LocalVar was created to address several needs associated with the longitudinal maintenance of a variant collection. A demo is available that will allow readers to explore the functionality described in this section (http://www.watkinscv.com/app-demos/LocalVar). Once the collection is loaded, the main page (Figure 5) shows an interactive table of the entire collection. This is enhanced with an autocomplete search bar that can pre-empt duplicate entries and a drop-down text area where new single or bulk entries can be added to the collection.

When a variant record from this collection table is clicked or searched, the user is navigated to a record details page (Figure 6). If the HGVS expression of the record is also found in ClinVar, the clinical significance from ClinVar and all associated synonymous HGVS expressions from ClinVar will also be displayed. Additionally, a custom link is provided to view these extra data on the ClinVar online portal using the variationID (ClinVar identifier stored in the HGVS bins) for that variant. In this record details page, any field of the record, except for the system-generated VRS identifier, can be directly edited. Manual changes to the HGVS expression will initiate the auto-creation of a new corresponding VRS identifier and an update of corresponding ClinVar data. Any changes made are tracked by the LocalVar edit history. This history is prominently displayed on the record details page. There is a two-step process for removing variant records. Deleted records will initially be moved into a “trash” collection, shown in Figure 7. Within this trash collection, variant records can still be restored to the main collection without any loss of data and with such an event being recorded in the edit history for that record. These records can also be permanently removed from the trash collection but only after another prompt warning the user that the removed record will not be recoverable.

The HGVS bins are also used to generate a collection of suggested data updates for the user. An example of suggested updates is shown in Figure 8 and can be navigated to using the fixed navigation sidebar. The first suggestion type, “Update Interpretation,” is created for each record in the collection with an HGVS expression that matches a ClinVar entry and has a different interpretation than what is in ClinVar. The user can choose whether to accept this suggestion (which will update the value of the interpretation column for that record) or to reject the suggestion. If rejected, the user is prompted by the tool with the option of marking the “conflicting” interpretations as synonymous. This would be suitable for instances where, for example, the variant collection used the term “Indeterminate” while ClinVar uses the term “Uncertain Significance” to refer to a variant of uncertain significance. If the user chooses to use this option, all conflicts of those two terms in the collection would be removed and the tool would store that preference for any subsequent suggestions. This allows LocalVar to “learn” how to map institution interpretations to those found in ClinVar while remaining institution-agnostic. It also reduces the number of erroneous suggestions for the user and increases their likelihood of finding significant interpretation conflicts. The second suggestion type, “Merge Duplicate,” allows the user to merge records in the collection that have separate unique collection identifiers but the same HGVS expression. As shown in Figure 9, the user is given the opportunity to select which fields to carry into the newly merged record. The third suggestion type, “Merge Synonym,” utilizes the HGVS bins to allow users to merge records in the collection that have HGVS expressions that are recorded as synonyms by ClinVar. The user is given the opportunity to select which HGVS expression to carry into the merged entry. Any row in the main “View Collection” table can also be selected for the option of merging two or more records into one. In order to merge multiple records into one, the user must select at least one value for each column. For all merge events, the resulting record is saved under the collection ID selected by the user and the records whose collection IDs were not selected are moved to the trash. All such events are tracked in the history of the records involved.

Another feature that was added to LocalVar is the ability to easily download three different “reports.” This option is prominently displayed on the fixed sidebar and can be selected from anywhere in the tool. The first report is a .csv snapshot of the entire collection. This updates every time the collection is modified and allows users to easily capture the collection in its current state and either move to another collection managing software or share the collection with interested partners. The second report is a .json file of the entire history of the collection. This allows users to have a detailed record of every edit, accepted suggestion, variant addition or deletion, etc. The JSON format of this file allows the history to be easily searched as each edit event is tied to a specific record. The third report is a .json file of the HGVS bins used to associate the variants in the collection with those from ClinVar. The JSON format of this file also makes it easily searchable and straightforward. This is an effort to make LocalVar suggestions transparent and relatively simple to validate or otherwise audit.