{
  "abstract": "Background Vast amounts of genome sequencing data generated from large-scale research studies like HostSeq provide an opportunity to summarise the spectrum of pathogenic variation in a subset of the Canadian population. Sharing variant-level data with public databases, like ClinVar, is crucial for advancing our understanding of genomic variants related to Mendelian diseases. However, such entries are often incomplete or contain discrepancies which render interpretation and classifications less useful.Methods The GENCOV and HostSeq cohorts were annotated and summarised using custom workflows to identify variants with a pathogenic and likely pathogenic (P/LP) classification in ClinVar. These variants were further filtered using custom gene panels, gnomAD frequency, variant type, gene-disease relationship and the number of reputable ClinVar laboratory submissions. Manually assessed variants from the GENCOV study were compared with ClinVar classifications to identify discrepancies.Results A total of 1956 unique variants were manually classified as P/LP through the GENCOV study. Of these, 65% (1276) were also identified in ClinVar, and among those, 69% (889) had concordant P/LP classifications. The manual assessment of unique exonic variants in GENCOV yielded a higher number of putative P/LP variants (1595), including truncating and missense variants compared with the 127 unique exonic P/LP variants in HostSeq.Conclusion These results highlight that a large proportion of P/LP variation is either absent or has conflicting evidence for pathogenicity in ClinVar, emphasising the importance of periodic reassessment, discrepancy resolution and updates to ensure completeness and accuracy of public databases.",
  "authors": [
    {
      "affiliations": [
        "Mount Sinai Hospital, Toronto, Ontario, Canada",
        "Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario, Canada"
      ],
      "name": "Erika Frangione"
    },
    {
      "affiliations": [
        "Mount Sinai Hospital, Toronto, Ontario, Canada",
        "Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario, Canada"
      ],
      "name": "Radhika Mahajan"
    },
    {
      "affiliations": [
        "Mount Sinai Hospital, Toronto, Ontario, Canada",
        "University of Toronto, Toronto, Ontario, Canada"
      ],
      "name": "Juan De Los Rios"
    },
    {
      "affiliations": [
        "Mount Sinai Hospital, Toronto, Ontario, Canada",
        "Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario, Canada"
      ],
      "name": "Selina Casalino"
    },
    {
      "affiliations": [
        "Mount Sinai Hospital, Toronto, Ontario, Canada",
        "Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario, Canada"
      ],
      "name": "Navneet Aujla"
    },
    {
      "affiliations": [
        "University of Toronto, Toronto, Ontario, Canada",
        "William Osler Health System, Brampton, Ontario, Canada"
      ],
      "name": "Saranya Arnoldo"
    },
    {
      "affiliations": [
        "University of Toronto, Toronto, Ontario, Canada",
        "William Osler Health System, Brampton, Ontario, Canada"
      ],
      "name": "Alexandra Binnie"
    },
    {
      "affiliations": [
        "Mount Sinai Hospital, Toronto, Ontario, Canada",
        "University of Toronto, Toronto, Ontario, Canada"
      ],
      "name": "Bjug Borgundvaag"
    },
    {
      "affiliations": [
        "Women’s College Hospital, Toronto, Ontario, Canada"
      ],
      "name": "Marc Dagher"
    },
    {
      "affiliations": [
        "Mount Sinai Hospital, Toronto, Ontario, Canada",
        "University of Toronto, Toronto, Ontario, Canada"
      ],
      "name": "Luke Devine"
    },
    {
      "affiliations": [
        "University Health Network, Toronto, Ontario, Canada"
      ],
      "name": "Hanna Faghfoury"
    },
    {
      "affiliations": [
        "University of Toronto, Toronto, Ontario, Canada",
        "University Health Network, Toronto, Ontario, Canada"
      ],
      "name": "Steven Marc Friedman"
    },
    {
      "affiliations": [
        "Mount Sinai Hospital, Toronto, Ontario, Canada",
        "Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario, Canada"
      ],
      "name": "Chun Yiu Jordan Fung"
    },
    {
      "affiliations": [
        "Mackenzie Health, Richmond Hill, Ontario, Canada"
      ],
      "name": "Zeeshan Khan"
    },
    {
      "affiliations": [
        "Mount Sinai Hospital, Toronto, Ontario, Canada",
        "Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario, Canada",
        "University of Toronto, Toronto, Ontario, Canada"
      ],
      "name": "Gregory Morgan"
    },
    {
      "affiliations": [
        "William Osler Health System, Brampton, Ontario, Canada"
      ],
      "name": "David Richardson"
    },
    {
      "affiliations": [
        "Mackenzie Health, Richmond Hill, Ontario, Canada"
      ],
      "name": "Seth Stern"
    },
    {
      "affiliations": [
        "University of Toronto, Toronto, Ontario, Canada",
        "University Health Network, Toronto, Ontario, Canada",
        "Mackenzie Health, Richmond Hill, Ontario, Canada"
      ],
      "name": "Ahmed Taher"
    },
    {
      "affiliations": [
        "Mount Sinai Hospital, Toronto, Ontario, Canada",
        "University of Toronto, Toronto, Ontario, Canada"
      ],
      "name": "Jennifer Taher"
    },
    {
      "affiliations": [
        "Mount Sinai Hospital, Toronto, Ontario, Canada",
        "Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario, Canada",
        "University of Toronto, Toronto, Ontario, Canada"
      ],
      "name": "Jordan Lerner-Ellis"
    },
    {
      "affiliations": [
        "Mount Sinai Hospital, Toronto, Ontario, Canada",
        "Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario, Canada",
        "University of Toronto, Toronto, Ontario, Canada",
        "William Osler Health System, Brampton, Ontario, Canada",
        "Women’s College Hospital, Toronto, Ontario, Canada",
        "University Health Network, Toronto, Ontario, Canada",
        "Mackenzie Health, Richmond Hill, Ontario, Canada"
      ],
      "name": "GENCOV Study Workgroup"
    },
    {
      "affiliations": [],
      "name": "HostSeq Implementation Committee"
    }
  ],
  "title": "Clinically significant DNA variation from the GENCOV and HostSeq COVID-19 genome sequencing studies",
  "uid": "4d41ef63-ec08-5abc-95fb-64f27c404fdb"
}