Variants of uncertain significance

Variants of uncertain significance


Fabry disease is caused by alterations in the gene GLA. To date, more than 1,000 different of these variants are known. Some of these variants have already been discussed by some physicians and scientists in the past as to whether they cause Fabry disease or not. One therefore also speaks of variants of uncertain significance (abbreviated: VUS). Significance here means clinical significance, i.e. the variant leads to clinically detectable, physical changes in the carrier of this variant.

In recent years, many of the variants that were originally considered uncertain have been classified as benign by physicians, as well as by laboratory physicians. As a result, laboratories have moved to no longer report the presence of these variants in genetic testing for Fabry disease. This means that both the patient and his or her physician are no longer informed that a variant of uncertain significance is present. Patients who are carriers of these variants and clearly have symptoms associated with Fabry disease will be denied therapy. Even more, patients who have already received therapy with ERT or chaperone therapy for years and whose symptoms have improved, in some cases enormously, have been denied therapy again since the beginning of the second quarter of 2023!

We, the Morbus Fabry Selbsthilfegruppe e.V. (German Fabry Patient Association), vehemently disagree with this practice. Neither should patients be deprived of an effective therapy nor of the complete result of a genetic test! Accordingly, we have written a statement on this topic in April 2023 and presented it to the public at the FIN Fabry Expert Meeting 2023 in Amsterdam.

(FIN is the Fabry International Network, the international umbrella organization for Fabry patient organizations worldwide.)

Statement of the MFSH regarding reclassification of GLA variants as “benign” or “neutral” (April 2023)

This is a statement by the Morbus Fabry Selbsthilfegruppe MFSH (German Fabry Patient Association) regarding GLA variants such as D313Y and A143T.

A number of GLA variants, including the above two, have been described by some Fabry specialists as “benign” or “neutral” in scientific publications, and a number of other Fabry-treating physicians adopted this notion and service providers for genetic testing have stopped reporting of these variants.

Our experience with patients shows that these variants appear to be disease-causing at least in a number of individuals. In those patients that are most severely affected, symptoms are neither mild nor late-onset. Descriptions of individual patients reported in peer-reviewed journals confirm that these GLA variants cause, at least in a number of patients, Fabry disease. In addition, the demonstrably altered physico-chemical properties of the mutated enzyme, i.e. the reduced enzymatic activity, impaired pH stability and delayed processing of the precursor protein appear to be in support of a pathogenic impact. Experience shows that chaperone therapy is well suited for the treatment of these patients.

We discourage the use of the narrow diagnostic criteria proposed by Van der Tol et al. Instead, we suggest to consider the broader range of symptoms which were described by Lenders and Brand as “classical manifestations in Fabry disease” and which are in part found in patients with the above mentioned GLA variants. Some GLA variants might lead to a continuum of clinical presentations, as has been suggested for the D313Y variant. Palaiodimou et al. show that the specific criteria defined by Van der Tol et al. 11 are far less common in these patients than neurological manifestations.

The adoption of the notion of a benign impact of certain variants by service providers for genetic testing leads to a situation where physicians suspecting a genetic cause for a patient’s symptoms do not learn that a GLA variant was indeed found. In our opinion, diagnosis of these patients should be performed by physicians with patient contact. Therefore, we suggest that service providers for genetic testing adopt a classification of these variants as “likely pathogenic” based on ACMG criteria PS3, PP2 and PP3. Alternatively, a classification as “established risk allele” or “predisposing” for Fabry disease and stroke is possible.


Statement with citations

Help for affected patients

You have a variant of uncertain significance?

Then please get in touch with us! Write us an email at or call us at 02473 937 6488. This will help us to keep track of therapy rejections. We will also be happy to put you in touch with a group of other affected patients. This group has been dealing with this issue together with us for a long time.

MFSH presentation on the variant D313Y

The position of the German Fabry Patient Association was presented by the President Dr. Berthold Wilden and the General Manager Natascha Sippel at the FIN Fabry Expert Meeting in Amsterdam on April 22, 2023:


Slides MFSH Presentation on D313Y (english version)


Transcript lecture Natascha Sippel:


I would like to explain how we came to be given this speaking time here today:


My Fabry diagnosis came out of the blue in 2018. I ended up in the hospital and was very lucky because my cardiologist had me tested for Fabry disease. In March 2019, I attended the annual meeting of the German Fabry Patient Association and immediately got involved.


At that first meeting, I met a woman my age who, like me, had been on treatment for a year. However, unlike me, she was obviously very ill. Here I heard for the first time that her doctor had said that she did not really have Fabry disease.


At the 10th event I attended, I met a woman whose fate touched me deeply. By now I had heard many patients’ stories. Together we walked back to the train station, but had to stop every 30 steps and take a short break. She explained to me that until recently she had been sitting in a wheelchair most of the time. Her leg pain started when she was four years old. No doctor could figure out what she was suffering from. She struggled through life with many symptoms and medications. Her health deteriorated over the years. Pacemaker at 19, wheelchair at 24, unable to work at 29, diagnosis at 30. After 4 years of therapy, she was able to attend an event without a wheelchair for the first time.


Her son developed the first clear symptoms at the age of 3!


At our meeting the next year, I met both women again. Both women were told that their variant was not a true Fabry disease. I couldn’t believe it and wanted to know more. Are there more patients out there and what do doctors use to justify this attitude? We started a survey among affected patients.


The most common arguments used by doctors:


  • high residual activity of the enzyme
  • no or almost no Gb3 or lyso-Gb3 deposits
  • high allele frequency (high incidence) in the population
  • no diseased males


Conclusion: another disease must be the trigger.


We formed a literature research team to find studies that support that the D313Y variant cannot cause Fabry disease. The team researched for more than 15 months, reading over 60 publications and summarizing all the information! When a statement was found, we went to great lengths to find the source for it!


I met more patients:


A young woman, 20 years old: her joint pain started at age 10. The pain moved from her knee to her hip and on to her shoulder – it was always the big joints. She really enjoyed school, but getting there was hell for her. Especially when climbing stairs, she was in extreme pain. She had to take her exam on a laptop because she was no longer able to write with a pencil for any length of time. At the age of 17, her condition became threatening. She collapsed more frequently, and her fingers turned deep blue or translucent white. After a two-week stay at the clinic to seek a diagnosis, the diagnosis was fibromyalgia.

During this time, her 40-year-old father had a heart biopsy. His heart pain started at the age of 20. The thickening heart was now causing extreme shortness of breath. Although he was treated for 10 years, he did not get better. The heart biopsy revealed three monogenic heart variants that could not cause problems on their own. Above them, the GLA variant D313Y was found. Since there was no therapy for the heart variants, the only treatment left was Fabry therapy. Shortly after starting treatment with the Chaperone therapy, his general condition improved. Today, after several years of treatment, he has fully returned to work.


Do father and daughter have the same disease? Yes, because Fabry is inherited from fathers to daughters. The daughter also got better and better under treatment. Today she studies, lives on the 2nd floor and can take stairs at a run again.


There he was – the male (adult) patient!


During one of my first home visits, I met a patient. She had severe headaches and cardiac arrhythmias. She had lost many of her physical and mental abilities and had difficulty reading and finding words. Her pain began in early childhood. Now she was bedridden and cared for by a nurse and her husband. Today, after 4 years of Chaperone therapy, she has already regained many abilities and her quality of life continues to improve. I and many other people were allowed to witness this development. She is now part of our research team.


Recently, a father called me. His son was sick from birth. At first it was just diarrhea, later vomiting. When he was three years old, he often screamed that his feet stung or burned. They had bad nights where they had to get up to seven times. Diagnosed and started ERT at age 4. The symptoms eased and after several months, the boy was almost symptom-free. Even the doctors felt vindicated. Everyone was happy. After several years, the symptoms suddenly returned. Morning vomiting, diarrhea, burning pain in the feet. A disaster for the parents and the boy. The doctors were unaware of any habituation effect. With the change of the home therapy nurse, the symptoms immediately decreased. How was this to be explained? It wasn’t until weeks later that the parents discovered that the former caregiver had an undiagnosed drinking problem. He lost his apartment and slept in his car. It was summer and the drug was not refrigerated. Complaints to the home therapy company mounted and he was discharged. New nurse, refrigerated medication, no more pain! This inadvertent omission of ERT was the best proof that this therapy was the right one.


Are these patients the absolute exceptions? We have conducted a survey. The results are clear. I cannot believe that a therapy specific to Fabry disease can cure other underlying diseases. It is not malpractice to treat a patient with Fabry therapy who has a mutation in the GLA gene, the Fabry gene. We have to keep in mind that there are not only nephrologic or cardiac variants, but also these neuropathic variants.


For me, as a layman, it is understandable that an analgesic would relieve not only my acute headache but also the pain of my ankle toe injured the day before. It is a mystery to me and I cannot understand why a Fabry-specific therapy would help with another disease.


In our presentation, you can see the summary of our research team in addition to the results of our survey. This shows which hypotheses should be pursued.

Classification of variants

In general, there are five classifications for the pathogenicity (i.e., ability to cause disease) of variants:


  • pathogenic (i.e., capable of causing disease)
  • likely pathogenic
  • uncertain significance
  • likely benign
  • benign
Links on the topic

The following websites deal with the topic in detail:

Fabry disease – A143T und D313Y



There are videos on the subject on YouTube:

Fabry Disease Explained

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