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Please provide input on my symptoms and how to handle...

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rs1004467 I am AG, so whatever, I'm a half-mutant. Ancestral allele T, Reference alleles C/T. The variant viewer says T>C So maybe 23andMe is looking at the opposite strand?
Yup. Just above the map there's "Assembly" then "SNP to Chrom" which says "Rev". If you hover "Rev" it clarifies that it's using the reverse orientation instead of the forward orientation. So their C and T are really G and A when on the forward orientation, which is what 23andMe uses.

When I look at dbSNP, it shows a red box on the graph in the swim-lane labeled "Association" and there's an association to blood pressure. I look at the article and see that they are talking about a fairly common mutation asociated with a rare hypertension. So, assuming opposite strand, then the G would be the mutation, and the risk allele.

You're good until you assume which allele is the risk one. Only the paper can tell you that for sure. If you look at table 4 it lists both alleles, with one labeled as "coded" and the other as "other". Then in the next column it clarifies that it's looking at the "coded" allele (A) when it lists its frequency. And the beta coefficient is positive, thus A results in higher systolic blood pressure, which is what is associated with that gene (mildly) malfunctioning.
To the right of the first rs#, I see a purple box and note the location is the same as that listed for i5001480. So, that's my second SNP. I note it is rs104894150, and I am AA. I see in the Gene Model(s) that the mutation is T to A, and the residue change is Y to N, the mutation is Y201N. I don't even need to use the variant viewer here. It's labeled missense, but looking in the referenced publications, it looks to be associated with infertility in menstruating women,even though it's a fairly mild reduction in gene activity. And I'm homozygous for the mutation.
Okay, you did great until assuming A is the "mutation". The gene is having its alleles reported in reverse, so the mutation is actually A to T, meaning you have the normal version. Figuring this out is quite tricky when the two alleles for the SNP are equivalent to each other when on reverse strands. So it can help to look at another missense mutation on the same gene where the alleles aren't "A and T" or "C and G".

If we look at a nearby missense mutation on the same gene, such as is at location 104,595,073 (i5001477, rs104894154) we can see that on the missense line it shows G->A when it should be C->T to get the mutation. Thus we know that in a reversed SNP, the alleles are reported in reverse for the missense information, hence what looks like T to A is really A to T.

Hence with AA reported by 23andMe, you have YY ([tyr]osine) version. Then if go to the variation viewer and look at the OMIM entry ( http://omim.org/entry/609300#0027 ), we can find out what's going on. The "T to A" bit doesn't help, because we don't know the orientation. But they clarify that it results in a Y to N mutation in the enzyme, hence N is the risk factor. Looking back at the original SNP page, we see that the N amino acid equates with the A allele, but the allele is reversed, hence it's the T allele from 23andMe results which result in the pathogenic N amino acid in the enzyme.

You know, I did gene this because I'm having post-menopausal adrenal steriod hormone issues - not making, not metabolizing what's supplemented, and I'm talking about it so you can check out my methods, but geez! if it keeps going at this rate, I'm going to get really discouraged about getting my adrenals healthy again.:eek:
There's really no indication of a problem here. You have the normal version of the 2nd SNP, and have a very common heterozygous version of the 1st SNP, which doesn't even have a big impact when it's homozygous.
 

Critterina

Senior Member
Messages
1,238
Location
Arizona, USA
You're good until you assume which allele is the risk one....Okay, you did great until assuming A is the "mutation".

This is like when you get your test back and learn more from your mistakes than all the lectures and homework problems combined. Thank you! :hug: I'm going to have to try the next few and have you check me out again.

There's really no indication of a problem here. You have the normal version of the 2nd SNP, and have a very common heterozygous version of the 1st SNP, which doesn't even have a big impact when it's homozygous.
That's a big relief! I have normal cholesterol, good HDL/LDL ratios, and am taking plenty of minerals (Bluebonnet chelated multiminerals with boron), but everything from pregnenelone to cortisol and DHEA to estrogens were undetectable, below normal, or in the bottom of the range. Then with low doses of progesterone, DHEA, estradiol, estrone, and testosterone, I went to over 100% (some over 400%) of everything except DHEA, which didn't move...I was looking for a genetic basis - not hoping to find it, but just wanting to know what I'm up against. I should probably post this on a hormone forum and see what feedback I get.