Curating Variant Information
Last updated
Last updated
Variant information is added while entering different types of evidence into the GCI. The interface accepts ClinVar Variation IDs (numerical), ClinGen Allele Registry IDs ("CA" followed by digits) and ClinGen Allele Registry Copy Nunber IDs ("CACN" followed by digits) as input.
Clicking the "Retrieve" button loads information on the specific variant you selected. Click "Save" if the variant is correct.
In general, only copy number variants that involve a single gene should be scored. Copy number variants that contain multiple genes should only be scored if contributions of the other genes can be ruled out. To aid in the scoring decision, the variant selection screen presents the names of the genes that overlap the selected copy number variant.
A new panel allows you to enter information on the selected variant; for guidance, please see the SOP Variant Evidence section. There a a few questions that must be answered in order to score each variant. The required fields are:
Variant Type is a dropdown menu; select from Predicted or Proven Null, Other Variant Type.
Is this variant is de novo? is a dropdown menu with Yes/No options; if you answer "yes", you also must select whether the maternity and paternity of the variant has been confirmed.
Is there functional data to support this variant? is a dropdown menu with Yes/No options.
Once the required data has been entered, you will be able to select the scoring status of the variant, i.e. whether the variant in the proband should be scored, whether the proband and variant should be flagged for review by the GCEP, or whether the evidence from this variant contradicts the gene-disease relationship. Guidance on variant scoring can be found in the SOP Variant Evidence section.
Based on the answers to these questions, a default score for the variant is assigned and shown in the interface. You can override the default score, but must provide an explanation if you do. Both the score and explanation will appear here and in the Scored Evidence table.
If the mode of inheritance (MOI) of your GDM does not allow scoring of variants, the "Select Status" dropdown menu will show a "Supports" option in place of the "Score" option, and no score can be added. For a list of MOIs and their scoring options, please see the SOP Table 1: Mode of Inheritance (MOI) choices in the GCI.
In the above example, only one variant is shown. If a second variant is added it will appear on a second row of the table, and the totals for both variant scores will be summed (up to score limits, see SOP).
If Homozygous is selected, there is no requirement to enter a second variant. The first variant entered will be automatically entered twice into the scoring table.
As of August 2024, scoring probands for AR conditions now requires specification of phase status. When entering biallelic variants into the GCI, the curator will have to check a box to attest if variants are either:
Homozygous
OR
Proven or suspected in trans
"Proven in trans" means each parent confirmed heterozygous, or the two variants are close enough to each other to discern phase from sequence data. "Suspected in trans" is intended for situations where data from both parents may be unavailable, but the proband's phase can be inferred based on one parent’s genotype and/or certain sibling genotypes.
Once you confirm that the two variants are proven or suspected in trans, there will be a second set of checkboxes where you can choose if the variants are:
Proven in trans
Suspected in trans
Phase unknown.
If curator selects phase = proven in trans or suspected in trans, two variant names must be provided to score the evidence. Once two variants in trans are entered and scored as outlined in the above Scoring Variants section, then the record can be saved.
"Phase Unknown" means that proband phase cannot be inferred, as no genotypes are provided aside from the proband’s. If “phase unknown” is selected, you can still enter the variants observed and save them, but there will be no option to score them.
Note: Because phase unknown variants are not being scored, they will not appear in the preview evidence scored tab nor in the classification summary’s scoring matrix. Therefore, in cases where the phase of the variants is entirely unknown, the curator is encouraged to mark phase unknown observations in the non-scorable evidence section on the curation panel in the GCI landing page (e.g. “curation central”) under the relevant PMID. Similarly, observations where only a single variant is observed, but a second variant is suspected despite note being reported, use non-scoreable evidence section for such observations.
Once two variants are entered and scored, the record can be saved. Note that phasing of up to two variants is supported for AR and semidominant gene-disease modes of inheritance at this time. Phasing for >2 variants is not currently supported.
