Terminology for function changes

[DanielPuthawala]

Discussion of the functionVariant mockup in the contraint model discussion here (and reposted below for convenience) prompted a discussion on the terminology and nomenclature we should recommend for use in relation to function variants. We are discussing the functionConsequence part of the functionConstraint.

The problem is that we the ways in which function variants are described are often very similar to the ways that CNVs are described, for example, a Copy Number Gain variant could also be described as a Gain-of-Function variant. Likewise, a Copy Number Loss (in the case of a complete gene deletion) could also be described as a Complete Loss of Function. But this term similarity can lead to several problems, that we would like to avoid.

First, it masks the distinction between copy number variation and function variation, which are describing independent properties of the variant which sometimes do correlate, but can also independently vary. For example, good old BRAF V600E is a missense variant that is not a copy-number variant, but does cause in a change in protein function, resulting in its status as a Gain-of-Function variant.

Second is the human corollary Murphy's law, illustrated by the HGVS "Dup" problem . If there is an obvious way that the nomenclature can be misunderstood and thus misused, people will.

So the question is, what should we call the categorical types of function change? For reference, the current version of categoricalCNV has the following:

A representation of the change in copies of a sequence in a system. MUST be one of "efo:0030069" (complete genomic loss), "efo:0020073" (high-level loss), "efo:0030068" (low-level loss), "efo:0030067" (loss), "efo:0030064" (regional base ploidy), "efo:0030070" (gain), "efo:0030071" (low-level gain), "efo:0030072" (high-level gain).