Mitochondrial disease confirmed!

[Learner1]

I have 2 MT-ND5 that have 0.0% frequency.

12,706. T>C
12,851 G>A

How do I know if there's any significance?

 

[wigglethemouse]

How do I know if there's any significance?

@Learner1 I usually just use Google and follow the links in the official databases. Perhaps go through this thread and read @BeautifulDay posts about places to search.

12706
https://www.ncbi.nlm.nih.gov/clinvar/RCV000010338/
Leigh disease associated with a novel mitochondrial DNA ND5 mutation.
https://www.ncbi.nlm.nih.gov/pubmed/11938446

 

[nandixon]

I had the following MT-ND5 mutations in my 23andMe data which seemed to be real.
12,501 G>A
13,780 A>G
https://forums.phoenixrising.me/threads/mitochondrial-disease-confirmed.57697/post-959044

12501 is rs28397767
https://www.ncbi.nlm.nih.gov/snp/rs28397767
This is a synonymous variant but:

For a long time synonymous single nucleotide polymorphisms were considered as silent mutations. However, nowadays it is well known that they can affect protein conformation and function, leading to altered disease susceptibilities, differential prognosis and/or drug responses, among other clinically relevant genetic traits. This occurs through different mechanisms: by disrupting the splicing signals of precursor mRNAs, affecting regulatory binding-sites of transcription factors and miRNAs, or by modifying the secondary structure of mRNAs.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5347174/

13780 is rs41358152
https://www.ncbi.nlm.nih.gov/snp/rs41358152
This is a missense variant, so more likely to be pathogenic. (But has to be considered a false positive till proven by more careful mtDNA testing. )

 

[wigglethemouse]

Thanks @nandixon! It was my understanding too that proteomics was required to see the effect that variation had on that person.

 

[Learner1]

Thanks @wigglethemouse and @nandixon

I don't have LHON, Leigh, or any known muro disease. However, I do have a bunch of rare mutations on MT-ATP6, MT-CO1, MT-CYB, MT-ND3, MT-ND4, and MT-ND5, along with NDUFS4, NDUFA6, NDUFB1, ATP5S, ATP5G1, ATP5G2, ATP5H, ABCA12, COX15, COQ9, ATFA, and UQCRC2.

Wondering if I was born with all of these or if there have been epigenetic changes due to Cipro, carboplatin, paclitaxel, arsenic, etc. I've had very high 8OHdG in the past, but it is normal now. Being on the robust mito nutrient protocol I've been on for the past 3 years has been greatly helped me.

And, I'm wondering if others around here have similar groupings of these as Light seemed to have found.

Also, loss of immune function has been found to be a feature of mito diseases, which was the case for me, along with chronic infections.

 

[Learner1]

Thanks @nandixon! It was my understanding too that proteomics was required to see the effect that variation had on that person.

How does one get a proteomics test?

 

[nandixon]

I have 2 MT-ND5 that have 0.0% frequency.

12,706. T>C
12,851 G>A

How do I know if there's any significance?

I have 12706 (rs267606893) as well (see: https://forums.phoenixrising.me/threads/mitochondrial-disease-confirmed.57697/page-5#post-2202148)

So this is telling us it's likely a false positive for both of us (due to, e.g, an interfering nuclear DNA fragment with the same subsequence).

Your 12851 may now actually be 12850 (I think) which is rs28705385.
https://www.ncbi.nlm.nih.gov/snp/rs28705385
This is a missense variation.

 

[wigglethemouse]

Your 12851 may now actually be 12850 (I think) which is rs28705385.

@Learner1 may I suggest purchasing @BeautifulDay book - it has some tips on looking up MT variants. And if I remember right it describes why some locations are offset by 1 in some reports. Thread here
https://forums.phoenixrising.me/thr...-free-wednesday-and-thursday-on-amazon.62359/

 

[nandixon]

Thanks @nandixon! It was my understanding too that proteomics was required to see the effect that variation had on that person.

It would just need to be a more carefully done mitochondrial genomic analysis as the first step to make sure that variation is even really present for you.

 

[nandixon]

@wigglethemouse, For example, Knight Diagnostic Laboratories offers this:
https://www.ncbi.nlm.nih.gov/gtr/tests/552176/

 

[wigglethemouse]

@wigglethemouse, For example, Knight Diagnostic Laboratories offers this:
https://www.ncbi.nlm.nih.gov/gtr/tests/552176/

Interesting thanks. I couldn't find test number 1910 on their website https://knightdxlabs.ohsu.edu/

If it was as simple as identifying a mtDNA variation it would be worth it. I was told that almost 1000 genes affect mitochondrial function and that you need to evaluate upstream and downstream pathways. Mitochondria have been a living organism for so long that there may be many compensating mechanisms by cells or other organisms in the body.

I also read some papers on neuromuscular disorders which said that it may not just be the affect of one gene mutation, it may be several in combination, and I think @BeautifulDay also touched on this in her book in relation to mtDNA, as did Alan Light in his presentation last year with the interesting observations that ME/CFS folks have more combined mtDNA mutations + Immune gene mutations than healthy controls.

Way to complicated for me I think without the assistance of a mito expert who are extremely rare it seems.

 

[nandixon]

Interesting thanks. I couldn't find test number 1910 on their website https://knightdxlabs.ohsu.edu/

I don't see 1910 (the Comprehensive Mitochondrial panel) listed either, just genetic testing for some individual mitochondrial diseases (MELAS, etc). Maybe they stopped offering it, or it's a special request thing.

 

[nandixon]

For anyone who has used Dante Labs I'd like to know if you're also seeing the MT-ND5 12706 T>C (rs267606893) SNP coming up in your results. This seems likely to be a miscall.

I used Veritas Genetics, which was a big mistake - AVOID USING THEM - because they won't provide the FASTQ file, which is essentially your raw genetic data. The FASTQ file is important to have so that not only can you update your results to the latest human genome reference standard (e.g., GRCh37/hg19 to GRCh38) whenever you want but you can also check the data for quality issues. I went with them to get my results sooner but now Dante is offering a 90-day turnaround guarantee.

 

[nandixon]

@Learner1, I'm assuming the T>C result you gave for MT-ND5 12706 (rs267606893) is from GeneDX... What does 23andMe have for you for this SNP? You may find it under i5007072:
https://you.23andme.com/tools/data/?query=i5007072&filter_by_platforms=true

And what is your 23andMe for rs2854122:
https://you.23andme.com/tools/data/?query=rs2854122&filter_by_platforms=true

It looks like several years ago that 23andMe was testing for rs2854122 at position 12705 under a prior reference system. That SNP was then merged into rs267606893 at position 12706 under the new reference system.

23andMe has me being "C" for rs2854122 (I was tested several years ago), yet they are imputing me as being T (i.e., normal) for rs267606893 (aka i5007072). This makes me think they realized they made a false positive call for rs2854122 and later changed it to normal for purposes of imputing rs267606893.

Thanks!

 

[Learner1]

@Learner1, I'm assuming the T>C result you gave for MT-ND5 12706 (rs267606893) is from GeneDX...

That's correct.

What does 23andMe have for you for this SNP? You may find it under i5007072:
https://you.23andme.com/tools/data/?query=i5007072&filter_by_platforms=true

No genes or markers found matching "i5007072".

And what is your 23andMe for rs2854122:
https://you.23andme.com/tools/data/?query=rs2854122&filter_by_platforms=true

C

It looks like several years ago that 23andMe was testing for rs2854122 at position 12705 under a prior reference system. That SNP was then merged into rs267606893 at position 12706 under the new reference system.

23andMe has me being "C" for rs2854122 (I was tested several years ago), yet they are imputing me as being T (i.e., normal) for rs267606893 (aka i5007072). This makes me think they realized they made a false positive call for rs2854122 and later changed it to normal for purposes of imputing rs267606893.

Thanks!

It can't find rs267606893 either.

My 23andme was done in 2010-2011, perhaps?

 

[nandixon]

@Learner1, I'm on 23andMe's chip version V3, which they started using in November 2010. I wonder if you might be on v2.

It can't find rs267606893 directly for me either, but it does find it when I use i5007072 (23andMe's internal reference number).

So I had to rethink things after finding that they don't give a rs267606893 (i5007072) for you. I'm guessing now that 23andMe did actually test me for rs267606893 but it was originally at MT-ND5 position 12707 and moved to 12706 under the new reference system. (And I was also tested for rs2854122 which was originally at position 12706 and moved to 12705, and ultimately merged with rs267606893.)

So 23andMe is saying I have the normal (T) nucleotide base at 12706 versus Veritas is saying I have the pathogenic variant (C) there. And I think normal is probably correct given that the 12706 variant apparently has a high penetrance (rate of disease expression) and seems quite lethal.

 

[tornerose]

Did you have any follow-up testing done for that one?

I'm showing up in the whole genome sequencing (WGS) results I recently received as having the variant in the neighboring SNP:

MT-ND4 11252 A>G rs879229170
(note that position 11253 is rs200145866)

That’s interesting!

I did a new test with Dante Labs. After 9 months they finally uploaded my file today. However, the data on mitochondrial DNA are missing (even though I ordered the mito panel in addition to WGS). So I don’t know if the mutation persists. I’ll let you know when/if I get the data.

 

[Dan_USAAZ]

I'm not sure if this provides any clarity. Possibly just confirms what you ( @Learner1 & @nandixon ) are interpreting in your earlier tests. My 23andMe was run about 18 months ago and lists both rs2854122 and rs267606893.

When I try to search dbSNP for rs2854122 it indicates that they have been merged.

Not sure why they are still listed in 23andMe as having different genomic positions and different genotypes for me.

 

[Learner1]

Novel missense/nonsense SNPs on MT-ND4 on GeneDX, not 23andme:

 

[wigglethemouse]

@Learner1 When I see an Allele frequency of 0.00% I get suspicious - especially when there are 4 different locations.