MTHFR

methylenetetrahydrofolate reductase

Basic information

Region (hg38): 1:11785723-11806455

Links

ENSG00000177000 ∙ NCBI:4524 ∙ OMIM:607093 ∙ HGNC:7436 ∙ Uniprot:P42898 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Transcripts

Transcript IDs starting with ENST are treated as Ensembl, all others as RefSeq. Showing 4 of 31.

Transcript ID	Protein ID	Coding exons	MANE Select	MANE Plus Clinical
NM_005957.5	NP_005948.3	11	yes	-
ENST00000376590.9	ENSP00000365775.3	11	yes	-
NM_001330358.2	NP_001317287.1	12	-	-
NM_001410750.1	NP_001397679.1	12	-	-

Phenotypes

GenCC

Source: genCC

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

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Homocystinuria due to MTHFR deficiency	AR	Biochemical; Cardiovascular; Hematologic	Medical 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 situations	Biochemical; Cardiovascular; Hematologic; Neurologic	3889647; 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 (810 variants)
• not_provided (114 variants)
• Neural_tube_defects,_folate-sensitive (112 variants)
• Inborn_genetic_diseases (99 variants)
• Thrombophilia_due_to_thrombin_defect (41 variants)
• Schizophrenia (38 variants)
• not_specified (34 variants)
• MTHFR-related_disorder (33 variants)
• Intellectual_disability (4 variants)
• See_cases (4 variants)
• Bilateral_tonic-clonic_seizure (2 variants)
• Mendelian_syndromes_with_cleft_lip/palate (2 variants)
• Global_developmental_delay (2 variants)
• Secondary_microcephaly (1 variants)
• Infantile_spasms (1 variants)
• Neural_tube_defect (1 variants)
• Delayed_speech_and_language_development (1 variants)
• Abnormality_of_metabolism/homeostasis (1 variants)
• Prostate_cancer (1 variants)
• Rare_genetic_intellectual_disability (1 variants)
• Generalized_cerebral_atrophy/hypoplasia (1 variants)
• Mental_deterioration (1 variants)
• Vascular_dementia (1 variants)
• Spasticity (1 variants)
• Autism (1 variants)
• Lower_limb_spasticity (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. These statistics are base on transcript: NM_005957.5. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous	1	4	5	289	2	301
missense	12	51	212	23	3	301
nonsense	19	29	1			49
start loss	2	2				4
frameshift	27	35	1			63
splice donor/acceptor (+/-2bp)	8	23	2			33
Total	69	144	221	312	5

Highest pathogenic variant AF is 0.0005057931

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MTHFR	protein_coding	protein_coding	ENST00000376592	11	21198

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
		125699	0	49	125748	0.000195

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.896	342	392	0.873	0.0000251	4306
Missense in Polyphen		124	156.37	0.793		1746
Synonymous	-1.37	182	160	1.14	0.0000106	1283
Loss of Function	1.90	20	31.5	0.634	0.00000167	338

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000148	0.000148
Ashkenazi Jewish	0.00	0.00
East Asian	0.000326	0.000326
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.000274	0.000264
Middle Eastern	0.000326	0.000326
South Asian	0.000261	0.000261
Other	0.00	0.00

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

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

	All	Recessive	Dominant
Mendelian	High	Medium	Medium
Primary Immunodeficiency	High	High	High
Cancer	High	High	High

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