In addition, the aberrant promoter hypermethylation of this gene is associated with male infertility and recurrent spontaneous abortion.

While multiple published studies have drawn relationships between these SNPs and a wide variety of diseases, the American College of Medical Genetics has issued an official Practice Guideline recommending against testing or reporting on these two variants, citing "Recent meta-analyses have disproven an association between hyperhomocysteinemia and risk for coronary heart disease and between MTHFR polymorphism status and risk for venous thromboembolism.

The 677T allele (leading to a valine substitution at amino acid 222) encodes a thermolabile alternative enzyme variant with reduced activity.

[19] The degree of enzyme thermolability (assessed as residual activity after heat inactivation) is much greater in 677TT individuals (18–22%) compared with 677CT (56%) and 677CC (66–67%).

[22] Low folate status with the consequent loss of FAD enhances the thermolability of the enzyme, thus providing an explanation for the normalised homocysteine and DNA methylation levels in folate-replete 677TT individuals.

[28] The C677T genotype used to be associated with increased risk of recurrent pregnancy loss (RPL) in non Caucasians,[29] however this link has been disproved in recent years.

[citation needed] The American College of Medical Genetics recommendation guidelines currently state that people with recurrent pregnancy loss should not be tested for variants in the MTHFR gene.

One study of an elderly Japanese population[30] found correlations between the MTHFR 677CT mutation, an Apo E polymorphism, and certain types of senile dementia.

Other research has found that individuals with folate-related mutations can still have a functional deficiency even when blood levels of folate are within the normal range,[31] and recommended supplementation of methyltetrahydrofolate to potentially prevent and treat dementia (along with depression).

[33] The CDC provides a web page with information on the "MTHFR Gene, Folic Acid, and Preventing Neural Tube Defects".

In studies of human recombinant MTHFR, the protein encoded by 1298C cannot be distinguished from 1298A in terms of activity, thermolability, FAD release, or the protective effect of 5-methyl-THF.

[34] MTHFR A1298C may play a role as either a driver in the development of major depressive disorder or as a predictive or diagnostic marker, possibly in combination with C677T.

[36] Severe MTHFR deficiency is rare (about 50 cases worldwide) and caused by mutations resulting in 0–20% residual enzyme activity.

Given the unique genetic and environmental characters of the Uyghur population, these findings may be helpful for exploring the pathogenesis of this complex disease.

Furthermore, this improper epigenetic phenomenon was observed in semen samples of infertile males belonging to couples with a history of recurrent spontaneous abortion.

[42] The promotion of supplements and other treatments for MTHFR polymorphisms, especially centered on autistic spectrum disorder,[43] have been characterised as snake oil.