Disease Association Filters

This page summarizes filters related to variant – disease and gene – disease associations. Filter availability can vary depending on the selected variant categories. If filters are applied to more than one variant category in the same condition group, only filters relevant for all variant categories are available. For more information, refer to Filter by Variant Category.

Genes

In addition to filtering by the gene list, variants can be filtered by genes based on their associations with diseases and phenotypes.

How to Create Disease/Phenotype-Based List

1. Select the genes filter.

   • In the displayed dialog box window, select the Include genes from the diseases checkbox.

   • Start typing a phenotype or disease to display a list of potential matches to add to the list.

   • Select a checkbox next to Resource to include it in the list.

   • Select a high, medium, or low confidence score.

   • Select an overlap distance between 0.00 and 1.00.

   • The disease and related diseases display in the Related Diseases area with the distance and gene count. Deselect any unnecessary related diseases.

   • Add any other genes to the gene list.

   • Add additional genes in the Additional genes area.

2. Select Apply to save changes to the gene list.

Resources of Gene - Disease Associations

The following tables detail the ontology sources that Connected Insights uses to determine relationships between genes and diseases.

Gene Disease Relationship Resources

Resource	Description
OMIM	Online Mendelian Inheritance in Man
HPO	Human Phenotype Ontology
Phenopedia	Human Genome Epidemiology (HuGE)
GEL PanelApp	Genomics England PanelApp
ILMN	• Clinvar – NCBI ClinVar •MedGen – NCBI portal to information about conditions and phenotypes related to Medical Genetics. •GTR – NCBI Genetic Testing Registry •GeneRIF – NCBI Gene Reference into Function

Disease Relationship Resources

Resource	Description
ICD-9	International Classification of Diseases, Ninth Revision
ICD-10	International Classification of Diseases, Tenth Revision
MeSH	Medical Subject Headings
UML	Unified Medical Language system. A repository of ontology resources.
SNOMEDCT	Systematized Nomenclature of Medicine Clinical Terms

Overlap Distance

Phenotype to gene search finds similar phenotypes and diseases across various ontology sources, independent of the underlying vocabulary in each source. If an equivalent concept does not exist across the sources, Connected Insights calculates the distance between nodes in the ontological hierarchies and assigns a score from 0 to 1, where:

• Values closer to 0 indicate that the concepts are more equivalent. A value of 0 indicates that the concepts are the same.

• Values closer to 1 indicate that the concepts are more dissimilar. A value of 1 indicates that the concepts can only be connected at the root node and are therefore excluded from query results.

The determination of distance accounts for the fact that sibling concepts on leaf nodes (eg, hypertrophic cardiomyopathy, and dilated cardiomyopathy) are more closely related to each other than siblings close to the root (eg, abnormal vascular morphology, and abnormal heart morphology).

Confidence

Confidence scores for gene - disease associations are calculated using the following rules:

• Expert-curated data from OMIM, HPO, Phenopedia, and ClinVar are assigned a high confidence score.

• High, moderate, or low confidence scores are converted from GeL PanelApp strong, medium, and low scores, respectively.

• GTR confidence scores are based on information content metrics, which measure the specificity of a genetic test for a particular phenotype and a gene.

• GeneRIF associations, which are derived using data mining, and assigned medium confidence.

COSMIC Cancer Gene Census

Filters variants based on gene role in cancer annotated by COSMIC Cancer Gene Census (CGC).

Cancer Gene Census

Role in Cancer	Description
TSG	Known tumor suppressor gene (TSG).
Oncogene	Known oncogene.
Fusion	Known fusion gene.

OMIM

Filters variants based on genes with known gene-disease associations in the OMIM database.

• Present in OMIM — An OMIM entry exists for the gene.

• Has associated OMIM phenotypes (including ?) — A relationship exists between the phenotype and a matching gene at the transcript level. Provisional relationships, indicated by "?" in OMIM, are included.

• Has associated OMIM phenotypes (excluding ?) — A relationship exists between the phenotype and a matching gene at the transcript level. Provisional relationships, indicated by "?" in OMIM, are excluded.

Selecting associated phenotypes enables options to refine the filter by mode of inheritance.

Mode of Inheritance Descriptions

Mode of Inheritance	Description
AD	Autosomal Dominant
AR	Autosomal Recessive
XL	(X-linked)
XLD	(X-linked Dominant)
XLR	(X-linked Recessive)
YL	(Y-linked)
MI	Mitochondrial
Mu	Multifactorial
DD	Digenic Dominant
DR	Digenic Recessive
SMu	Somatic Mutation
SMo	Somatic Mosaicism
IC	Isolated Cases

COSMIC

Filters by presence in the COSMIC database. For more information, refer to Acronyms and Terms.

❕ The COSMIC filter is only selectable for small variants.

Cancer Hotspots

Filters by number of samples in cancer hotspots.

ClinVar

Filters on interpretation categories and the review status provided in the ClinVar database.

Interpretation Category Descriptions

Interpretation Category	Definition in Connected Insights
Pathogenic	The variant has at least one aggregate variant record (VCV entry) or aggregate variant –disease record (RCV) with classification category Pathogenic in the ClinVar database.
Likely Pathogenic, UncertainSignificance, Likely Benign, Benign	The variant has at least one aggregate variant record (VCV entry) or aggregate variant –disease record (RCV) with classification category Pathogenic in the ClinVar database.
None	The variant has no records in ClinVar or has at least one aggregate variant record (VCV entry)or aggregate variant – disease record (RCV) with interpretation categories Drug Response,Protective, and others (any other categories excluding Pathogenic, Likely Pathogenic,Uncertain Significance, Likely Benign, and Benign).

To filter by ClinVar review status, use the definitions provided from the ClinVar status review guidelines on the National Center for Biotechnology Information website.

Interpretation Category Descriptions

Number of Stars	Definition in Connected Insights	Review Status Descriptions
Four	The highest review status across all VCV and RCV records for the variant is four stars.	Practice guideline. For more information,refer to the ClinVar status review guidelines on the National Center for Biotechnology Information website.
Three	The highest review status across all VCVand RCV records for the variant is three stars.	Reviewed by export panel. For more information, refer to the ClinVar status review guidelines on the National Center for Biotechnology Information website.
Two	The highest review status across all VCVand RCV records for the variant is two stars.	Criteria provided, multiple submitters, no conflicts. Two or more submitters with assertion criteria and evidence (or a public contact) provided the same interpretation.
One	The highest review status across all VCV and RCV records for the variant is one star.	Criteria provided, conflicting interpretations. Multiple submitters provided assertion criteria and evidence(or a public contact) but there are conflicting interpretations. The independent values are enumerated for clinical significance.
None	The highest review status across all VCV and RCV records for the variant is no stars.	No assertion criteria provided. For more information, refer to the ClinVar status review guidelines on the National Center for Biotechnology Information website.