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GeneBe

MTHFR

methylenetetrahydrofolate reductase

Basic information

Region (hg38): 1:11785722-11806455

Links

ENSG00000177000NCBI:4524OMIM:607093HGNC:7436Uniprot:P42898AlphaFoldGenCCjaxSfariGnomADPubmedClinVar

Phenotypes

GenCC

Source: genCC

  • homocystinuria due to methylene tetrahydrofolate reductase deficiency (Definitive), mode of inheritance: AR
  • homocystinuria due to methylene tetrahydrofolate reductase deficiency (Supportive), mode of inheritance: AR
  • homocystinuria due to methylene tetrahydrofolate reductase deficiency (Definitive), mode of inheritance: AR
  • homocystinuria due to methylene tetrahydrofolate reductase deficiency (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

ConditionInheritanceIntervention CategoriesIntervention/Rationale Manifestation CategoriesReferences
Homocystinuria due to MTHFR deficiencyARBiochemical; Cardiovascular; HematologicMedical therapy (eg, with folate, betaine, riboflavin, hydroxycobalamin) can be effective; In individuals with heterozygous variants, there may be an increased risk of thrombophilia, and considerations may be warranted in certain situationsBiochemical; Cardiovascular; Hematologic; Neurologic3889647; 1998339; 1866027; 1627352; 8456826; 7920641; 7647779; 7726158; 7564788; 8691945; 8826441; 8892013; 8940272; 8994411; 9133512; 9341863; 9244205; 9372726; 9068801; 9878639; 10323741; 10384377; 10536004; 10679944; 10862840; 10923034; 10961793; 11508552; 11170082; 11274424; 11938441; 12142069; 12673793; 15896655; 15979034; 16145688; 16216822; 17409006; 18658082; 18708589; 19697151; 20236116; 20356773; 20850942; 22578003; 22646290; 22665071; 22721898; 22773907; 22807619; 22856671; 22947400; 23124942
Variants in MTHFR may interact with variants in other genes, such as F5 to result in susceptibility to hematologic manifestations

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MTHFR gene.

  • Homocystinuria due to methylene tetrahydrofolate reductase deficiency (609 variants)
  • not provided (121 variants)
  • Neural tube defects, folate-sensitive (92 variants)
  • Inborn genetic diseases (48 variants)
  • not specified (21 variants)
  • Schizophrenia;Homocystinuria due to methylene tetrahydrofolate reductase deficiency;Neural tube defects, folate-sensitive;Thrombophilia due to thrombin defect (5 variants)
  • See cases (4 variants)
  • Neural tube defects, folate-sensitive;Thrombophilia due to thrombin defect;Homocystinuria due to methylene tetrahydrofolate reductase deficiency;Schizophrenia (4 variants)
  • Intellectual disability (3 variants)
  • MTHFR THERMOLABILE POLYMORPHISM (2 variants)
  • Gastrointestinal stromal tumor (2 variants)
  • Neural tube defects, folate-sensitive;Schizophrenia;Homocystinuria due to methylene tetrahydrofolate reductase deficiency;Thrombophilia due to thrombin defect (2 variants)
  • MTHFR-related condition (2 variants)
  • Thrombophilia due to thrombin defect (2 variants)
  • Neural tube defects, folate-sensitive;Schizophrenia;Thrombophilia due to thrombin defect;Homocystinuria due to methylene tetrahydrofolate reductase deficiency (2 variants)
  • Neoplasm of stomach (1 variants)
  • Schizophrenia (1 variants)
  • Neural tube defect (1 variants)
  • methotrexate response - Toxicity (1 variants)
  • Mental deterioration;Delayed speech and language development;Lower limb spasticity;Bilateral tonic-clonic seizure;Global developmental delay (1 variants)
  • Homocystinuria due to methylene tetrahydrofolate reductase deficiency;Schizophrenia;Thrombophilia due to thrombin defect;Neural tube defects, folate-sensitive (1 variants)
  • Rare genetic intellectual disability (1 variants)
  • Stroke disorder (1 variants)
  • Schizophrenia;Homocystinuria due to methylene tetrahydrofolate reductase deficiency;Thrombophilia due to thrombin defect;Neural tube defects, folate-sensitive (1 variants)
  • Thrombophilia due to thrombin defect;Neural tube defects, folate-sensitive;Schizophrenia;Homocystinuria due to methylene tetrahydrofolate reductase deficiency (1 variants)
  • Abnormality of metabolism/homeostasis (1 variants)
  • Thrombophilia due to thrombin defect;Schizophrenia;Neural tube defects, folate-sensitive;Homocystinuria due to methylene tetrahydrofolate reductase deficiency (1 variants)
  • Mendelian syndromes with cleft lip/palate (1 variants)
  • Schizophrenia, susceptibility to (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MTHFR gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type Pathogenic Likely pathogenic VUS Likely benign Benign Sum
synonymous
1
clinvar
237
clinvar
6
clinvar
244
missense
6
clinvar
23
clinvar
136
clinvar
8
clinvar
3
clinvar
176
nonsense
17
clinvar
13
clinvar
30
start loss
2
clinvar
1
clinvar
3
frameshift
19
clinvar
17
clinvar
36
inframe indel
2
clinvar
7
clinvar
9
splice donor/acceptor (+/-2bp)
6
clinvar
17
clinvar
23
splice region
?
0
non coding
?
1
clinvar
44
clinvar
70
clinvar
27
clinvar
142
Total 51 74 187 315 36

Highest pathogenic variant AF is 0.0000328

Variants in MTHFR

This is a list of pathogenic ClinVar variants found in the MTHFR region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position Type Phenotype Significance ClinVar
1-11786035-G-GT Neural tube defects, folate-sensitive Benign (Jun 14, 2016)292153
1-11786191-A-G Neural tube defects, folate-sensitive Uncertain significance (Jun 14, 2016)292157
1-11786602-ATTTT-A Neural tube defects, folate-sensitive Likely benign (Jun 14, 2016)292164
1-11786602-ATTTTTTTT-A Neural tube defects, folate-sensitive Uncertain significance (Jun 14, 2016)292165
1-11786602-A-ATT Neural tube defects, folate-sensitive Uncertain significance (Jun 14, 2016)292166
1-11786618-TTTTG-T Neural tube defects, folate-sensitive Uncertain significance (Jun 14, 2016)292167
1-11788023-G-A Homocystinuria due to methylene tetrahydrofolate reductase deficiency Uncertain significance (Jun 11, 2018)292189
1-11788203-CCTT-C Neural tube defects, folate-sensitive Uncertain significance (Jun 14, 2016)292196
1-11788224-C-T Neural tube defects, folate-sensitive Uncertain significance (Jun 14, 2016)292197
1-11789149-G-A Neural tube defects, folate-sensitive Uncertain significance (Jun 14, 2016)292205
1-11789662-T-C Neural tube defects, folate-sensitive Uncertain significance (Jun 14, 2016)292212
1-11789977-CA-C Neural tube defects, folate-sensitive Uncertain significance (Jun 14, 2016)292218
1-11790308-T-G Homocystinuria due to methylene tetrahydrofolate reductase deficiency Benign (Jan 22, 2024)292223
1-11790307-G-GGGTA Neural tube defects, folate-sensitive Uncertain significance (Jun 14, 2016)292222
1-11790310-T-TAAG Neural tube defects, folate-sensitive Uncertain significance (Jun 14, 2016)292224
1-11790505-CA-C Neural tube defects, folate-sensitive Uncertain significance (Jun 14, 2016)292225
1-11790562-G-C Likely benign (Aug 01, 2022)2638240
1-11790639-G-A Likely benign (Feb 01, 2023)2638241
1-11790673-C-T Uncertain significance (Jul 29, 2014)194070
1-11790681-C-G Intellectual disability • Homocystinuria due to methylene tetrahydrofolate reductase deficiency • Neural tube defects, folate-sensitive Conflicting classifications of pathogenicity (Oct 30, 2023)975602
1-11790681-C-T Homocystinuria due to methylene tetrahydrofolate reductase deficiency Likely benign (Aug 28, 2021)1540182
1-11790682-A-G Homocystinuria due to methylene tetrahydrofolate reductase deficiency Pathogenic (-)187906
1-11790683-T-C Homocystinuria due to methylene tetrahydrofolate reductase deficiency Likely benign (Mar 13, 2022)1087028
1-11790692-C-T not specified • Homocystinuria due to methylene tetrahydrofolate reductase deficiency • Inborn genetic diseases • Schizophrenia;Homocystinuria due to methylene tetrahydrofolate reductase deficiency;Neural tube defects, folate-sensitive;Thrombophilia due to thrombin defect Benign/Likely benign (Sep 01, 2023)498489
1-11790693-G-A not specified • Homocystinuria due to methylene tetrahydrofolate reductase deficiency Benign (Nov 02, 2022)281891

GnomAD

Source: gnomAD

GeneTypeBio TypeTranscript Coding Exons Length
MTHFRprotein_codingprotein_codingENST00000376592 1121198
pLI Probability
LOF Intolerant
pRec Probability
LOF Recessive
Individuals with
no LOFs
Individuals with
Homozygous LOFs
Individuals with
Heterozygous LOFs
Defined p
3.21e-100.9131256990491257480.000195
Z-Score Observed Expected Observed/Expected Mutation Rate Total Possible in Transcript
Missense0.8963423920.8730.00002514306
Missense in Polyphen124156.370.7931746
Synonymous-1.371821601.140.00001061283
Loss of Function1.902031.50.6340.00000167338

LoF frequencies by population

EthnicitySum of pLOFs p
African & African-American0.0001480.000148
Ashkenazi Jewish0.000.00
East Asian0.0003260.000326
Finnish0.00004620.0000462
European (Non-Finnish)0.0002740.000264
Middle Eastern0.0003260.000326
South Asian0.0002610.000261
Other0.000.00

dbNSFP

Source: dbNSFP

Function
FUNCTION: Catalyzes the conversion of 5,10- methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co- substrate for homocysteine remethylation to methionine. {ECO:0000269|PubMed:25736335}.;
Disease
DISEASE: Methylenetetrahydrofolate reductase deficiency (MTHFRD) [MIM:236250]: Autosomal recessive disorder with a wide range of features including homocysteinuria, homocysteinemia [MIM:603174], developmental delay, severe mental retardation, perinatal death, psychiatric disturbances, and later-onset neurodegenerative disorders. {ECO:0000269|PubMed:10679944, ECO:0000269|PubMed:20236116, ECO:0000269|PubMed:25736335, ECO:0000269|PubMed:25818041, ECO:0000269|PubMed:7726158, ECO:0000269|PubMed:8940272, ECO:0000269|PubMed:9781030}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Ischemic stroke (ISCHSTR) [MIM:601367]: A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. Ischemic strokes, resulting from vascular occlusion, is considered to be a highly complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors. {ECO:0000269|PubMed:15534175}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Neural tube defects, folate-sensitive (NTDFS) [MIM:601634]: The most common NTDs are open spina bifida (myelomeningocele) and anencephaly. {ECO:0000269|PubMed:10323741, ECO:0000269|PubMed:7564788, ECO:0000269|PubMed:8826441}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Schizophrenia (SCZD) [MIM:181500]: A complex, multifactorial psychotic disorder or group of disorders characterized by disturbances in the form and content of thought (e.g. delusions, hallucinations), in mood (e.g. inappropriate affect), in sense of self and relationship to the external world (e.g. loss of ego boundaries, withdrawal), and in behavior (e.g bizarre or apparently purposeless behavior). Although it affects emotions, it is distinguished from mood disorders in which such disturbances are primary. Similarly, there may be mild impairment of cognitive function, and it is distinguished from the dementias in which disturbed cognitive function is considered primary. Some patients manifest schizophrenic as well as bipolar disorder symptoms and are often given the diagnosis of schizoaffective disorder. {ECO:0000269|PubMed:15729744, ECO:0000269|PubMed:18583979}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;
Pathway
Fluoropyrimidine Pathway, Pharmacodynamics;Antimetabolite Pathway - Folate Cycle, Pharmacodynamics;One carbon pool by folate - Homo sapiens (human);Methotrexate Pathway (Cancer Cell), Pharmacodynamics;Thiopurine Pathway, Pharmacokinetics/Pharmacodynamics;S-Adenosylhomocysteine (SAH) Hydrolase Deficiency;Methionine Metabolism;Folate malabsorption, hereditary;Methionine Adenosyltransferase Deficiency;Glycine N-methyltransferase Deficiency;Methylenetetrahydrofolate Reductase Deficiency (MTHFRD);Hypermethioninemia;Methylenetetrahydrofolate Reductase Deficiency (MTHFRD);Methotrexate Action Pathway;Folate Metabolism;Homocystinuria-megaloblastic anemia due to defect in cobalamin metabolism, cblG complementation type;Cystathionine Beta-Synthase Deficiency;Glycine Metabolism;Selenium Micronutrient Network;Vitamin B12 Metabolism;Folate-Alcohol and Cancer Pathway Hypotheses;Fluoropyrimidine Activity;Folate Metabolism;One carbon donor;One Carbon Metabolism;Trans-sulfuration and one carbon metabolism;One carbon metabolism and related pathways;Ethanol effects on histone modifications;Folate metabolism;Metabolism;folate transformations I;Metabolism of folate and pterines;Metabolism of water-soluble vitamins and cofactors;Metabolism of vitamins and cofactors (Consensus)

Recessive Scores

pRec
0.909

Intolerance Scores

loftool
0.210
rvis_EVS
0.09
rvis_percentile_EVS
60.71

Haploinsufficiency Scores

pHI
0.131
hipred
N
hipred_score
0.379
ghis
0.548

Essentials

essential_gene_CRISPR
N
essential_gene_CRISPR2
N
essential_gene_gene_trap
N
gene_indispensability_pred
E
gene_indispensability_score
1.00

Gene Damage Prediction

AllRecessiveDominant
MendelianHighMediumMedium
Primary ImmunodeficiencyHighHighHigh
CancerHighHighHigh

Mouse Genome Informatics

Gene name
Mthfr
Phenotype
liver/biliary system phenotype; reproductive system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); vision/eye phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); limbs/digits/tail phenotype; skeleton phenotype; homeostasis/metabolism phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype;

Gene ontology

Biological process
response to hypoxia;neural tube closure;cellular amino acid metabolic process;methionine metabolic process;one-carbon metabolic process;blood circulation;methionine biosynthetic process;regulation of histone methylation;response to vitamin B2;tetrahydrofolate interconversion;response to amino acid;S-adenosylmethionine metabolic process;folic acid metabolic process;homocysteine metabolic process;response to folic acid;oxidation-reduction process;response to interleukin-1;heterochromatin maintenance
Cellular component
cytosol;synapse
Molecular function
methylenetetrahydrofolate reductase (NAD(P)H) activity;protein-containing complex binding;flavin adenine dinucleotide binding;NADP binding;FAD binding;modified amino acid binding