It has taken a while to report back on my results. I have shingles, slowly recovering but not yet back to where I was before it happened.
So far, I've only looked at the 28 SNPs flagged with at least one pathogenic report. Some of these had mixed reports (benign as well as pathogenic). The direct links given for each report of status make it easy to decide how much significance to place on the reports.
None of the SNPs appears to have serious consequences for me.
1) Five of them are homozygous.
a) Of these, two are actually the major allele and really don't mean anything.
i) One is rs1799983, NOS3 (nitric oxide synthase 3): c.894T>G (p.D298E), the same SNP as
@Waverunner reported (do you have the major or minor allele?)
There seems to be considerable confusion about this SNP. dsSNP shows G as the ancestral allele and gives MAF data for T which is consistent with the frequency data reported by Genos (G=78-81%), yet shows the change as Genos reports it - viz T>G, asp>glu.
OMIM and several papers I looked at to try to sort this out report the change as G>T, glu>asp, which makes more sense.
In any case, there is a single report of pathogenicity of the GG allele which is the reason Genos has flagged my result.
Supposedly the allele is associated with hypertension resistant to conventional treatment. No supporting research is provided with the claim.
So my conclusion is IGNORE.
ii) Similarly for rs1494555, IL7R (IL7 receptor): c.412G>A (p.V138I) - slightly different confusion but there is no way the report of compound heterozygous (I have a single copy of the other allele) of this common allele could be really associated with the very serious rare condition of severe combined immunodeficiency - IGNORE.
b) Of the remaining 3 which really are +/+, there are mixed reports of pathogenic and benign and little research outside of the narrow claims for pathogenicity.
i) One, rs4792311, ELAC2 (elaC ribonuclease Z2): c.650C>T (p.S217L); MAF 27%; does seem to have a fairly robust link to prostate cancer susceptibility (the reason for the pathogen classification), but no studies that I could find for other cancer types.
So on the face of it, since I don't have a prostate gland, nothing to be concerned about. The protein is interesting however and I have flagged it in my mind to follow up on.
Actually to me, this is the most interesting SNP of all, though since very little is known about it, my interest is theoretical.
The enzyme is involved in processing of tRNA precursors (in both the nucleus and mitochondrion) and is essential for tRNA biosynthesis and hence for translation of the genetic code into protein synthesis.
Other mutations have shown that the enzyme is essential for mitochondrial protein synthesis (including complex I and IV) and for OXPHOS.
These other mutations show what happens when this enzyme goes seriously wrong. My variant doesn’t appear to have such serious consequences but subtler effects on mitochondrial function have just not been studied.
Maybe it is a variant that doesn’t matter much unless the system is placed under increased demand – such as by this terrible disease.
ii) rs743616, ARSA (arylsulfatase A): c.1178C>G (p.T393S); MAF 43-50%; has been associated with metachromatic leukodystrophy, a lysosomal storage disease affecting metabolism of sphingolipids.
There is no supporting evidence for the pathogenic classification so again it doesn't seem to be of real concern, but again the protein is interesting so I'll follow up on it, particularly given the evidence of disrupted sphingolipid metabolism in ME/CFS.
iii) rs2266782 FMO3 (flavin-containing monooxygenase 3): c.472G>A (p.E158K); MAF 35-44%; has been associated with the relatively benign, though I imagine, unpleasant, condition of trimethylaminuria - leading to fish odour. I don't have this condition but the protein is again interesting, being involved in detox of endogenous and exogenous biogenic amines. I'll keep an eye on it.
2) Most of the 23 SNPs which are +/- fall into the category of tyrosinase, ie, the protein product has a very narrow well defined effect and only causes trouble if +/+. So again IGNORE.
A few however have potentially widespread effects and not much is really known about them, so again I have flagged them in my own mind for follow up. These include
i) rs34719006, ATP8B1 (ATPase, aminophospholipid transporter, class I, type 8B, member 1): c.208G>A (p.D70N) +/+ is linked to hereditary cholestatis, +/- to cholestasis of pregnancy.
The protein transports mitochondrial cardiolipin and maintains the asymmetric distribution of phospholipids in cell membranes which is necessary for function of various transporters; as a result it is thought to influence bile acid transporters, including the farnesoid X receptor (the subject of some interesting recent speculation on PR).
The link of +/- to a pregnancy related condition is of interest to me as it implies that when the system is under increased demand, +/- for this SNP may have consequences.
ii) rs10509305 STOX1 (storkhead box1): c.1824A>C (p.E608D) Pathogenicity is associated with pre-eclampsia. The protein is a transcription factor which seems to regulate the invasiveness of the trophoblast.
Of more general interest is that it regulates the cell cycle through effects on cyclin B and seems to be a genetic switch in ROS/RNS balance.
iii) rs10065172 IRGM (immunity-related GTPase family M) : c.313C>T (p.(=)) The protein is involved in autophagy and the SNP is associated with Crohn’s, so is of interest, but the main reason I flagged it is as an example of how a synonymous codon change might have some consequence. The nucleotide change disrupts binding of miR-196 which is overexpressed in Crohn’s and down regulates IRGM, interfering with autophagy.
So no smoking guns, just a few interesting suspects. I imagine when I work my way through the 87 VUS reports there'll be a few more suspects to add.
Genos makes the report available in a Promethease compatible form so I'll run it through that program sometime and see what it pulls out.
