Here’s a breakdown of the information regarding gene-drug associations and variant evidence levels from the provided text:
1. Clinical Practice Guideline-Supported Associations:
* The study focused on gene-drug associations supported by clinical practice guidelines.
* They specifically considered PharmGKB annotations with evidence levels of 2A and 2B. These levels indicate a moderate level of evidence, requiring support from at least two autonomous publications.
2. Medically Actionable Genes:
* They identified pathogenic and likely pathogenic variants in genes listed by the ACMG SF (v3.2).
* The ACMG list includes 81 medically actionable genes.
* 28 of these genes are related to hereditary cancer.
* 53 are linked to cardiovascular, metabolic, and other genetic conditions with available medical interventions.
* No allele frequency threshold was applied to this set, recognizing that rare variants can be clinically important.
3. PharmGKB evidence Levels:
* PharmGKB categorizes variant-drug associations into six levels of evidence: 4, 3, 2B, 2A, 1B, and 1A.
* 1A represents the highest level of evidence.
* 4 represents the lowest level of evidence.
* The study focused on annotations starting from level 2B (moderate evidence, at least two supporting publications).
* When a variant had multiple drug associations at different evidence levels, the drug with the highest level of evidence was prioritized.
4. Example: SNP rs4149056
* The study analyzed the top five drugs associated with SNP rs4149056.
* They also noted the number of studies supporting each drug association to assess robustness.
* Data was retrieved from PharmGKB on September 11, 2023.
