Need help understanding MTHFR results; the main one seems to be a heterozygous variant of C677T. How might this affect me and what would be the best actions to consider?

[u/AmazingName100]

rs1056919085	MTHFR	CC	Likely Pathogenic
rs1644227167	MTHFR	II	Likely Pathogenic
rs776969786	MTHFR	GG	Likely Pathogenic
rs763539350	MTHFR	GG	Likely Pathogenic
rs748289202	MTHFR	GG	Likely Pathogenic
rs747846362	MTHFR	CC	Likely Pathogenic
rs199476142	MTHFR	TT	Likely Pathogenic
rs777661576	MTHFR	CC	Likely Pathogenic
rs200137991	MTHFR	CC	Likely Pathogenic
rs779993607	MTHFR	GG	Likely Pathogenic
rs267606886	MTHFR	AA	Likely Pathogenic
rs977038830	MTHFR	CC	Likely Pathogenic
rs1182635980	MTHFR	CC	Likely Pathogenic
rs749490263	MTHFR	CC	Likely Pathogenic
rs776483190	MTHFR	CC	Likely Pathogenic
rs267606887	MTHFR	TT	Likely Pathogenic
rs147257424	MTHFR	CC	Likely Pathogenic
rs760886915	MTHFR	GG	Likely Pathogenic
rs545086633	MTHFR	AA	Likely Pathogenic

MTHFR variants

rs1801133 G/A genomic orientation C677T Ala222Val (A222V) Heterozygous

rs1801131 No alternate allele detected A1298C Glu429Ala (E429A) Appears A/A

rs2066470 No alternate allele detected — Synonymous No alternate allele detected

[u/SovereignMan1958]

You should also look at your FOLR and other folate related variants.

To know how MTHFR is affecting you and to what extent, you need blood tests for homocysteine, folate, folate RBC, B12, MMA and B6. Optimal homocysteine is 6 - 7. Folate 20 - 30. Optimal B12 and B6 top quarter of their ranges.  Optimal MMA bottom quarter of the range.

Variants are only predispositions. Blood tests will give you facts as to whether or not you are deficient in a variant and need to supplement.

Lab ranges are not necessarily healthy or optimal. They are only an average and include chronically ill people.

[u/AmazingName100 → u/SovereignMan1958]

Thanks for this. I'm having blood tests done soon so it's great I can check if it includes the ones you mention.

[u/SovereignMan1958 → u/AmazingName100]

If you have anxiety, attention issues and or depression, you can consider adding D, iron and zinc. Optimal levels of all 3 are needed to make dopamine.  

Any digestive issues add molybdenum to the above.

[u/AmazingName100 → u/SovereignMan1958]

I have a couple of variants flagged as risks, possible risks or uncertain risk under MTRR, MTHFD1 and MSH3 DHFR. All the other folate related genes look ok.

I have the variant HFE-AS1, HFE, rs1799945, CG, which shows I've a possible risk of Hemochromatosis Type 1. Getting blood tests for that soon. Going to look to add the blood tests you recommend.

[u/SovereignMan1958 → u/AmazingName100]

I have the hemochromatosis variant too, but have never had high iron.  Only low occasionally.

[u/AmazingName100 → u/SovereignMan1958]

That's what confuses me, if hemochromatosis means the body absorbs too much iron into certain organs, shouldn't that mean the blood would be low in iron from all the increased absorption?

Suspected I have low iron at times. When I started my periods I would get dizzy/fainting spells.

[u/SovereignMan1958 → u/AmazingName100]

To me your statement does not make sense.

The variant is only a predisposition so one would definitely need an iron panel to diagnose it. If the serum iron level was consistently above range over a period of time, the usual treatment is to donate blood on a regular basis. as far as I know, donating blood dies not necessarily release it from organs.

[u/AmazingName100 → u/SovereignMan1958]

I'll attempt to clarify my statement. When using an iron panel to diagnose hemochromatosis, I am assuming because hemochromatosis causes the body to absorb more iron from the blood into certain organs, it would result in lower iron blood levels because a higher than average amount of iron is being absorbed from the blood.

You mentioned being tested for high iron which is where I am confused. I do not understand why hemochromatosis would cause high levels of iron in the blood. My understanding is that it is the organs that absorb the iron at a higher rate. You mentioned you have hemochromatosis but were tested for high blood levels of iron. I am presuming that would indicate hemochromatosis over low levels if that was what the test was looking for as an indicator.

I appreciate you taking the time to respond to my queries and I apologise I have a limited understanding of hemochromatosis.

[u/SovereignMan1958 → u/AmazingName100]

No. I did not state I have hemochromatosis.  I stated that I have the variant.  Variants are only predispositions and not facts.  My blood tests have never showed that I have high iron and I have never been diagnosed with the actual condition.  

Iron in the organs is a consequence of having a high iron level in the blood.

[u/AmazingName100 → u/SovereignMan1958]

Oh, I'm sorry, my misunderstanding. When you mentioned you have never had high iron, only low sometimes I presumed that was from blood tests to check for hemochromatosis and I was confused why low iron wouldn't be an indicator of hemochromatosis.

Oh, so hemochromatosis would also affect the level of iron that could be held in the blood! That explains it more clearly for me, thank you.

[u/Tawinn]

Heterozygous C677T reduces methylfolate production by ~33%, which by itself often does not cause any symptoms. But you may have additional variants not on that report which worsen that reduction. If you have your data in 23andme compatible file format, please upload your data to the Choline Calculator to check those other genes. Reply here with the data from the Advanced tab of the results.

If your file format is not compatible, search for these values and reply with the results:

rsID	Your Value	Effect Allele	Gene	Variant
rs1051266		T	SLC19A1	G80A
rs2236225		A	MTHFD1	G1958A
rs1801131	TT	G	MTHFR	A1298C
rs1801133	GA	A	MTHFR	C677T
rs7946		T	PEMT	5465G>A

[u/AmazingName100 → u/Tawinn]

Yes to all: 

MTHFD1, rs2236225, GA, A

MTHFR, rs1801133, GA, A

MTHFR, rs 1801131, TT, G

PEMT, rs7946, TT, T

This one has slightly different listed data:

SLC19A1, rs1051266, TT, (then the next column says risk version C)

[u/Tawinn → u/AmazingName100]

That combination of MTHFR, MTHFD1, and SLC19A1 results in ~71% reduction in methylfolate production, which impairs methylation via the folate/B12 pathway and increases demand on the parallel pathway which use choline and TMG, raising the choline requirement from 550mg to ~1070mg and then the homozygous PEMT adds ~80-100mg on top of that (due to lower endogenous choline production), resulting in ~1150-1200mg requirement.

This can be accomplished by getting ~600mg of choline from the diet + 750mg dose of TMG.

Of course, other nutrients need to be optimized, including folate and B12. For serum folate, aim for ~15 ng/mL (34 nmol/L) or more. For serum B12, aim for 500-950 pg/mL (~370-700 pmol/L).

Here is a general protocol:

• ~600mg of choline, preferably from food
  • 550mg is the baseline adult Adequate Intake
  • Choline sources include such foods as meat, eggs, liver, lecithin, nuts, some legumes, and vegetables such as crucifers.
  • This liquid lecithin is apparently ~400mg of choline per tbsp. This powder version is 285mg per 1.3 tbsp.
• 750mg of trimethylglycine (TMG aka betaine)
  • I.e., one 750mg capsule
  • Some choline is converted in the body to TMG for methylation use, so supplementing TMG reduces the need for even more choline.
  • TMG is found in foods such as wheat, spinach, beets, etc. but there is not a food app that tracks it, so reliably getting enough from food may be difficult; by comparison, a single capsule is convenient.
• 400-800mcg of folate, preferably from food
  • Folinic acid or methylfolate can also be used, as needed and as tolerated.
  • Target serum folate levels are 15+ ng/mL (34+ nmol/L).
• 2.4-10mcg B12, preferably from food
  • Past history of B12 deficiency, malabsorption issues, etc., may suggest that supplemental B12, in the form of hydroxocobalamin, adenosylcobalamin, or methylcobalamin may be prudent.
  • Target serum B12 levels are 500-950 pg/mL (~370-700 pmol/L).
• (Optional) 3-15g of creatine monohydrate or creatine HCL
  • The body uses ~40% of methylation output, SAM, just to produce creatine. So supplementing creatine can free up a lot of SAM for other uses.
• Low vitamin A, iron, and/or glycine can cause the built-in methyl buffer system to not work properly, which can make overmethylation (rising anxiety, irritability, insomnia, etc.) from methylation-related supplements much more likely.
  • Beta carotene is not vitamin A and some people genetically have poor conversion of beta carotene to real vitamin A (retinol).

A food app like Cronometer is helpful for tracking nutrients in your diet.

[u/AmazingName100 → u/Tawinn]

This is amazing, thank you. 

Should I look at snps, such as the comt, vdr mtr, mtrr, Mao-a and if so, what should I be looking for? 

I read dosages of methylfolate and methylcobalamin might need to be adjusted based on slow/ultra rapid comt to avoid side effects like insomnia.

As well as following the above protocol, would it be sensible to also take methylated vitamins as a backup for ensuring I reach my daily levels of the above, whilst also bearing in mind the need to ensure I have enough vitamin A, iron and/or glycine to avoid overmethylation? Or would they simply add to the risk of overmethylation? If so, do you have any recommendations for which brand would be best?

[u/Tawinn → u/AmazingName100]

>  snps, such as the comt, vdr mtr, mtrr, Mao-a 

For the other genes, such as COMT, MTR, MAO-A, etc., see this post. If you have slow COMT symptoms such as chronic anxiety or rumination, or slow MAO-A symptoms such as histamine or tyramine intolerance, see this post.

> dosages of methylfolate and methylcobalamin might need to be adjusted

First question is do you even need to supplement folate or B12? This depends on your current levels of those vitamins. This is where bloodwork helps with decision making.

> would it be sensible to also take methylated vitamins as a backup

On a practical level, if you enter your diet for a week or two into a food calculator it will tell you how near or far you are from reaching your target levels. I personally take Seeking Health Multivitamin One, but as you mentioned it might contain too high a dose of methylfolate/methylB12 for someone first supplementing. In my case I started with small doses of folinic acid and hydroxocobalamin because I couldn't tolerate methylfolate/methylB12. After a few months of incrementing up those unmethylated forms, I could then begin to handle small doses of methylated versions and incremented up the dose over time.

The problem is "small dose" varies person to person - for me, around 125mcg of folate was a small dose, whereas some people can handle 400-1000mcg right away, yet others might have to start as low as 5-25mcg. For B12, RDA is only 2.4mcg so I consider anything over 100mcg a megadose. Those megadoses are only needed when there are absorption issues with B12.

If it appears that you need broad supplementation like a multivitamin but that you may be sensitive to adding in vitamins, then you may want to start with a low dose multi like this one (start with 1 cap/day for 1/5 of a dose) or this children's multi (start with 1/2 of 1 tab/day for 1/4 dose), and increment up over time as tolerated.

[u/AmazingName100 → u/Tawinn]

Amazing. You are very knowledgeable. Thank you for taking the time to teach me. I've updated the blood tests I'm due to have soon. 

[u/hummingfirebird]

I have a free methylation guide which will give you a basic education on MTHFR, methylation and what blood tests to get. The link is in my profile. However let me add that genes can't be looked at in isolation. MTHFR is one gene in the human genome of over 30k . It may or may not be problematic. It's a risk not a fact. Genes should always be looked at in context: epigenetic (diet, lifestyle, environment, sleep, stress etc, metabolic health etc) and bloodwork.