In the current state of medical research, studies don’t often differentiate between C677T mutations and A1298C mutations so lots of the research applies to both – lumping MTHFR polymorphisms into one category, and “wild-type” genes (the research term for “normal”) into another. Still, we are starting to get a few more specific pieces of information. Let’s go over the technical details first.
- 677 is the marker for this particular MTHFR gene.
- The official genetics labeling of this gene is Rs1801133.
- The C…T stand for the nucleotide bases you actually have. C = cytosine, T = thymine. Essentially C677T means At location 677 there is typically a cytosine (C) but there is actually thymine (T).
- The “wild-type” or typical form of this gene is C677C.
- You have two possible copies – one from each parent.
- Two wild-type copies = typical genetics. No polymorphism. (C677C)
- One wild-type and one altered (bad) copy = heterozygous. (C677T)
- Two altered (bad) copies = homozygous. (this is sometimes just written as C677T and sometimes as 677TT. Occasionally I see T677T, but that tends to be confusing.)
- The C677T polymorphism results in an amino acid substitution in the final protein of the MTHFR enzyme. This is an ala222-to-val (A222V) substitution. This means in the MTHFR enzyme that the gene manufactures, there is supposed to be an alanine, but instead, we see a valine.
- This substitution happens in the part of the enzyme that is presumed to be the catalytic region.
So… What Does That Mean?
We can sum it up pretty simply.
T;T individuals (homozygous) have about 30% of the expected activity of the enzyme. This means ~ 60% compromise.
C;T folks (heterozygous) have about 65% of the expected activity of the enzyme. Meaning ~28% compromise.
It is really important to notice that both of these groups have some enzyme activity – this copy of the MTHFR enzyme is still working, it’s just got a lower capacity because the enzyme “magic chair” is lumpy. If you have no idea what I’m talking about, follow the link to see the simplest possible description of what enzymes do.
Is This Mutation Worse Than Other Mutations?
Honestly, the biggest difference that we know of between the C677T and the A1298C mutation is just the level of enzyme compromise. Because this particular polymorphism is associated with a bigger compromise, more research has been done on this polymorphism. The research does indicate that this mutation has more serious effects, but logically that is likely due to the level of compromise.
What that means is that independent of the degree to which it slows down the enzyme, there isn’t really any difference between C677T and A1298C that we know of. Of course, more research might reveal something, but at this time the degree of compromise in the enzyme activity seems to be the strongest determinant of how much you are affected.
But Amy – That Isn’t What The Internets Say!
I know. I have seen every kind of article claiming that A1298C mutations have more tendency towards neurotransmitter imbalance than C677T, Also, that C677T mutations are more likely to lead to high homocysteine. But as far as I can tell, this started with someone making some kind of conclusion, and then the rest of the internet echoing that same conclusion back to them without bothering to actually do the research.
As far as all of the research I have seen, the thing that matters is how compromised your MTHFR enzyme is, in combination with how much folate you’re getting. As more research is completed this idea might be refined, revised, or even overturned completely, but for now, this is it.
Of course, someone might have a compelling argument why I’m wrong and honestly, I would love to hear it, and even more, I”d love to see the research!
Just for convenience, here is a table with levels of compromise.
|Mutation||% Enzyme Activity|
(Presented as a range because different studies find different values.)
|C677T||51 – 73%|
|C677TT||22 – 32%|
|A1298C||60 – 92%|
|A1298CC||52 – 60%|
|Compound heterozygous.||~36 – 60%|
It’s kind of fascinating, actually, that we speak with such conviction about things like level of compromise, when in reality there are very few studies, and those studies don’t actually agree with each other. The three that were used for the above ranges are linked below, just in case you’re curious. You will note that the difference between a 36% activity and a 60% activity is almost a factor of two, and yet between two different studies, the range was that broad. So obviously, the research has a long way to go.
- The effect of 677C—>T and 1298A—>C mutations on plasma homocysteine and 5,10-methylenetetrahydrofolate reductase activity in healthy subjects
- A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects?
- A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity.
To Clarify – There Probably Are Differences Between C677T and A1298C – We Just Don’t Understand Them Yet.
Because we’re in the early phase of research, the bulk of studies look at wild-type genes vs. polymorphisms as a group and then sometimes pull out smaller data like homozygous vs. heterozygous and detail things like that. Once we’ve built up a more complete body of research, then the smaller questions will start to be explored. I strongly suspect that we will find differences in the challenges faced by both groups and I also suspect that they won’t be nearly so cut and dry as “this group has homocysteine challenges where the other group has a hard time making neurotransmitters.” My suspicion is more along the lines of differences in response to therapeutic interventions and treatments.
Clinically, The Overmethylation vs. Undermethylation Distinction Is Far More Useful Than The Particular Mutation.
The basic state differences actually tell us likely responses to supplements, while the particular mutation does no such thing so clinically it is far more relevant than the particular genetic issue. The one thing that knowing your genetics does tell us, is the actual level of compromise, which can be important (but can also usually be extrapolated from symptoms).
This is part of why I don’t think genetic testing is necessary for all people who suspect they have an MTHFR issue. At the end of the day, the symptoms that you experience are far more telling than the actual polymorphisms.
MTHFR is a common genetic mutation that can contribute to anxiety, depression, fatigue, chronic pain, infertility, and more serious conditions like breast implant illness, heart attack, stroke, chronic fatigue syndrome, and some types of cancer. If you know or suspect you have an MTHFR variant, schedule a free 15-minute meet-and-greet appointment with MTHFR expert Dr. Amy today.Book Your Appointment