What are the main resources used in clinical settings?

In this video, Prof Helen Firth spoke about determining if a variant has been observed previously and the importance of context.

If the variant has been observed in healthy individuals (population dataset), then the variant is likely to be part of natural variation and not disease-causing. In the case where a variant has been seen in a cohort of individuals with rare genetic conditions (disease dataset), then this variant is likely to indicate that the variant causes disease. In the previous steps Using population data to aid variant interpretation and Specific databases for specific countries we discussed the importance of population datasets and provided information about useful resources. Building from that, the most frequently used disease datasets are described below:

ClinVar

A freely available, public archive of human genetic variants and interpretations of their relationships to diseases and other conditions, maintained at the National Institutes of Health (NIH). ClinVar uses a four-star rating system to represent the Review Status of each submission.

• Four-star review status refers to “practice guideline” assertions.
• Three-star review status refers to “expert panel” assertions.
• Two-star review status refers to the criteria provided, multiple submitters with no conflicts.
• One or zero-star review status reflects the number of submitters, the depth of data submitted and any conflicting interpretations.

DECIPHER

Openly shared records of patients with rare disease, which includes candidate diagnostic variants and granular phenotype data. You will learn how to use DECIPHER in Week 2.

Leiden Open Variation Database (LOVD)

An online gene-centered collection and display of DNA variants from public Locus-Specific DataBases (LSDBs) which store information on variants in the human genome and the observed phenotypic consequences.

• LSDBs (usually listed in LOVD), often provide additional information and tools for locus-specific mutations. These are usually curated by expert groups with a special interest in these diseases. Some examples include the following:

eDystrophin provides a comprehensive database on dystrophinopathies.

DOVE helps you to determine the variant type, length, reading frame alterations, potential effects on splicing, and exon skipping eligibility for dystrophinopathies.

CFTR2 provides information on whether a variant or variant combination is CF-causing. It also provides information on sweat chloride, lung function, pancreatic status, and Pseudomonas infection rate in patients in the CFTR2 database with this variant or variant combination.

The Human Gene Mutation Database (HGMD)

A collection of published pathogenic variants responsible for human inherited disease. HGMD Public is available as a free public version with restricted content for academic use.