Controversial mutations

What “sets us apart” from the other Fabry patients?

Various mutations in the alpha-galactosidase A gene (GLA gene) are thought to be the cause of Fabry disease. So far over 1000 different mutations are known.

Fabry disease is a multi-system disease that can affect a variety of organs in the body. There is no connection between a mutation and the effects on the disease or specific symptoms. Many of these mutations only occur within a family, which is why they are also called private.

There are some mutations that are common in the population. Within these mutations, the full range of phenotypes has been observed. Everything has been described, from the so-called classic type to the late onset with involvement of only one organ to the symptom-free man. There is therefore a wide range of variants within a mutation, from symptom-free to severely affected. Two of these common mutations are:

  • D313Y (laboratory designations: c.937G>T    or    p.D313Y    or    p.Asp313Tyr)
  • A143T (laboratory designations:  c.427G>A   or    p.A143T   or    p.Ala143Thr)

The clinical relevance of these mutations is controversial. Recently, various institutes have switched to classifying certain mutations that were previously classified as pathogenic or of unclear significance as neutral and no longer report the corresponding findings/sequencing results to the submitting doctor at all. Patient and doctor are no longer informed about the genetic defect.

Therefore, always observe the information on genetic testing!

Classification of mutations

There are five classifications of pathogenicity of mutations:

  • pathogenic
  • likely pathogenic
  • uncertain significance
  • likely benign
  • benign

In the literature, a distinction is also made between:

  • classic Fabry
  • late-onset Fabry

In our experience, however, many so-called late-onset variants often have early symptoms (already in childhood), which were usually not taken seriously at the time. I.e. this designation is incorrect.


And that’s where we come in, D313Y and A143T are increasingly excluded from diagnosis and therapy. We would like to draw attention to the fact that we exist and to ensure that no one is excluded from diagnosis and therapy.

All mutations known to us that are currently being questioned:

These mutations are currently under discussion and are already being ruled out in many new studies, so that no new insights can be gained.

DNAProtein (short)Protein (long)
c.159C>A
c.159C>G
p.N53Kp.Asn53Lys
c.196G>Cp.E66Qp.Glu66Gln
c.352C>Tp.R118Cp.Arg118Cys
c.353G>Ap.R118Hp.Arg118His
c.376A>Gp.S126Gp.Ser126Gly
c.427G>Ap.A143Tp.Ala143Thr
c.454T>Cp.Y152Hp.Tyr152His
c.685T>Gp.F229Vp.Phe229Val
c.870G>C
c.870G>A
p.M290Ip.Met290Ile
c.937G>Tp.D313Yp.Asp313Tyr
c.989A>Gp.Q330Rp.Gln330Arg
c.1067G>Ap.R356Qp.Arg356Gln
c.1102G>Ap.A368Tp.Ala368Thr
c.335G>Ap.R112Hp.Arg112His

We ourselves are seriously ill with one of these mutations. We have significant impairments and a long ordeal behind us. Some of us are still receiving therapy and are seeing significant improvements. But we know patients who already have kidney failure or have had a heart attack and are still not receiving therapy.

We all have a long doctor’s odyssey behind us and were infinitely relieved to finally have a diagnosis, even if the disease cannot be cured. However, since it is treatable, we wish that access to therapy for the supposedly non-disease-causing mutations would not be excluded.

Due to the discussion about which mutations cause illness and which do not, we carried out a literature search for scientific publications and studies. Here are our results of the scientific discussion.