C677T Mutations – What You Need To Know

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.

C677T Nomenclature

  • 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.)
C677T51 – 73%
C677TT22 – 32%
A1298C60 – 92%
A1298CC52 – 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.

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.

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Who Should Care About MTHFR Mutation?

On the internets, it seems like everyone cares about MTHFR right now, but honestly, it isn’t necessarily important for everyone. Not even for everyone with a known mutation.

Just having a polymorphism is not a cause for panic. Having an MTHFR mutation, even one that is considered significant will never have any symptoms, signs, or health risks from the polymorphism. Just having the gene doesn’t mean anything at all in terms of supplements you should take, things you should do, or really anything else. In fact, over supplementing can be as harmful to your health as under supplementing.

This girl thinks you should care about MTHFR mutations.

Two Main Factors Make MTHFR Matter

  1. Your circumstances
  2. Your symptoms

Let’s review what MTHFR might do, and then we’ll talk more about circumstances and symptoms.

Possible Health Consequences of the MTHFR mutations

MTHFR mutations have been implicated in at least one research study in:

  • Midline Abnormalities: neural tube defects, anencephaly, spina bifida, cleft palate, cleft lip, and facial asymmetries.
  • Cancer: including breast, lung, brain, stomach, head and neck, and kidney.
  • Cardiac disease: including thrombosis (increased tendency to clot), deep vein thrombosis, high homocysteine levels, pre-eclampsia (high blood pressure in and around pregnancy), vascular dementia.
  • Fertility issues: including miscarriages or multiple pregnancy loss, low sperm count, history of children with birth defects.
  • Neurological issues: including migraines, autism, Alzheimer’s dementia.
  • Mood and Psychological issues: including anxiety, depression, obsessive-compulsive traits or tendencies, bipolar disorder, and schizophrenia. Also, reduced reactions to certain medications like SSRIs for depression, and increased tendency toward addictions.
  • Abnormal Reactions to Medications and Therapies – including methotrexate, FOLFOX (a combination chemotherapeutic agent), SSRI medications for depression, some vitamins including folic acid, methyl-B12, betaine, and others.

When Should You Be Concerned?

This is simple. These are the circumstances that matter:

  • Fertility and Pregnancy – if you suspect you or your partner might have an MTHFR issue and you’re considering having a baby, it matters to know so you can get your health right before you build a baby.
  • Treatments for Depression and Anxiety aren’t Working – this is a strong indicator that there is something underlying the issue that isn’t being addressed, and none of the medications out there manage MTHFR issues.
  • You Have a Strong Family History of Early Cardiac Death – it might not be related to MTHFR, but if it is then knowing your MTHFR status gives you something you can work on, instead of waiting for the ax to fall.
  • You Have Three Known Bad Copies of MTHFR – this is three compromised copies of significant MTHFR SNPs (C677T and A1298C) out of four.

Who Should Care about MTHFR Polymorphisms?

These are the symptoms that matter. If you or your genetically related family members have more than three of the following, then your life might get better by addressing your methylation, whether you know about your MTHFR or not.

  • Anxiety
  • Overachieving tendencies
  • Perfectionism
  • Obsessive thoughts
  • Insomnia
  • Cleft lip or cleft palate
  • Spina bifida
  • Abnormal or unexplained clotting
  • Bad reaction to birth control pills
  • Alcohol intolerance
  • Schizophrenia
  • Bipolar disorder
  • Repeat miscarriages
  • Unexplained low sperm count
  • Alzheimer’s dementia
  • Addictions
  • High homocysteine levels
  • Food or chemical sensitivities
  • Intense competitive drive
  • Serum folic acid tests is abnormally high or abnormally low
  • “New car smell” gives you a headache or other symptoms.
  • Taking B vitamins sometimes makes you feel depressed

Who Should Not Be Worried About MTHFR Polymorphisms?

  1. People who know they have no bad copies.
  2. People who know they have one bad copy but have no related symptoms or family histories.
  3. People who don’t know their genetic profile who also don’t have related symptoms or family histories.

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Health Problems Linked to MTHFR mutations

Mutation Sounds So Serious and Certain – Can I Change This?

I use the term “mutations” or “mutant” mostly because I like them. MUTANT sounds so very X-men and god knows I’m a sci-fi geek. Technically, the correct term is “polymorphisms,” which is less dramatic and doesn’t imply eyeball laser beams. Polymorphisms are simply small differences – one letter substitutions – in a gene. SNP (Single Nucleotide Polymorphisms, pronounced “snip”) are part of the wonderful and astounding variability of human genetics.

SNPs or single nucleotide polymorphisms are essentially a letter substitution in your genetic story. Like the difference between “Tom is tall” and “Tom is fall”. This is why there are health problems associated with MTHFR mutations.

According to the National Institute of Health, SNPs occur in our DNA almost once per 1,000 nucleotides. Since we have over 3 billion nucleotides (or base pairs) in the human genome, this means the average person has somewhere in the neighborhood of 4-5 million SNPs. That’s a LOT of “mutations.”

The vast majority of SNPs don’t have any impact at all, but as we discussed here, some do. I am, of course, referring to the magic chair that is the MTHFR enzyme.

Health Problems Are Linked to some MTHFR SNPs Because They Change the “Magic Chair.”

If you have no idea what I’m talking about, check out last week’s post here. The basic idea is that the MTHFR polymorphisms C677T and A1298C are actually consequential because they change the shape, and therefore the function, of the MTHFR enzyme in one of the most important chemical pathways in our body, the methylation pathway.

MTHFR mutations that matter are A1298C and C677T

Quick and Dirty List of Health Problems Linked to MTHFR

These health issues have been linked to MTHFR in at least one high-quality study (a great database of relevant studies is here for C677T and here for A1298C):

  • Midline Abnormalities: neural tube defects, anencephaly, spina bifida, cleft palate, cleft lip, tongue-tie, facial asymmetries.
  • Cancer: including breast, lung, brain, stomach, head and neck, thyroid, bladder, leukemia, and kidney.
  • Cardiac disease: including thrombosis (increased tendency to clot), deep vein thrombosis, high homocysteine levels, pre-eclampsia (high blood pressure in and around pregnancy), vascular dementia, glaucoma, heart murmurs, stroke, pulmonary embolism.
  • Fertility issues: including miscarriages or multiple pregnancy loss, placental abruption, low sperm count, history of children with birth defects.
  • Neurological issues: including migraines, autism, ADD/ADHD, Parkinson’s disease, Alzheimer’s dementia.
  • Mood and Psychological issues: including anxiety, depression, obsessive-compulsive traits or tendencies, bipolar disorder, and schizophrenia. Also, reduced reactions to certain medications like SSRIs for depression, and increased tendency toward addictions.
  • Miscellaneous Conditions: including chronic fatigue, fibromyalgia, and numerous autoimmune disorders.

Symptoms That Could Be Linked to MTHFR

Outside of the slightly scary list of diagnosable illnesses and health problems linked to MTHFR, there are also a number of symptoms that are highly associated, but don’t really warrant a diagnosis (at least not until they reach an unmanageable level). These include:

  • Brain fog
  • Irritability
  • Obsessiveness
  • Workaholism
  • Sleep Issues
  • PMS
  • Difficult menopause
  • Food sensitivities
  • Chemical sensitivities
  • High levels of seasonal allergies
  • Attention issues
  • Anger and aggression
  • Gallbladder sludge and stones
  • Heart racing
  • Depression
  • Edginess
  • Headaches or migraines
  • Moodiness
  • Joint and muscle aches
  • Itching skin
  • Obesity or easy weight gain
  • Carb and sugar cravings
  • Sweating
  • Feeling “not right”
  • Addictive tendencies

Does Having MTHFR Mutations Mean I Have These Issues?

Nope. Just like having these issues doesn’t mean you have an MTHFR mutation.

So… What Does It Mean?

It means if you have any of these issues (which, honestly, most people do have at least one), then managing your MTHFR and methylation cycle in a proactive way can help you feel better, reduce your symptoms, reduce sensitivities, and hopefully prevent MTHFR-related disease in the long-term.

What IS This Witchcraft?

It’s called “epigenetics” and it is a field that has emerged in the last couple of decades as we learned how many genes really are actionable. Epigenetics is the study of the way diet, lifestyle, nutritional status, drug use, chemical exposure, self-care, and external factors influence the expression of your genes.

This video explains epigenenetics and also gives a bonus introduction to why the methylation pathway is so important to gene expression (do you see all those methyl groups?!?)

Help! I’m Drowning in MTHFR Doom!!

It can feel a little bit overwhelming – especially if you’re like me and can listen to the giant list of symptoms and find more than five that match up with issues you have in your own life. The good news is that YOU CAN TAKE CONTROL. You hav e the power, thanks to epigenetics, to change your state of health and the severity of these symptoms. Also, here’s some great news:

MTHFR Superpower – Speed and Strength!

It’s no eyeball laser beams, but it’s a start. It has been suggested that DNA undermethylation in MTHFR folks induces muscle growth. A recent study of Russian and Polish athletes found an athletic advantage in sprint-strength type activities for the A1298C polymorphs. Mutants, Unite!

Next week we’ll talk about MTHFR testing options, what the results actually mean. and who should test? Subscribe, so you don’t miss any episodes and pass it on to your grumpy, obsessive, workaholic friends because maybe they’re mutants too…

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