and the data are clear. A range of methodologies are used that support the conclusions, with both over-expression and under-expression related studies supporting some key conclusions.

      The overall model is that there is crosstalk between disseminated OC cells and mesothelial cells and macrophages. OC cells when disseminated into the peritoneal cavity stimulate mesothelial cells to produced IL20 and IL24, which via IL20RA trigger STAT3 to produced OAS/RNase L and production of IL-18, to promote an M1 phenotype. The M1 phenotype lowers metastasis. Highly metastatic cells block this pathway by decreasing IL20RA expression.

      These findings are interesting, with potential therapeutic ramifications.

      scietyCreator:Reviewer 1 scietyType:PeerReview
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    biorxiv.org/content/10.1101/2021.01.03.425154v1
  4. www.nature.com www.nature.com
    Functional analysis of genetic variants in the high-risk breast cancer susceptibility gene PALB2
    79
    1. shannon_mcnulty 18 Mar 2021
      A cell-based functional assay for PALB2 variants

      AssayGeneralClass: BAO:0003061 reporter protein

      AssayMaterialUsed: CLO:0037317 mouse embryonic stem cell line

      AssayDescription: Stable expression of wild type and variant PALB2 cDNA constructs in Trp53 and Palb2-null mouse cell line containing DR-GFP reporter; I-SceI endonuclease introduces a double-stranded break in the reporter construct and efficient repair results in GFP expression, which is detected by flow cytometry

      AssayReadOutDescription: Relative homologous recombination (HR) efficiency represented as mean percentages of GFP-positive cells among the mCherry-positive cells relative to wild type, which was set to 100%

      AssayRange: %

      AssayNormalRange: HR levels comparable to that of cells expressing wild type PALB2; no numeric threshold given

      AssayAbnormalRange: HR levels ≤40% of wild type

      AssayIndeterminateRange: Not reported

      ValidationControlPathogenic: 12

      ValidationControlBenign: 9

      Replication: 2 independent experiments

      StatisticalAnalysisDescription: Not reported

      CGType:FunctionalAssay FuncAssay:1 BAO:0003061 CLO:0037317 MONDO:0016419 HGNC:26144 AssayRangeType:Quantitative UO:0000187
    5. shannon_mcnulty 18 Mar 2021
      Source Data

      AssayResult: 84.43

      AssayResultAssertion: Not reported

      ReplicateCount: 2

      StandardDeviation: 2.77

      StandardErrorMean: 1.96

      Comment: Exact values reported in “Source Data” file. Discrepancy in “Source Data” file: protein reported as L855P (based on matching values reported in the “Supplementary Data 1” file to values reported in the “Source Data” file.

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:21 CAID:CA494163316 ValidationControl:Benign
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    nature.com/articles/s41467-019-13194-2
  5. www.cell.com www.cell.com
    High-Throughput Reclassification of SCN5A Variants
    86
    1. shannon_mcnulty 18 Mar 2021
      Automated Patch ClampingCells were patch clamped with the SyncroPatch 384PE automated patch clamping device (Nanion). To prepare cells for patch clamping, cells were washed in PBS, treated with Accutase (Millipore-Sigma) for 3 min at 37°C, then recovered in CHO-S-serum free media (GIBCO). Cells were pelleted and resuspended in divalent-free reference solution (DVF) at ∼200,000–400,000 cells/mL. DVF contained (mM) NaCl 140, KCl 4, alpha-D(+)-glucose 5, HEPES 10 (pH 7.4) adjusted with NaOH. Cells were then added to a medium resistance (4–6 MΩ) 384-well recording chamber with 1 patch aperture per well (NPC-384, Nanion), which contained DVF and internal solution: CsCl 10, NaCl 10, CsF 110, EGTA 10, HEPES 10 (pH 7.2) adjusted with CsOH. Next, to enhance seal resistance, 50% of the DVF was exchanged with a calcium-containing seal enhancing solution: NaCl 80, NMDG 60, KCl 4, MgCl2 1, CaCl2 10, alpha-D(+)-glucose 5, HEPES 10 (pH 7.4) adjusted with HCl. The cells were washed three times in external recording solution: NaCl 80, NMDG 60, KCl 4, MgCl2 1, CaCl2 2, alpha-D(+)-glucose 5, HEPES 10 (pH 7.4) adjusted with HCl. Currents elicited in response to activation, inactivation, and recovery from inactivation protocols were then recorded (Figure S2). A late current measurement was captured every 5 s. After 1 min, 50% of the external solution was exchanged with external solution containing 200 μM tetracaine hydrochloride (Sigma; effective concentration 100 μM tetracaine). After tetracaine addition, late current measurements were obtained every 5 s for 1 additional minute. At least 10 cells expressing wild-type SCN5A were included for comparison in each SyncroPatch experiment (Figure 1), and at least 2 independent transfections and at least 10 replicate cells were studied per mutant. Recordings were performed at room temperature.We also conducted experiments to assess the effects of incubation at low temperature or mexiletine (a sodium channel blocker), interventions reported to increase cell surface expression of mistrafficked channels.27Clatot J. Ziyadeh-Isleem A. Maugenre S. Denjoy I. Liu H. Dilanian G. Hatem S.N. Deschênes I. Coulombe A. Guicheney P. Neyroud N. Dominant-negative effect of SCN5A N-terminal mutations through the interaction of Na(v)1.5 α-subunits.Cardiovasc. Res. 2012; 96: 53-63Crossref PubMed Scopus (62) Google Scholar,  28Makiyama T. Akao M. Tsuji K. Doi T. Ohno S. Takenaka K. Kobori A. Ninomiya T. Yoshida H. Takano M. et al.High risk for bradyarrhythmic complications in patients with Brugada syndrome caused by SCN5A gene mutations.J. Am. Coll. Cardiol. 2005; 46: 2100-2106Crossref PubMed Scopus (99) Google Scholar,  29Pfahnl A.E. Viswanathan P.C. Weiss R. Shang L.L. Sanyal S. Shusterman V. Kornblit C. London B. Dudley Jr., S.C. A sodium channel pore mutation causing Brugada syndrome.Heart Rhythm. 2007; 4: 46-53Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar,  30Valdivia C.R. Ackerman M.J. Tester D.J. Wada T. McCormack J. Ye B. Makielski J.C. A novel SCN5A arrhythmia mutation, M1766L, with expression defect rescued by mexiletine.Cardiovasc. Res. 2002; 55: 279-289Crossref PubMed Scopus (77) Google Scholar,  31Valdivia C.R. Tester D.J. Rok B.A. Porter C.B. Munger T.M. Jahangir A. Makielski J.C. Ackerman M.J. A trafficking defective, Brugada syndrome-causing SCN5A mutation rescued by drugs.Cardiovasc. Res. 2004; 62: 53-62Crossref PubMed Scopus (106) Google Scholar For these experiments, cells stably expressing loss-of-function variants were generated as described above. The cells were incubated for 24 h at 30°C, or at 37°C with or without 500 μM mexiletine hydrochloride (Sigma), washed with HEK media, and were patch clamped as described above.

      AssayGeneralClass: BAO:0000062 patch clamp

      AssayMaterialUsed: CLO:0037237 HEK293-derived cell

      AssayDescription: HEK293T-derived cells stably expressing wild type or variant SCN5A were patch clamped and currents elicited in response to activation, inactivation, and recovery from inactivation were recorded, as well as late current measurements.

      AssayReadOutDescription: Peak current density relative to wild type, which was set to 100%

      AssayRange: %

      AssayNormalRange: Peak current density 75-125% of wild type

      AssayAbnormalRange: Peak current density 10-50% of wildtype

      AssayIndeterminateRange: Peak current density 50-75% of wildtype

      ValidationControlPathogenic: 0

      ValidationControlBenign: 10

      Replication: At least 2 independent transfections and at least 10 replicate cells per variant (see ReplicateCount in FunctionalAssayResult annotations for each variant).

      StatisticalAnalysisDescription: Two-tailed t tests or two-tailed Mann-Whitney U tests were used to compare variant parameters between groups of variants, while differences in dispersion between groups were tested with Levene’s test.

      CGType:FunctionalAssay FuncAssay:1 BAO:0000062 CLO:0037237 MONDO:0011001 AssayRangeType:Quantitative UO:0000187
    3. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 59.3

      AssayResultAssertion: Indeterminate

      ReplicateCount: 30

      StandardErrorMean: 8.3

      Comment: This variant had mild loss of function (peak current >50% and <75% of wildtype), therefore it was considered inconclusive and neither abnormal nor normal in vitro function. (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:77 CAID:CA019516 ClinVarID:201546
    4. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 28.4

      AssayResultAssertion: Abnormal

      ReplicateCount: 13

      StandardErrorMean: 8.6

      Comment: This variant had partial loss of function of peak current (10-50% of wildtype), therefore it was considered abnormal (in vitro features consistent with Brugada Syndrome Type 1). (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:76 CAID:CA064645 ClinVarID:518750
    6. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 37.2

      AssayResultAssertion: Abnormal

      ReplicateCount: 26

      StandardErrorMean: 3.8

      Comment: This variant had partial loss of function of peak current (10-50% of wildtype), therefore it was considered abnormal (in vitro features consistent with Brugada Syndrome Type 1). (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:70 CAID:CA018943 ClinVarID:67960
    7. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 23.1

      AssayResultAssertion: Abnormal

      ReplicateCount: 33

      StandardErrorMean: 3.2

      Comment: This variant had partial loss of function of peak current (10-50% of wildtype), therefore it was considered abnormal (in vitro features consistent with Brugada Syndrome Type 1). (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:69 CAID:CA018904 ClinVarID:67957
    8. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 89.5

      AssayResultAssertion: Normal

      ReplicateCount: 29

      StandardErrorMean: 14.6

      Comment: This variant had normal function (75-125% of wildtype peak current, <1% late current, no large perturbations to other parameters). These in vitro features are consistent with non-disease causing variants. (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:68 CAID:CA018863 ClinVarID:67952
    9. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 0.9

      AssayResultAssertion: Abnormal

      ReplicateCount: 18

      StandardErrorMean: 0.5

      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)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:67 CAID:CA018848 ClinVarID:67951
    10. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 5.4

      AssayResultAssertion: Abnormal

      ReplicateCount: 19

      StandardErrorMean: 1.5

      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)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:66 CAID:CA018812 ClinVarID:201523
    11. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 14.8

      AssayResultAssertion: Abnormal

      ReplicateCount: 27

      StandardErrorMean: 2.5

      Comment: This variant had partial loss of function of peak current (10-50% of wildtype), therefore it was considered abnormal (in vitro features consistent with Brugada Syndrome Type 1). (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:64 CAID:CA018747 ClinVarID:67940
    12. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 78.9

      AssayResultAssertion: Normal

      ReplicateCount: 38

      StandardErrorMean: 7.2

      Comment: This variant had normal function (75-125% of wildtype peak current, <1% late current, no large perturbations to other parameters). These in vitro features are consistent with non-disease causing variants. (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:62 CAID:CA018516 ClinVarID:67920
    13. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 43.3

      AssayResultAssertion: Abnormal

      ReplicateCount: 14

      StandardErrorMean: 12.2

      Comment: This variant had partial loss of function of peak current (10-50% of wildtype), therefore it was considered abnormal (in vitro features consistent with Brugada Syndrome Type 1). (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:61 CAID:CA018503 ClinVarID:67918
    14. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 59.7

      AssayResultAssertion: Indeterminate

      ReplicateCount: 41

      StandardErrorMean: 6.3

      Comment: This variant had mild loss of function (peak current >50% and <75% of wildtype), therefore it was considered inconclusive and neither abnormal nor normal in vitro function. (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:60 CAID:CA352145324
    15. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 10.2

      AssayResultAssertion: Abnormal

      ReplicateCount: 12

      StandardErrorMean: 3.4

      Comment: This variant had partial loss of function of peak current (10-50% of wildtype), therefore it was considered abnormal (in vitro features consistent with Brugada Syndrome Type 1). (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:59 CAID:CA018163 ClinVarID:67884
    16. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 0.3

      AssayResultAssertion: Abnormal

      ReplicateCount: 24

      StandardErrorMean: 0.3

      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)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:57 CAID:CA018079 ClinVarID:67876
    17. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 0

      AssayResultAssertion: Abnormal

      ReplicateCount: 11

      StandardErrorMean: 0

      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)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:56 CAID:CA018048 ClinVarID:67874
    18. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 3

      AssayResultAssertion: Abnormal

      ReplicateCount: 16

      StandardErrorMean: 1.5

      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)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:55 CAID:CA018042 ClinVarID:67873
    19. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 32.6

      AssayResultAssertion: Abnormal

      ReplicateCount: 10

      StandardErrorMean: 6.2

      Comment: This variant had partial loss of function of peak current (10-50% of wildtype), therefore it was considered abnormal (in vitro features consistent with Brugada Syndrome Type 1). (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:54 CAID:CA017969 ClinVarID:67869
    20. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 36

      AssayResultAssertion: Abnormal

      ReplicateCount: 14

      StandardErrorMean: 6

      Comment: This variant had partial loss of function of peak current (10-50% of wildtype), therefore it was considered abnormal (in vitro features consistent with Brugada Syndrome Type 1). (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:52 CAID:CA017946 ClinVarID:67866
    21. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 13.9

      AssayResultAssertion: Abnormal

      ReplicateCount: 15

      StandardErrorMean: 2.8

      Comment: This variant had partial loss of function of peak current (10-50% of wildtype), therefore it was considered abnormal (in vitro features consistent with Brugada Syndrome Type 1). (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:53 CAID:CA017955 ClinVarID:67867
    22. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 3.5

      AssayResultAssertion: Abnormal

      ReplicateCount: 29

      StandardErrorMean: 0.8

      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)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:51 CAID:CA017913 ClinVarID:67864
    23. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 0.2

      AssayResultAssertion: Abnormal

      ReplicateCount: 25

      StandardErrorMean: 0.2

      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)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:50 CAID:CA352146767
    24. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 102.6

      AssayResultAssertion: Normal

      ReplicateCount: 31

      StandardErrorMean: 16.5

      Comment: This variant had normal function (75-125% of wildtype peak current, <1% late current, no large perturbations to other parameters). These in vitro features are consistent with non-disease causing variants. (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:47 CAID:CA017837 ClinVarID:67857
    25. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 1.6

      AssayResultAssertion: Abnormal

      ReplicateCount: 15

      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)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:46 CAID:CA017808 ClinVarID:67854
    26. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 12

      AssayResultAssertion: Abnormal

      ReplicateCount: 10

      StandardErrorMean: 2.2

      Comment: This variant had partial loss of function of peak current (10-50% of wildtype), therefore it was considered abnormal (in vitro features consistent with Brugada Syndrome Type 1). (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:45 CAID:CA017796 ClinVarID:67852
    27. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 102.4

      AssayResultAssertion: Normal

      ReplicateCount: 39

      StandardErrorMean: 15.5

      Comment: This variant had normal function (75-125% of wildtype peak current, <1% late current, no large perturbations to other parameters). These in vitro features are consistent with non-disease causing variants. (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:43 CAID:CA017557 ClinVarID:67830
    28. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 47

      AssayResultAssertion: Indeterminate

      ReplicateCount: 10

      StandardErrorMean: 15.5

      Comment: This variant had a mix of multiple abnormalities: a partial loss of function of peak current (10-50% of wildtype) and a gain of function >10mV shift in activation voltage. Therefore it was considered to have inconclusive in vitro properties (neither normal nor abnormal in vitro function). (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:41 CAID:CA017513 ClinVarID:9399
    29. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 114.7

      AssayResultAssertion: Normal

      ReplicateCount: 42

      StandardErrorMean: 15.2

      Comment: This variant had normal function (75-125% of wildtype peak current, <1% late current, no large perturbations to other parameters). These in vitro features are consistent with non-disease causing variants. (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:39 CAID:CA017472 ClinVarID:67820
    30. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 36

      AssayResultAssertion: Abnormal

      ReplicateCount: 19

      StandardErrorMean: 5.9

      Comment: This variant had partial loss of function of peak current (10-50% of wildtype), therefore it was considered abnormal (in vitro features consistent with Brugada Syndrome Type 1). (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:38 CAID:CA017399 ClinVarID:67810
    31. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 121.4

      AssayResultAssertion: Normal

      ReplicateCount: 34

      StandardErrorMean: 13.2

      Comment: This variant had normal function (75-125% of wildtype peak current, <1% late current, no large perturbations to other parameters). These in vitro features are consistent with non-disease causing variants. (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:35 CAID:CA352139743
    32. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 1.1

      AssayResultAssertion: Abnormal

      ReplicateCount: 27

      StandardErrorMean: 0.8

      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)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:33 CAID:CA016490 ClinVarID:67757
    33. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 29.8

      AssayResultAssertion: Abnormal

      ReplicateCount: 13

      StandardErrorMean: 5.7

      Comment: This variant had partial loss of function of peak current (10-50% of wildtype), therefore it was considered abnormal (in vitro features consistent with Brugada Syndrome Type 1). (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:32 CAID:CA016482 ClinVarID:67756
    34. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 3.2

      AssayResultAssertion: Abnormal

      ReplicateCount: 16

      StandardErrorMean: 0.5

      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)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:30 CAID:CA016428 ClinVarID:67752
    35. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 0.8

      AssayResultAssertion: Abnormal

      ReplicateCount: 23

      StandardErrorMean: 0.6

      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)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:28 CAID:CA016384 ClinVarID:67747
    37. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 16

      AssayResultAssertion: Abnormal

      ReplicateCount: 26

      StandardErrorMean: 2.3

      Comment: This variant had partial loss of function of peak current (10-50% of wildtype), therefore it was considered abnormal (in vitro features consistent with Brugada Syndrome Type 1). (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:26 CAID:CA016274 ClinVarID:67742
    38. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 2.9

      AssayResultAssertion: Abnormal

      ReplicateCount: 20

      StandardErrorMean: 2.1

      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)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:25 CAID:CA016228 ClinVarID:67737
    39. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 117.2

      AssayResultAssertion: Abnormal

      ReplicateCount: 36

      StandardErrorMean: 11.7

      Comment: This variant had normal peak current and increased late current (>1% of peak), therefore it was considered a GOF variant (in vitro features consistent with Long QT Syndrome Type 3). (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:22 CAID:CA016182 ClinVarID:67732
    40. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 21

      AssayResultAssertion: Abnormal

      ReplicateCount: 12

      StandardErrorMean: 5.1

      Comment: This variant had partial loss of function of peak current (10-50% of wildtype), therefore it was considered abnormal (in vitro features consistent with Brugada Syndrome Type 1). (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:21 CAID:CA060381 ClinVarID:628262
    41. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 38.9

      AssayResultAssertion: Abnormal

      ReplicateCount: 27

      StandardErrorMean: 7.2

      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)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:20 CAID:CA352143353
    42. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 120.5

      AssayResultAssertion: Normal

      ReplicateCount: 41

      StandardErrorMean: 10.5

      Comment: This variant had normal function (75-125% of wildtype peak current, <1% late current, no large perturbations to other parameters). These in vitro features are consistent with non-disease causing variants. (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:19 CAID:CA016076 ClinVarID:67727
    43. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 105.3

      AssayResultAssertion: Normal

      ReplicateCount: 41

      StandardErrorMean: 10.8

      Comment: This variant had normal function (75-125% of wildtype peak current, <1% late current, no large perturbations to other parameters). These in vitro features are consistent with non-disease causing variants. (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:18 CAID:CA016059 ClinVarID:48294
    44. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 77.5

      AssayResultAssertion: Normal

      ReplicateCount: 30

      StandardErrorMean: 8.6

      Comment: This variant had normal function (75-125% of wildtype peak current, <1% late current, no large perturbations to other parameters). These in vitro features are consistent with non-disease causing variants. (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:17 CAID:CA352143498
    45. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 41.7

      AssayResultAssertion: Abnormal

      ReplicateCount: 15

      StandardErrorMean: 10.8

      Comment: This variant had partial loss of function of peak current (10-50% of wildtype), therefore it was considered abnormal (in vitro features consistent with Brugada Syndrome Type 1). (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:15 CAID:CA015974 ClinVarID:67721
    46. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 63.8

      AssayResultAssertion: Indeterminate

      ReplicateCount: 25

      StandardErrorMean: 10.1

      Comment: This variant had mild loss of function (peak current >50% and <75% of wildtype), therefore it was considered inconclusive and neither abnormal nor normal in vitro function. (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:13 CAID:CA015925 ClinVarID:67719
    47. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 0.9

      AssayResultAssertion: Abnormal

      ReplicateCount: 12

      StandardErrorMean: 0.6

      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)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:14 CAID:CA015938 ClinVarID:67720
    48. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 68.1

      AssayResultAssertion: Indeterminate

      ReplicateCount: 18

      StandardErrorMean: 8.7

      Comment: This variant had mild loss of function (peak current >50% and <75% of wildtype), therefore it was considered inconclusive and neither abnormal nor normal in vitro function. (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:12 CAID:CA352144555
    49. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 32

      AssayResultAssertion: Abnormal

      ReplicateCount: 31

      StandardErrorMean: 5

      Comment: This variant had partial loss of function of peak current (10-50% of wildtype), therefore it was considered abnormal (in vitro features consistent with Brugada Syndrome Type 1). (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:9 CAID:CA014455 ClinVarID:67642
    50. shannon_mcnulty 18 Mar 2021
      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)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:8 CAID:CA014429 ClinVarID:67640
    51. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 3.4

      AssayResultAssertion: Abnormal

      ReplicateCount: 22

      StandardErrorMean: 0.8

      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)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:7 CAID:CA014336 ClinVarID:67635
    52. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 0

      AssayResultAssertion: Abnormal

      ReplicateCount: 39

      StandardErrorMean: 0

      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)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:6 CAID:CA014324 ClinVarID:67634
    53. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 0.6

      AssayResultAssertion: Abnormal

      ReplicateCount: 25

      StandardErrorMean: 0.4

      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)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:5 CAID:CA014305 ClinVarID:67633
    54. shannon_mcnulty 18 Mar 2021
      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)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:3 CAID:CA057036 ClinVarID:229230
    55. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 113.2

      AssayResultAssertion: Normal

      ReplicateCount: 30

      StandardErrorMean: 13.9

      Comment: This variant had normal function (75-125% of wildtype peak current, <1% late current, no large perturbations to other parameters). These in vitro features are consistent with non-disease causing variants. (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:2 CAID:CA352149766
    57. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 1.3

      AssayResultAssertion: Abnormal

      ReplicateCount: 67

      StandardErrorMean: 0.3

      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)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:81 CAID:CA019844 ClinVarID:68047
    58. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 0.8

      AssayResultAssertion: Abnormal

      ReplicateCount: 14

      StandardErrorMean: 0.6

      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)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:80 CAID:CA019833 ClinVarID:68045
    59. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 34.2

      AssayResultAssertion: Abnormal

      ReplicateCount: 14

      StandardErrorMean: 6.7

      Comment: This variant had partial loss of function of peak current (10-50% of wildtype), therefore it was considered abnormal (in vitro features consistent with Brugada Syndrome Type 1). (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:79 CAID:CA019709 ClinVarID:68031
    60. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 109.6

      AssayResultAssertion: Normal

      ReplicateCount: 11

      StandardErrorMean: 19.8

      Comment: This variant had normal function (75-125% of wildtype peak current, <1% late current, no large perturbations to other parameters). These in vitro features are consistent with non-disease causing variants. (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:74 CAID:CA019140 ClinVarID:67986
    61. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 117.8

      AssayResultAssertion: Normal

      ReplicateCount: 15

      StandardErrorMean: 14.5

      Comment: This variant had normal function (75-125% of wildtype peak current, <1% late current, no large perturbations to other parameters). These in vitro features are consistent with non-disease causing variants. (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:73 CAID:CA019045 ClinVarID:67971
    62. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 39

      AssayResultAssertion: Abnormal

      ReplicateCount: 16

      StandardErrorMean: 6.4

      Comment: This variant had partial loss of function of peak current (10-50% of wildtype), therefore it was considered abnormal (in vitro features consistent with Brugada Syndrome Type 1). (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:48 CAID:CA017871 ClinVarID:67861
    63. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 119.6

      AssayResultAssertion: Normal

      ReplicateCount: 22

      StandardErrorMean: 19.5

      Comment: This variant had normal function (75-125% of wildtype peak current, <1% late current, no large perturbations to other parameters). These in vitro features are consistent with non-disease causing variants. (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:36 CAID:CA016995 ClinVarID:67787
    64. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 0.2

      AssayResultAssertion: Abnormal

      ReplicateCount: 15

      StandardErrorMean: 0.2

      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)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:34 CAID:CA016523 ClinVarID:67758
    65. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 32.8

      AssayResultAssertion: Abnormal

      ReplicateCount: 16

      StandardErrorMean: 5

      Comment: This variant had partial loss of function of peak current (10-50% of wildtype), therefore it was considered abnormal (in vitro features consistent with Brugada Syndrome Type 1). (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:24 CAID:CA016221 ClinVarID:67736
    66. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 89.4

      AssayResultAssertion: Normal

      ReplicateCount: 26

      StandardErrorMean: 12.7

      Comment: This variant had normal function (75-125% of wildtype peak current, <1% late current, no large perturbations to other parameters). These in vitro features are consistent with non-disease causing variants. (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:72 CAID:CA064275 ClinVarID:463345 ValidationControl:Benign
    67. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 85.1

      AssayResultAssertion: Normal

      ReplicateCount: 35

      StandardErrorMean: 10.6

      Comment: This variant had normal function (75-125% of wildtype peak current, <1% late current, no large perturbations to other parameters). These in vitro features are consistent with non-disease causing variants. (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:49 CAID:CA017888 ClinVarID:201506 ValidationControl:Benign
    68. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 103.2

      AssayResultAssertion: Normal

      ReplicateCount: 33

      StandardErrorMean: 12.7

      Comment: This variant had normal function (75-125% of wildtype peak current, <1% late current, no large perturbations to other parameters). These in vitro features are consistent with non-disease causing variants. (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:42 CAID:CA017547 ClinVarID:67829 ValidationControl:Benign
    69. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 120.5

      AssayResultAssertion: Normal

      ReplicateCount: 33

      StandardErrorMean: 13.6

      Comment: This variant had normal function (75-125% of wildtype peak current, <1% late current, no large perturbations to other parameters). These in vitro features are consistent with non-disease causing variants. (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:40 CAID:CA017494 ClinVarID:67824 ValidationControl:Benign
    70. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 94.8

      AssayResultAssertion: Normal

      ReplicateCount: 33

      StandardErrorMean: 12.6

      Comment: This variant had normal function (75-125% of wildtype peak current, <1% late current, no large perturbations to other parameters). These in vitro features are consistent with non-disease causing variants. (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:31 CAID:CA016475 ClinVarID:48295 ValidationControl:Benign
    71. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 109.1

      AssayResultAssertion: Normal

      ReplicateCount: 26

      StandardErrorMean: 14.8

      Comment: This variant had normal function (75-125% of wildtype peak current, <1% late current, no large perturbations to other parameters). These in vitro features are consistent with non-disease causing variants. (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:23 CAID:CA016206 ClinVarID:67734 ValidationControl:Benign
    72. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 101

      AssayResultAssertion: Normal

      ReplicateCount: 41

      StandardErrorMean: 8.9

      Comment: This variant had normal function (75-125% of wildtype peak current, <1% late current, no large perturbations to other parameters). These in vitro features are consistent with non-disease causing variants. (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:11 CAID:CA059817 ClinVarID:242192 ValidationControl:Benign
    73. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 104.3

      AssayResultAssertion: Normal

      ReplicateCount: 30

      StandardErrorMean: 16.3

      Comment: This variant had normal function (75-125% of wildtype peak current, <1% late current, no large perturbations to other parameters). These in vitro features are consistent with non-disease causing variants. (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:83 CAID:CA019926 ClinVarID:68055 ValidationControl:Benign
    74. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 105.8

      AssayResultAssertion: Normal

      ReplicateCount: 36

      StandardErrorMean: 12.7

      Comment: This variant had normal function (75-125% of wildtype peak current, <1% late current, no large perturbations to other parameters). These in vitro features are consistent with non-disease causing variants. (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:82 CAID:CA019856 ClinVarID:68049 ValidationControl:Benign
    75. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 103.2

      AssayResultAssertion: Normal

      ReplicateCount: 37

      StandardErrorMean: 21.8

      Comment: This variant had normal function (75-125% of wildtype peak current, <1% late current, no large perturbations to other parameters). These in vitro features are consistent with non-disease causing variants. (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:65 CAID:CA064027 ValidationControl:Benign
    76. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 51.9

      AssayResultAssertion: Indeterminate

      ReplicateCount: 12

      StandardErrorMean: 18.8

      Comment: This variant had a mild loss of function in peak current (50-75% of wildtype). It had unmeasured late current, but has been previously reported to have high late current (GOF feature). Therefore it was considered to meet neither the abnormal or normal functional parameter. (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:75 CAID:CA019148 ClinVarID:9377
    77. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 64.8

      AssayResultAssertion: Abnormal

      ReplicateCount: 31

      StandardErrorMean: 11.1

      Comment: This variant had a mild loss of function in peak current (50-75% of wildtype). It also had a very large increase in recovery from inactivation (>10-fold slower). Therefore it was considered to have a partial loss of function (in vitro function consistent with Brugada Syndrome). (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:63 CAID:CA018735 ClinVarID:67939
    78. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 2.2

      AssayResultAssertion: Abnormal

      ReplicateCount: 16

      StandardErrorMean: 1

      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)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:58 CAID:CA018087 ClinVarID:67877
    79. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 114.3

      AssayResultAssertion: Abnormal

      ReplicateCount: 16

      StandardErrorMean: 22.4

      Comment: This variant had normal peak current and increased late current (>1% of peak), therefore it was considered a GOF variant (in vitro features consistent with Long QT Syndrome Type 3). (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:44 CAID:CA017679 ClinVarID:9370
    80. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 23.2

      AssayResultAssertion: Abnormal

      ReplicateCount: 14

      StandardErrorMean: 7.1

      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)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:16 CAID:CA016002 ClinVarID:67723
    81. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 113

      AssayResultAssertion: Normal

      ReplicateCount: 17

      StandardErrorMean: 28.6

      Comment: This variant had normal function (75-125% of wildtype peak current, <1% late current, no large perturbations to other parameters). These in vitro features are consistent with non-disease causing variants. (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:10 CAID:CA058963
    82. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 0.1

      AssayResultAssertion: Abnormal

      ReplicateCount: 19

      StandardErrorMean: 0.1

      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)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:4 CAID:CA014257 ClinVarID:67631
    83. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 86.7

      AssayResultAssertion: Normal

      ReplicateCount: 28

      StandardErrorMean: 8.6

      Comment: This variant had normal function (75-125% of wildtype peak current, <1% late current, no large perturbations to other parameters). These in vitro features are consistent with non-disease causing variants. (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:78 CAID:CA019690 ClinVarID:9396
    84. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 0.7

      AssayResultAssertion: Abnormal

      ReplicateCount: 17

      StandardErrorMean: 0.6

      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)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:37 CAID:CA017341 ClinVarID:67807
    85. shannon_mcnulty 18 Mar 2021
      Most Suspected Brugada Syndrome Variants Had (Partial) Loss of Function

      AssayResult: 115.6

      AssayResultAssertion: Normal

      ReplicateCount: 19

      StandardErrorMean: 24.7

      Comment: This variant had normal function (75-125% of wildtype peak current, <1% late current, no large perturbations to other parameters). These in vitro features are consistent with non-disease causing variants. (Personal communication: A. Glazer)

      CGType:FunctionalAssayResult CG:BulkAnnotation FuncAssay:1 Variant:29 CAID:CA016420 ClinVarID:67751
    Visit annotations in context

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    cell.com/ajhg/fulltext/S0002-9297(20)30162-2
  6. jmg.bmj.com jmg.bmj.com
    Blood functional assay for rapid clinical interpretation of germline TP53 variants
    1
    1. dkanavy 18 Mar 2021
      This new quantitative assay, based on both RT-QMPSF and RT-MLPA, was first validated on 31 lymphoblastoid cell lines derived from patients with LFS harbouring different germline heterozygous TP53 variants

      AssayGeneralClass: BAO:0010044 targeted transcriptional assay

      AssayMaterialUsed: BTO:0000773 lymphoblastoid cell line derived from control individuals or individuals with germline TP53 variants

      AssayDescription: Comparative transcriptomic analysis using RNA-Seq to compare EBV cell lines of wild type and pathogenic TP53 in the context of genotoxic stress induced by doxorubicin treatment. 10 biomarkers corresponding to p53 targets were measured to determine a functionality score.

      AdditionalDocument: PMID: 23172776

      AssayReadOutDescription: In the treated condition, the peak height of each of the 10  p53 target genes was measured and divided by the sum of the heights of the three control genes. This value was then divided by the same ratio calculated in the untreated condition. In the assay, the mean of the 10 values defines the p53 functionality score. The final p53 functionality score is the mean of the scores obtained in RT-MLPA and RT-QMPSF assays.

      AssayRange: An arbitrary functionality score was calculated from the induction score of the 10 p53 targets.

      AssayNormalRange: N/A

      AssayAbnormalRange: N/A

      AssayIndeterminateRange: N/A

      AssayNormalControl: wild type TP53

      AssayAbnormalControl: LFS patient cells

      ValidationControlPathogenic: 8 Individuals with dominant-negative TP53 missense variants, 10 Individuals with null TP53 variants, and 13 Individuals with other TP53 missense variants

      ValidationControlBenign: 3 patients with wild type TP53

      Replication: experiments were performed in triplicates.

      StatisticalAnalysisDescription: Differentially expressed genes between doxorubicin-treated and untreated cells were arbitrarily defined using, as filters, a P<0.01 and fold-change cutoffs >2 or <2, for up and down regulation, respectively. The resultant signal information was analyzed using one-way analysis of variance (ANOVA, P= 0.001), assuming normality but not equal variances with a Benjamani–Hochberg correction for multiple comparisons using three groups: controls, null, and missense mutations.

      SignificanceThreshold: P=0.001

      Comment: statistical analysis and P value from previous publication.

      FuncAssay:1 BAO:0010044 BTO:0000773 MONDO:0018875 HGNC:11998 AssayReadOutType:Quantitative CGType:FunctionalAssay
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    jmg.bmj.com/content/early/2020/10/13/jmedgenet-2020-107059
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    MiSiC, a general deep learning-based method for the high-throughput cell segmentation of complex bacterial communities
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    1. samporteous 17 Mar 2021

      Reviewer #1 (Public Review):

      In this work, Panigrahi et. al. develop a powerful deep-learning-based cell segmentation platform (MiSiC) capable of accurately segmenting bacteria cells densely packed within both homogenous and heterogeneous cell populations. Notably, MiSiC can be easily implemented by a researcher without the need for high-computational power. The authors first demonstrate MiSiC's ability to accurately segment cells with a variety of shapes including rods, crescents and long filaments. They then demonstrate that MiSiC is able to segment and classify dividing and non-dividing Myxococcus cells present in a heterogenous population of E. coli and Myxococcus. Lastly, the authors outline a training workflow with which MiSiC can be trained to identify two different cell types present in a mixed population using Myxococcus and E. coli as examples.

      While we believe that MiSiC is a very powerful and exciting tool that will have a large impact on the bacterial cell biological community, we feel explanations of how to use the algorithm should be more greatly emphasized. To help other scientists use MiSiC to its fullest potential, the range of applications should be clarified. Furthermore, any inherent biases in MiSiC should be discussed so that users can avoid them.

      Major Concerns:

      1) It is unclear to us how a MiSiC user should choose/tune the value for the noise variance parameter. What exactly should be considered when choosing the noise variance parameter? Some possibilities include input image size, cell size (in pixels), cell density, and variance in cell size. Is there a recommended range for the parameter? These questions along with our second minor correction can be addressed with a paragraph in the Discussion section.

      2) Could the authors expand on using algorithms like watershed, conditional random fields, or snake segmentation to segment bacteria when there is not enough edge information to properly separate them? How accurate are these methods at segmenting the cells? Should other MiSiC parameters be tuned to increase the accuracy when implementing these methods?

      3) Can the MiSiC's ability to accurately segment phase and brightfield images be quantitatively compared against each other and against fluorescent images for overall accuracy? A figure similar to Fig. 2C, with the three image modalities instead of species would nicely complement Fig. 2A. If the segmentation accuracy varies significantly between image modalities, a researcher might want to consider the segmentation accuracy when planning their experiments. If the accuracy does not vary significantly, that would be equally useful to know.

      4) The ability of MiSiC to segment dense clusters of cells is an exciting advancement for cell segmentation algorithms. However, is there a minimum cell density required for robust segmentation with MiSiC? The algorithm should be applied to a set of sparsely populated images in a supplemental figure. Is the algorithm less accurate for sparse images (perhaps reflected by an increase in false-positive cell identifications)? Any possible biases related to cell density should be noted.

      5) It is exciting to see the ability of MiSiC to segment single cells of M. xanthus and E. coli species in densely packed colonies (Fig. 4b). Although three morphological parameters after segmentation were compared with ground truth, the comparison was conducted at the ensemble level (Fig. 4c). Could the authors use the Mx-GFP and Ec-mCherry fluorescence as a ground truth at the single cell level to verify the results of segmentation? For example, for any Ec cells identified by MiSiC in Fig. 4b, provide an index of whether its fluorescence is red or green. This single-cell level comparison is most important for the community.

      scietyCreator:Reviewer 1 scietyType:PeerReview
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    biorxiv.org/content/10.1101/2020.10.07.328666v1
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    Parallel evolution between genomic segments of seasonal human influenza viruses reveals RNA-RNA relationships
    1
    1. f.bryant 17 Mar 2021

      Reviewer #1 (Public Review):

      In this paper, authors did a fine job of combining phylogenetics and molecular methods to demonstrate the parallel evolution across vRNA segments in two seasonal influenza A virus subtypes. They first estimated phylogenetic relationships between vRNA segments using Robinson-Foulds distance and identified the possibility of parallel evolution of RNA-RNA interactions driving the genomic assembly. This is indeed an interesting mechanism in addition to the traditional role for proteins for the same. Subsequently, they used molecular biology to validate such RNA-RNA driven interaction by demonstrating co-localization of vRNA segments in infected cells. They also showed that the parallel evolution between vRNA segments might vary across subtypes and virus lineages isolated from distinct host origins. Overall, I find this to be excellent work with major implications for genome evolution of infectious viruses; emergence of new strains with altered genome combination.

      Comments:

      I am wondering if leaving out sequences (not resolving well) in the phylogenic analysis interferes with the true picture of the proposed associations. What if they reflect the evolutionary intermediates, with important implications for the pathogen evolution which is lost in the analyses?

      Lines 50-51: Can you please elaborate? I think this might be useful for the reader to better understand the context. Also, a brief description on functional association between different known fragments might instigate curiosity among the readers from the very beginning. At present, it largely caters to people already familiar with the biology of influenza virus.

      Lines 95-96 Were these strains all swine-origin? More details on these lineages will be useful for the readers.

      Lines 128-132: I think it will be nice to talk about these hypotheses well in advance, may be in the Introduction, with more functional details of viral segments.

      Lines 134-136: Please rephrase this sentence to make it more direct and explain the why. E.g. "... parallel evolution between PB1 and HA is likely to be weaker than that of PB1 and PA" .

      Lines 222-223: Please include a set of hypotheses to explain you results? Please add a perspective in the discussion on how this contribute might to the pandemic potential of H1N!?.

      Lines 287-288: I am wondering how likely is this to be true for H1N1.

      scietyType:PeerReview scietyCreator:Reviewer 1
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    biorxiv.org/content/10.1101/2021.01.14.426718v1
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    Expansion of CD10neg neutrophils and CD14+HLA-DRneg/low monocytes driving proinflammatory responses in patients with acute myocardial infarction
    1
    1. f.bryant 17 Mar 2021

      Reviewer #1 (Public Review):

      In this paper, the authors tried to investigate complex roles of immune cells during acute myocardial infarction (AMI) by examining immune cells in blood samples from acute coronary syndrome (ACS) patients. They found an increase in the circulating levels of CD14+HLA-DRneg/low monocytes and CD16+CD66b+CD10neg neutrophils in the blood of ACS patients compared to healthy people, all of which were correlated with elevated levels of inflammatory markers in serum. Those findings were then further explored at a mechanistic level by using in vitro and in vivo experiments. Interestingly, the researchers also found that high cytomegalovirus (CMV) antibody titers could affect the immunoregulatory mechanisms in AMI patients. Taken together, the findings of the researchers could potentially contribute to the development of a more effective strategy to prevent cardiac deterioration and cardiovascular adverse events after AMI.

      Strengths:

      This paper contains novel insight regarding role of neutrophil and monocyte subset in pathophysiology of AMI. Although the increased level of CD10neg subsets of neutrophils in AMI patients has recently been reported (Marechal, P., et al. 2020. Neutrophil phenotypes in coronary artery disease. Journal of Clinical Medicine), the current paper aptly complemented the previous findings obtained by using its in vitro and in vivo mice model. This study also has robust methods to support their conclusion.

      Weakness:

      To further improve the strength of their conclusion, the experiments investigating the effects of immunoregulatory function of immature neutrophils and HLA-DRneg/low monocytes subsets would be advised.

      scietyType:PeerReview scietyCreator:Reviewer 1
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    biorxiv.org/content/10.1101/2020.09.21.306118v2