Case-level genetic evidence can be entered for:
A group -- when there are many probands with similar characteristics in a single paper.
A family -- when you want to document specifics about multiple family members OR if you want to score segregation information.
An individual -- when you want to report a single proband.
These categories are not mutually exclusive, i.e. an individual can be part of a family or a group.
A single publication can be the source of multiple types of evidence. Variant evidence can only be scored on an individual. For example, you could start with a group as an easy way to document phenotype information shared by all individuals in the group, but you would need to further document each individual to be able to score variant evidence.
Case-Control genetic evidence can be added when statistical analysis is used to evaluate enrichment of variants in cases compared to controls.
The top section of the curation interface shows the publication currently being curated.
All required fields (marked with a star) must be filled in before the curated record for an individual can be saved. The required fields are:
Individual Label is a free-text identifier assigned by the curator. It should be used to uniquely identify an individual described in a publication. Please use any identifiers that the authors use for the individual or family in the paper (e.g. MRX69 Individual III-2). Never use a real name. In addition, labels must be different across publications. If the same identifier, such as “Proband 1”, is used across several publications, the system considers this to be the same individual, which will affect scoring and website display. Please use different labels for probands, for example by adding the first author name followed by the identifier in the paper (i.e. “Wang Proband 1”). Note that there is a limit of 60 characters.
Is this Individual a proband is a dropdown menu that only allows a Yes/No selection. Answer “Yes” if you intend to count this person in your scoring.
Disease for Individual becomes a required field if the individual is a proband; usually select “Copy disease term from Gene-Disease Record.”
Sex
While not required, some fields are necessary to enable scoring. At minimum, you must enter a variant and provide the required information there (see the Adding Variant Information section).
The following section enables curation of the disease and phenotype(s) of the individual. If the individual is a proband, a disease entry is required, usually by selecting “Copy disease term from Gene-Disease Record.” All other fields are optional.
The following section enables curation of the demographics of the individual. The only required field is "Sex". The dropdown menu contains extensive options, including "unknown" if no information is provided in the publication. Additional information about the individual should be entered if it is given in the publication.
Remember to click the "Save" button at the bottom of the page. If you click "Cancel" or navigate away from the page without saving, all entered data will be lost.
The top section of the curation interface shows the publication currently being curated.
Use this option for entering many individuals with similar characteristics from the same paper. All required fields (marked with a star) must be filled in before the curated record for a group can be saved. The required fields are:
Group Label is a free-text identifier assigned by the curator. It should be used to uniquely identify a group described in a publication. If possible, use the identifiers that the authors use to label the group in the paper.
Group -- Common Disease(s) & Phenotype(s) requires information in at least one of the two categories: Disease(s) in common (usually select “Copy disease term from Gene-Disease Record”) or Phenotype(s) in common (HPO terms or free text).
Total number of individuals in the group
The Demographics section allows you to enter a variety of demographics information that describes the group. Please enter as many pieces of information as are available in the publication.
The Information section contains the final required field, "Total number of individuals in group". You can add a variety of additional information about the group if it is available in the publication.
In the Methods section, you can add information about methods used to obtain genetic data for the group, e.g. previous testing, genotyping, and associated methods.
The Additional Information section allows you to enter any other potentially relevant information about the group in a free-text format. If the same group is described in additional publications, you can enter the PubMed IDs of these publications in the space provided here.
The information entered here will only be saved upon clicking the blue "Save" button at the bottom of the page. If any required information is missing, a red warning label will appear and the missing fields will be highlighted in red.
If you click "Cancel" or navigate away from the page without saving, all entered data will be lost.
Saving the group information returns you to Curation Central. The curation panel will now show the newly entered group; you can add or edit information by clicking on the "Edit" icon. If you need to add family and/or individual information for any family or individual in the group, you can simply select the appropriate button here.
The top section of the curation interface shows the publication currently being curated.
The "Curate Family Information" page is split into relevant sections based on the type of evidence. The first three sections are in a similar format to the same sections in the "Curate Group Information" page. All required fields (marked with a star) must be filled in before the curated record for a family can be saved. The required fields are:
Family Label is a free-text identifier assigned by the curator. It should be used to uniquely identify a family described in a publication. If possible, use the identifiers that the authors use to label the family in the paper.
Family -- Disease(s) & Phenotype(s) requires information in at least one of the two categories: Disease(s) in common (usually select “Copy disease term from Gene-Disease Record”) or Phenotype(s) in common (HPO terms or free text).
Family -- Segregation requires information on the number of affected individuals with the relevant genotype.
In the "Family -- Demographics" section, use the drop-down menus to enter any information about family demographics that were provided in the publication.
In the "Family -- Methods" section, you can enter details about prior testing within the family and the genotyping method(s) used to establish that members of the family carry a variant in the gene of interest.
The "Family -- Segregation" section is composed of two subsections. The "Tested Individuals" section allows you to enter the number of affected/unaffected individuals with/without the genotype under consideration. In addition, if information on segregations within the family is available, you can enter this number here. An estimated LOD score will be calculated if the required number of segregations for the mode of inheritance is met and will be shown in the following "LOD Score" section.
The "LOD Score" section allows you to enter the LOD score if one was included in the publication. Selecting "Yes" in the "Published LOD score?" dropdown menu will enable you to enter the numerical value in the "Published Calculated LOD score" field.
If there is either a published LOD score or an estimated LOD score based on reported segregations, and if this score should be included in the final aggregate calculation, select "Yes" in the following dropdown menu.
A box is provided to add free text to "Explain reasoning" behind a decision to include or exclude a published LOD score. An additional free text box allows "Additional Segregation Information" to be entered.
Depending on your selection, the estimated or published LOD score will appear in the corresponding section of the Evidence Matrix and Scored Evidence summary.
The "Family -- Variant(s) Segregating with Proband" section enables you to associate a proband and the segregating variant with this family.
The "Proband Label" field is a free-text field and should contain information that uniquely identifies the proband. If possible, use the label given in the publication; do not use a real name.
The disease ID(s) for the disease(s) associated with the Family is automatically shown and can be copied to the proband. Alternatively, a different disease term can be selected.
The options for checkboxes presented below the disease term differ depending on the mode of inheritance. The example below shows the option for dominant inheritance; if the proband is known to be hemizygous, check the provided box. For recessive inheritance, you will have the option to indicate the presence of one homozygous variant or two variants in trans (see below).
The final "Family Additional Information" section allows you to enter any additional relevant information about the family. In particular, if the same family is described in any other publications, this could be noted here.
Remember to click the "Save" button at the bottom of the page. If you click "Cancel" or navigate away from the page without saving, all entered data will be lost.
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.
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.
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.
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.
The built-in algorithm for LOD score calculation is not always appropriate. Please see the "Additional Logic" section of the .
For extensive guidance on LOD scores, please see the Segregation Analysis section of the .
To associate the relevant variant(s) with the proband, click the "Add Variant" button. For further information on adding variant information, see the section.
If you are scoring segregation without an associated proband in the GCI, note that once you have entered the information on a proband, if you do not enter a proband name and save, it will only associate the LOD score to segregation section only, and will not automatically associate a proband with the family. This may be accurate as some older literature on linkage analysis may have only talked about a family without a proband or identified variant. This would be categorized on the final gene curation record as “segregation without a proband.” However, if you do intend to associate a proband, please enter in a “proband name” when prompted, or if you forget, you can go to the GCI gene curation main page, choose the appropriate PMID, pick the family, and click the “add individual” button. See for example .
A new panel allows you to enter information on the selected variant; for guidance, please see the Variant Evidence section. There a a few questions that must be answered in order to score each variant. The required fields are:
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 Variant Evidence section.
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 Table 1: Mode of Inheritance (MOI) choices in the GCI.
The top section of the curation interface shows the publication currently being curated.
Case-control studies are those in which statistical analysis is used to evaluate enrichment of variants in cases compared to controls. Each case-control study should be independently assessed based on the criteria outlined in the SOP (Case-Control Data section) to evaluate the quality of the study design. The score status of case-control studies can now also be selected as "Review" or "Contradicts".
All required fields (marked with a star) must be filled in before the curated record for an individual can be saved. The required fields are:
Case-Control Label, Case Cohort Label and Control Cohort Label are free-text identifiers assigned by the curator. They should be used to uniquely identify the cohorts described in a publication. If possible, use the identifiers given in the publication.
Disease(s) in Common -- usually select “Copy disease term from Gene-Disease Record”.
Number of Cases with variant(s) in the gene in question -- fill in the number given in the publication
Number of Controls with variant(s) in the gene in question -- fill in the number given in the publication
Number of all Cases genotyped/sequenced -- fill in the number given in the publication
Number of all Controls genotyped/sequenced -- fill in the number given in the publication
For the sections sections following the Case-Control Label, there is a split screen where Case Cohort information is entered in the left panel and Control Cohort information is entered in the right panel.
In the case cohort "Disease(s) & Phenotype(s)" section, you must enter either disease or phenotype information. Generally, you can simply copy the disease from the gene-disease record. In the "Demographics" and "Methods" subsections, enter as much information as is given in the publication.
Additional required information for both cases and controls must be entered in the "Power" section. Additional information can be entered for both cases and controls in the "Additional Information" section below.
The "Case-Control Evaluation" section enables you to enter information that is used by the GCEP to determine whether the study can be scored. A "Study type" must be entered in order to score the study. The following "Statistics", "Bias Category" and "Comments" subsections facilitate evaluation of the quality of the case-control study.
Case-control studies are evaluated and points are assigned at the discretion of experts. The "Case-Control Score" section now allows the selection of a scoring status that includes the "Review" and "Contradicts" options. To score a study, select "Score" and the appropriate numerical value from the "Score" drop-down menu.
Remember to click the "Save" button at the bottom of the page. If you click "Cancel" or navigate away from the page without saving, all entered data will be lost.
