Pathogenicity scoring system for human clinical genetics

A method for determining the clinical significance of a genetic variant, comprising determining, for the variant,

• (a) a function score based on known or projected impact of the variant on a biological function of a cell or protein;
• (b) a frequency score based on the frequency of the variant in a population;
• (c) a co-occurrence score based on how the variant co-occurs with a reference variant having known clinical significance relating to a clinical disease or condition;
• (d) a family segregation score based on how the variant segregates with a disease or condition in a family;
• and
• (e) optionally, a minor evidence score based on information from at least one functional impact prediction algorithm, whether the variant occurs within a critical protein domain, whether the variant would alter a post-translational modification, whether other known pathogenic variants occur within the same codon, and whether the variant is known to occur in at least one patient of a disease or condition;
• aggregating, on a computer, the function score, the frequency score, the co-occurrence score, the family segregation score, and optionally the minor evidence score to generate a clinical significance score indicating the clinical significance of the genetic variant,
• wherein the aggregation comprises summing up the function score, the frequency score, the co-occurrence score, the family segregation score, and optionally the minor evidence score with pre-determined weights or
• wherein the aggregation comprises taking the function score, the frequency score, the co-occurrence score, the family segregation score, and optionally the minor evidence score as inputs in a decision tree, each leaf of the decision tree comprising a value for the clinical significance score;
• and
• determining that the generated clinical significance score for the variant is above a threshold;
• and
• wherein an individual identified as having the variant or an immediate blood relative of the individual identified as having the variant is tested for a condition associated with the biological function of the cell or protein, responsive to the determination that the generated clinical significance score for the variant is above the threshold.