Who determines whether a genetic variant is pathogenic or not?

There are five classifications regarding the pathogenicity of mutations/variants:

  • pathogenic – causing disease
  • likely pathogenic – probably causing disease
  • uncertain significance
  • likely benign
  • benign

In Germany the Genetic Diagnostics Commission has decided that laboratories should only report pathogenic and likely pathogenic variants in their findings. Variants of unclear significance can be mentioned in the findings. Benign and probably benign variants should no longer be reported.

Since there are a large number of benign variants in genetics, it seems perfectly understandable to filter them out.

But who determines whether a variant is pathogenic or not? And what about the variants where scientists do not agree (=unclear significance)? And who does the classification?

The classification can and must be done by each laboratory/doctor/centre itself. There are ACMG (American College of Medical Genetics) guidelines for this. However, these guidelines are under discussion, e.g. for Fabry itself. They also leave considerable room for interpretation. For example, the D313Y variant is classified by laboratories as “likely benign”. With other studies as a reference, this variant can also be classified as “likely pathogenic” (see e.g. Varsome database).

The literature situation is currently inconclusive; more recent work points to pathogenic factors. Nevertheless, some variants (such as the D313Y or A143T) have been reclassified as benign by some laboratories/centres and are now not even reported.

So, on the one hand, the stipulation of the Genetic Engineering Commission and the decision of doctors and laboratories is incomprehensible, because this actively keeps patients away from diagnosis and therapy. On the other hand, it also impairs research or even prevents it altogether.

We continue to fight for the controversial mutations, but the fight is severely and systematically hindered.