How accurate are Promethease interpretations of test results? Result marked as “highly pathogenic”

[Kyla]

So, first off, I know that genetic tests are usually risk factors and not diagnostic.

But I have one result in my report that is not marked as risk factor, but instead as “highly pathogenic”. Since it is for an often fatal reaction to anaesthetics I would like to know more specifically what this means. Hoping someone more knowledgable than me in genetics can help me out.

I attempted to do a bit of research, and it seems that:

- the condition - “malignant hyperthermia” is indeed genetic
- The mutation I have does appear to be legitimately very rare
- The condition CAN be diagnosed by genetic tests.

BUT The research is largely over my head, and I am unclear as to whether the genetic result I had is the same test / would be sufficient for diagnosis. basically would like to clarify in case I am ever in the position of needing to know whether or not I can safely be given one of these anaesthetics.

To make things more confusing, my mother had a life-threatening reaction to one of the anaesthetics on this list, but she was told it was a DIFFERENT genetic condition (pseudocholinesterase deficiency), though I am not sure they did any genetic testing specifically (she is not 100% sure how they determined what caused the reaction, just that they “did tests” after her incident - judging by how quickly they got results I don’t think they were genetic tests).
It would seem to be astronomical odds to have two different extremely rare genetic reactions to the same anaesthetic in one family, but what do I know


Here is the Promethease interpretation:


rs200563280(C;T)
malignant hyperthermia Associated with malignant hyperthermia based on
rs200563280, aka p.Arg2241X or p.R2241X, is a SNP in the RYR1 gene deemed highly pathogenic for malignant hyperthermia.

from dbSNP:
http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=rs200563280#locus

and here is a link to this SNP on "clinvar" :
(note that there is one "conflicting" study but it appears to be for a different disease):

http://www.ncbi.nlm.nih.gov/clinvar/variation/159856/

TIA for any help.

 

[ahmo]

I've been using Promethease, can't answer as to it's accuracy. There's a new option for $10, from the Selfhacked guy. I've just done it, haven't yet gone over it. https://www.decodify.me/

 

[Jonathan Edwards]

I suggest you get a proper medical opinion on that, Kyla.

 

[Valentijn]

@Kyla - It looks like their reporting of that SNP is accurate. Heterozygous mutations on that gene can cause a lot of problems, though it sounds like the same mutation can result in mild or more severe symptoms.

OMIM is a great place to find all of the research on specific genes and specific mutations. Your mutation is at http://www.omim.org/entry/180901#0039 though only discussed in a homozygous context. Malignant hyperthermia, resulting from heterozygous mutations, is discussed at http://www.omim.org/entry/145600 but doesn't include specific reference to your mutation.

Central Core Disease is also caused by heterozygous mutations on that gene, and includes malignant hyperthermia. According to wikipedia, there's been an increase in the onset in adults (versus more typical onset shortly after birth): https://en.wikipedia.org/wiki/Central_core_disease

 

[GreyOwl]

There's a new option for $10, from the Selfhacked guy. I've just done it, haven't yet gone over it. https://www.decodify.me/

I just bought this and was not impressed. Notable SNPs according to selfhacked relate to serotonin receptor polymorphisms and how they are associated with increased somatisation in FM, whereas promethease thought it would be more useful for me to know about being BuChE atypical, and having only 30% of CYP2D6.

 

[Kyla]

I suggest you get a proper medical opinion on that, Kyla.

Thanks @Jonathan Edwards

I will ask my doctor, was just trying to get a sense of whether that interpretation was likely to be correct or whether I would get laughed out of my Doctor's office for suggesting it.

 

[Kyla]

@Kyla - It looks like their reporting of that SNP is accurate. Heterozygous mutations on that gene can cause a lot of problems, though it sounds like the same mutation can result in mild or more severe symptoms.

OMIM is a great place to find all of the research on specific genes and specific mutations. Your mutation is at http://www.omim.org/entry/180901#0039 though only discussed in a homozygous context. Malignant hyperthermia, resulting from heterozygous mutations, is discussed at http://www.omim.org/entry/145600 but doesn't include specific reference to your mutation.

Central Core Disease is also caused by heterozygous mutations on that gene, and includes malignant hyperthermia. According to wikipedia, there's been an increase in the onset in adults (versus more typical onset shortly after birth): https://en.wikipedia.org/wiki/Central_core_disease

Thanks @Valentijn
when I was looking through I saw that snp seems to be related to something called multi-minicore, which I think is related / similar to central core. It didn't seem to be a good fit for ME symptoms other than muscle weakness and exercise intolerance, but I'll take a bit more of a look.

 

[alicec]

There appears to have been conflicting claims about the pathogenicity of this SNP but by following some of the links you gave I found a recent fairly exhaustive study which has re-examined and reclassified the many SNPs that have been associated with the condition - see here.

To summarise and I quote

"We categorized p.Arg2241X as class 5, since it was described in affected patients and of the category of variants (nonsense) strongly predictive of an autosomal recessive RYR1-related myopathy."

Class 5 is their highest for pathogenicity. Note also X in the name of the SNP refers to a termination codon so the SNP makes a truncated protein - a nonsense variant.

Note also they are talking about an autosomal recessive mutation but yours is heterozygous.

As a final quote about this SNP they say in Discussion

"we identified the class 5 variant, p.Arg2241X, which has been associated with phenotypes inherited in a recessive pattern, but recent publications have questioned the pathogenicity of this variant15,24-26,28. The risk of MHS in most recessive myopathies is uncertain, and has only been proven for central core disease31. This example shows that even when one can identify pathogenic variants, it can be challenging to associate them unequivocally with specific phenotypes."

They still seem most concerned about the homozygous SNP but there is every reason for you to raise this with your doctor and be taken seriously.

 

[Kyla]

There appears to have been conflicting claims about the pathogenicity of this SNP but by following some of the links you gave I found a recent fairly exhaustive study which has re-examined and reclassified the many SNPs that have been associated with the condition - see here.

To summarise and I quote

"We categorized p.Arg2241X as class 5, since it was described in affected patients and of the category of variants (nonsense) strongly predictive of an autosomal recessive RYR1-related myopathy."

Class 5 is their highest for pathogenicity. Note also X in the name of the SNP refers to a termination codon so the SNP makes a truncated protein - a nonsense variant.

Note also they are talking about an autosomal recessive mutation but yours is heterozygous.

As a final quote about this SNP they say in Discussion

"we identified the class 5 variant, p.Arg2241X, which has been associated with phenotypes inherited in a recessive pattern, but recent publications have questioned the pathogenicity of this variant15,24-26,28. The risk of MHS in most recessive myopathies is uncertain, and has only been proven for central core disease31. This example shows that even when one can identify pathogenic variants, it can be challenging to associate them unequivocally with specific phenotypes."

They still seem most concerned about the homozygous SNP but there is every reason for you to raise this with your doctor and be taken seriously.

@alicec thanks for taking the time to read up on it.
they seem to be looking at the homozygous gene in relation to myopathy (multi minicore / central core) and the bottom paragraph is stating that it isn't related to MHS in the homozygous/recessive form - unlike the heterozygous form (which is associated with MH but not myopathy)
So I think this one actually still is consistent.

Still not looking forward to telling my doctor an Internet interpretation of a direct-to-consumer test has told me I might have this

 

[alicec]

Still not looking forward to telling my doctor an Internet interpretation of a direct-to-consumer test has told me I might have this

Print out a few papers about the SNP as back up. The one I linked is exhaustive and places it in the highest category.

 

[Kati]

It would be safe to carry a medic alert card and make mention to your physician. Perhaps your physician can send you for tests to confirm your private genetic test, so it is 'kosher' by their standards.

With the history of your mother, anesthesiologist would be sure to take note of that should you require surgery.

 

[merylg]

I confirmed some third party findings on my 23andMe raw data by consulting a Clinical Geneticist. He had a high regard for 23andMe. Just needed to sight my raw data from 23andMe & do a bit of follow-up. Some things were confirmed & significance elaborated. Some things were put in doubt as to their significance. Others no time to pursue.

 

[Valentijn]

Class 5 is their highest for pathogenicity. Note also X in the name of the SNP refers to a termination codon so the SNP makes a truncated protein - a nonsense variant.

And it's being cut off approximately halfway through the gene, so that's a huge part of it missing.

Note also they are talking about an autosomal recessive mutation but yours is heterozygous.

My understanding from brief skimming last night is that being homozygous for the pathogenic mutations on that gene often results in a severe or fatal condition apparent at birth. Whereas a heterozygous pathogenic mutation usually leaves the person functional enough to only be symptomatic when the wrong anesthesia is administered.

Though based on the summary OMIM notes on some of the mutations, people who are heterozygous for the same mutation (such as mother and daughter) might result in one being mildly affected and the other being more severely affected. It sounded like there is sometimes only the bad version of the gene protein being produced in muscle cells of heterozygous people, but other times both the good and bad versions are produced.

Alternatively, the researchers might have missed another heterozygous mutation on the gene for the more severe heterozygous cases, which would result in compound heterozygous status and function approximately the same as being homozygous.