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I understand that haploinsufficiency occurs when one of the two copies of a gene is mutated to the point of being unusable, and the single copy remaining is unable to cope with the cell's demands for a given peptide, resulting in a phenotypic deficiency.

In the clinVar database, there is a "haploinsufficiency score" (example here) which seems to range from 0 to 3 (though that is anecdotal only; based on the genes that I've looked at). I assume it refers to how phenotypic or how deficient the cell is. However, I fail to find a place where this is clearly outlined...

Am I correct in this assumption, and if so, what does a score of 3 (for example) represent?

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Okay, I finally found an official source outlining what the dosage sensitivity scores represent.

0 represents no evidence of dosage sensitivity: clinical interpretation is that dosage differences is "likely benign."

1 represents little evidence of dosage sensitivity: This can be marked if only secondary evidence shows dosage sensitivity; clinical interpretation is that dosage sensitivity is "uncertain."

2 represents "Emerging evidence," meaning that the evidence suggests fairly strongly that the gene is dosage sensitive, but that there is insufficient evidence to prove it. The clinical interpretation is that dosage sensitivity is "Uncertain, likely pathogenic."

3 represents "Sufficient evidence," meaning that the evidence is sufficient to prove that the gene is dosage sensitive. Clinical interpretation is "Pathogenic."


Source:

  • Riggs ER et al., Towards an evidence-based process for the clinical interpretation of copy number variation. Clin Genet. 81(5): 403–412.
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