MTRR

Summary

MTRR (5-methyltetrahydrofolate-homocysteine methyltransferase reductase, HGNC:7473) is a protein-coding gene on chromosome 5p15.31, encoding Methionine synthase reductase (Q9UBK8). Key enzyme in methionine and folate homeostasis responsible for the reactivation of methionine synthase (MTR/MS) activity by catalyzing the reductive methylation of MTR-bound cob(II)alamin.

This gene encodes a member of the ferredoxin-NADP(+) reductase (FNR) family of electron transferases. This protein functions in the synthesis of methionine by regenerating methionine synthase to a functional state. Because methionine synthesis requires methyl-group transfer by a folate donor, activity of the encoded enzyme is important for folate metabolism and cellular methylation. Mutations in this gene can cause homocystinuria-megaloblastic anemia, cbl E type. Alternative splicing of this gene results in multiple transcript variants.

Source: NCBI Gene 4552 — RefSeq curated summary.

At a glance

• Gene–disease (curated): methylcobalamin deficiency type cblE (Definitive, ClinGen)
• GWAS associations: 6
• Clinical variants (ClinVar): 1,087 total — 63 pathogenic, 80 likely-pathogenic
• Phenotypes (HPO): 68
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_002454

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7473
Approved symbol	MTRR
Name	5-methyltetrahydrofolate-homocysteine methyltransferase reductase
Location	5p15.31
Locus type	gene with protein product
Status	Approved
Aliases	cblE
Ensembl gene	ENSG00000124275
Ensembl biotype	protein_coding
OMIM	602568
Entrez	4552

Gene structure

Transcript identifiers

Ensembl transcripts: 37 — 18 protein_coding, 8 protein_coding_CDS_not_defined, 7 nonsense_mediated_decay, 4 retained_intron

ENST00000264668, ENST00000440940, ENST00000502509, ENST00000502550, ENST00000503550, ENST00000506115, ENST00000506877, ENST00000507202, ENST00000507414, ENST00000507837, ENST00000508047, ENST00000508101, ENST00000508354, ENST00000508890, ENST00000509379, ENST00000509961, ENST00000510279, ENST00000510525, ENST00000511461, ENST00000511639, ENST00000512217, ENST00000512311, ENST00000513439, ENST00000514220, ENST00000514369, ENST00000869929, ENST00000869930, ENST00000869931, ENST00000869932, ENST00000924322, ENST00000924323, ENST00000924324, ENST00000941608, ENST00000941609, ENST00000941610, ENST00000941611, ENST00000941612

RefSeq mRNA: 5 — MANE Select: NM_002454 NM_001364440, NM_001364441, NM_001364442, NM_002454, NM_024010

CCDS: CCDS47190

Canonical transcript exons

ENST00000440940 — 15 exons

Exon	Start	End
ENSE00003463827	7895734	7895852
ENSE00003466917	7897065	7897247
ENSE00003475818	7886615	7886703
ENSE00003486432	7885701	7885854
ENSE00003494921	7873373	7873526
ENSE00003539742	7896864	7896956
ENSE00003557767	7891372	7891414
ENSE00003564772	7892727	7892913
ENSE00003592227	7870770	7870923
ENSE00003601358	7889095	7889275
ENSE00003620200	7877944	7878322
ENSE00003632016	7869148	7869215
ENSE00003678206	7883155	7883277
ENSE00003684125	7875258	7875375
ENSE00003893868	7899914	7901113

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 96.99.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.0572 / max 325.6449, expressed in 1803 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
55673	18.1556	1801
55676	0.5928	188
55671	0.2830	191
55672	0.0258	10

Top tissues by expression

297 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	96.99	gold quality
pancreatic ductal cell	CL:0002079	95.03	gold quality
choroid plexus epithelium	UBERON:0003911	94.06	gold quality
upper lobe of left lung	UBERON:0008952	93.45	gold quality
biceps brachii	UBERON:0001507	93.30	gold quality
upper lobe of lung	UBERON:0008948	93.26	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	93.04	gold quality
nephron tubule	UBERON:0001231	93.02	gold quality
heart right ventricle	UBERON:0002080	92.83	gold quality
monocyte	CL:0000576	92.17	gold quality
rectum	UBERON:0001052	92.07	gold quality
mononuclear cell	CL:0000842	91.93	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	91.92	gold quality
metanephros cortex	UBERON:0010533	91.85	gold quality
gastrocnemius	UBERON:0001388	91.78	gold quality
hindlimb stylopod muscle	UBERON:0004252	91.77	gold quality
muscle of leg	UBERON:0001383	91.71	gold quality
adrenal tissue	UBERON:0018303	91.69	gold quality
right uterine tube	UBERON:0001302	91.68	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	91.64	gold quality
leukocyte	CL:0000738	91.62	gold quality
right lung	UBERON:0002167	91.61	gold quality
cauda epididymis	UBERON:0004360	91.40	gold quality
visceral pleura	UBERON:0002401	91.39	gold quality
left ovary	UBERON:0002119	91.36	gold quality
skeletal muscle organ	UBERON:0014892	91.32	gold quality
muscle organ	UBERON:0001630	91.31	gold quality
deltoid	UBERON:0001476	91.28	gold quality
corpus callosum	UBERON:0002336	91.26	gold quality
skeletal muscle tissue	UBERON:0001134	91.20	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	19.11

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ETS1, GLI2

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Variants influence the risk of spina bifida via the maternal rather than the embryonic genotype. (PMID:12375236)
• The kinetic and spectroscopic properties of the M22/S175 and I22/S175 and the I22/L175 and I22/S175 pairs of polymorphic variants of MSR have been compared. (PMID:12416982)
• polymorphisms should be regarded as independent risk factors for spina bifida (PMID:12590188)
• results indicate that MTRR and MTR genes may interact to increase the infants’ Neural tube defects risks (PMID:12649067)
• No differences in mean homocysteine, prevalence of hyperhomocysteinemia and significant coronary artery disease between genotypes AA, AG, GG. (PMID:12801615)
• Results of screening mutations 2756A–>G and 66A–>G in MTR and MTRR genes respectively show that are might have an effect on NTDs incidence (neural tube defects). (PMID:12810988)
• Methionine synthase polymorphism is a risk factor for Alzheimer disease. (PMID:12876480)
• polymorphisms in methionine synthase reductase is associated with increased risk for Down syndrome (PMID:12923861)
• Common MSR polymorphisms, I22/L175 and M22/S175, which result in less effective methionine synthase activation, do not have effects on flavin potentials or electron transfer kinetics that would impinge on catalytic efficiency of the variants. (PMID:14967039)
• MTRR polymorhism in the genes for folate and methionine metabolism might play a role in the occurance in patient with ALL and NHL. (PMID:15159311)
• Results describe two common polymorphic variants of ATP:cob(I)alamin adenosyltransferase that are found in normal individuals, and their interactions with methionine synthase reductase. (PMID:15347655)
• findings indicate that when the homozygous variant for the MTHFR 677CT polymorphism coexists with the MTRR 66 AG genotype, plasma homocysteine is significantly elevated relative to the other genotype groups (PMID:15514263)
• Polymorphisms in the folate metabolic pathway were associated with a lower likelihood of Cervical intrepithelial neoplsia. (PMID:15514969)
• SNPs in this enzyme affects homocysteine-regulating genes and may be important determinants of vitamin metabolism in heart transplantation. (PMID:15612980)
• 3 new MTRR mutations (c.7A>T, c.1573C>T, and c.1953-6_1953-2del5) were detected. The identification of mutations in MTRR, & restoration of methionine synthesis following MTRR minigene expression confirms that MTRR gene defects cause cblE homocystinuria. (PMID:15714522)
• Finds MTRR variant AA genotype associated with a significantly decreased squamous cell head and neck cancer risk. (PMID:15894670)
• the MTRR AA genotype acts to increase the micronuclei frequency resulting from cigarette smoking (PMID:16580699)
• we propose that MSR serves as a special chaperone for human methionine synthase and as an aquacobalamin reductase, rather than acting solely in the reductive activation of MS (PMID:16769880)
• we showed the first genetic evidence that MTHFR C677T, MS A2756G and MTRR A66G genotypes were independently associated with male infertility. Each SNP of the three enzymes may have a different impact on the folate cycle during spermatogenesis (PMID:16861746)
• The MTRR polymorphism is a maternal risk factor for spina bifida. (PMID:17024475)
• 66G/524C haplotype of the MTRR gene affect bone turn over rate. (PMID:17079868)
• Data indicate that maternal MTRR 66A>G polymorphism is not a risk factor for congenital heart defects (CHD), but maternal MTRR 66GG genotype with compromised vitamin B(12) status may possibly result in increased CHD risk. (PMID:17087642)
• Distributions for the homozygous mutant form of MTRR were similar between cases and controls, polymorphisim did not increase the risk of placental abruption. (PMID:17376725)
• Since MTR genes are located in 1q43 loci, our findings support the significance of chromosome 1q in etiopathogenesis of bipolar disorder and schizophrenia. (PMID:17417062)
• MTRR 2756A > G polymorphisms interact with elevated total homocysteine levels, leading to an increased risk of ischemic stroke. (PMID:17461517)
• Structure and function of activation and conformational heterogeneity of recombinant proteins. (PMID:17477549)
• The interaction between low levels of serum cobalamin and MTHFR (C677T or A1298C) or MTRR A66G gene polymorphisms was associated with increased tHcy. (PMID:17522601)
• MTRR polymorphism may play an important role in the risk of multiple myeloma. (PMID:17546637)
• These results not only highlight the involvement of the MSR and CBS genes in the etiology of cardiovascular disease, but also emphasize the strength of haplotype analyses in association studies. (PMID:17553479)
• methionine synthase reductase modulates the phenotype of a disease-causing mutation (PMID:17554763)
• Results suggest that the alterations of folate metabolism related to MTHFR, MTR and MTRR polymorphisms are not involved in clefting in South Brazil. (PMID:17581676)
• In our population of methotrexate (MTX)-treated rheumatoid arthritis patients the 2756GG genotype of the methionine synthase reductase gene was more common than expected and was associated with MTX-induced accelerated rheumatoid nodulosis. (PMID:17611986)
• similar frequencies of the MTHFR, the MTRR and the TYMS genotypes were seen in patients and controls (PMID:17655928)
• The risk of having a child with congenital malformation or FACS was three to four times higher for mothers who were MTHFR 677TT homozygotes compared with MTHFR 677CC homozygotes (PMID:17853476)
• Mechanism of coenzyme binding to human MSR revealed through the crystal structure of the FNR-like module and isothermal titration calorimetry. (PMID:17892308)
• MTRR polymorphism is related with disease activity in Crohn’s disease (PMID:17925002)
• no association between prostate cancer and the MTRR A66C polymorphism (PMID:17967524)
• These findings suggest that in obese subjects, homocysteine cycle efficiency is impaired by MTHFR, MTR, and MTRR inability to supply methyl-group donors, providing evidence that MTHFR, MTR, and MTRR gene polymorphisms are genetic risk factors for obesity. (PMID:17993766)
• The MTRR 66GG genotype was found to be associated with 2.74-fold risk (95% CI: 1.73, 4.34) for deep vein thrombosis among South Indians. This risk is increased further to 3.46-fold (95% CI: 1.38, 8.63) in the presence of the MTHFR 677CT/1298AC genotype. (PMID:18034637)
• the MTHFR and MTRR polymorphisms are associated with individual susceptibility to breast cancer among postmenopausal women (PMID:18174236)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mtrr	ENSDARG00000045398
mus_musculus	Mtrr	ENSMUSG00000034617
rattus_norvegicus	Mtrr	ENSRNOG00000017826
drosophila_melanogaster	CG14882	FBGN0038429
caenorhabditis_elegans		WBGENE00006510

Paralogs (5): NOS2 (ENSG00000007171), NOS1 (ENSG00000089250), POR (ENSG00000127948), NOS3 (ENSG00000164867), NDOR1 (ENSG00000188566)

Protein

Protein identifiers

Methionine synthase reductase — Q9UBK8 (reviewed: Q9UBK8)

Alternative names: Aquacobalamin reductase

All UniProt accessions (11): A0A3P9MRF3, D6RAY3, D6RAZ2, D6RF21, D6RGC7, D6RIS8, Q9UBK8, H0Y8S9, H0Y963, H0Y9D5, H0Y9Q0

UniProt curated annotations — full annotation on UniProt →

Function. Key enzyme in methionine and folate homeostasis responsible for the reactivation of methionine synthase (MTR/MS) activity by catalyzing the reductive methylation of MTR-bound cob(II)alamin. Cobalamin (vitamin B12) forms a complex with MTR to serve as an intermediary in methyl transfer reactions that cycles between MTR-bound methylcob(III)alamin and MTR bound-cob(I)alamin forms, and occasional oxidative escape of the cob(I)alamin intermediate during the catalytic cycle leads to the inactive cob(II)alamin species. The processing of cobalamin in the cytosol occurs in a multiprotein complex composed of at least MMACHC, MMADHC, MTRR and MTR which may contribute to shuttle safely and efficiently cobalamin towards MTR in order to produce methionine. Also necessary for the utilization of methyl groups from the folate cycle, thereby affecting transgenerational epigenetic inheritance. Also acts as a molecular chaperone for methionine synthase by stabilizing apoMTR and incorporating methylcob(III)alamin into apoMTR to form the holoenzyme. Also serves as an aquacob(III)alamin reductase by reducing aquacob(III)alamin to cob(II)alamin; this reduction leads to stimulation of the conversion of apoMTR and aquacob(III)alamin to MTR holoenzyme.

Subunit / interactions. Forms a multiprotein complex with MMACHC, MMADHC and MTR.

Subcellular location. Cytoplasm Cytoplasm.

Tissue specificity. Found in all tissues tested, particularly abundant in skeletal muscle.

Disease relevance. Homocystinuria-megaloblastic anemia, cblE type (HMAE) [MIM:236270] An autosomal recessive inborn error of metabolism resulting from defects in the cobalamin-dependent pathway that converts homocysteine to methionine. It causes delayed psychomotor development, megaloblastic anemia, homocystinuria, and hypomethioninemia. Cells from patients with HMAE fail to incorporate methyltetrahydrofolate into methionine in whole cells, but cell extracts show normal methionine synthase activity in the presence of a reducing agent. The disease is caused by variants affecting the gene represented in this entry. Neural tube defects, folate-sensitive (NTDFS) [MIM:601634] The most common NTDs are open spina bifida (myelomeningocele) and anencephaly. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Miscellaneous. It is debated whether the reduction of free aquacob(II)alamin occurs spontaneously or is enzyme catalyzed.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UBK8-2	B	yes
Q9UBK8-1	A

RefSeq proteins (5): NP_001351369, NP_001351370, NP_001351371, NP_002445, NP_076915 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001094	Flavdoxin-like	Domain
IPR001433	OxRdtase_FAD/NAD-bd	Domain
IPR001709	Flavoprot_Pyr_Nucl_cyt_Rdtase	Domain
IPR003097	CysJ-like_FAD-binding	Domain
IPR008254	Flavodoxin/NO_synth	Domain
IPR017927	FAD-bd_FR_type	Domain
IPR017938	Riboflavin_synthase-like_b-brl	Homologous_superfamily
IPR023173	NADPH_Cyt_P450_Rdtase_alpha	Homologous_superfamily
IPR029039	Flavoprotein-like_sf	Homologous_superfamily
IPR039261	FNR_nucleotide-bd	Homologous_superfamily

Pfam: PF00175, PF00258, PF00667

Enzyme classification (BRENDA):

• EC 1.16.1.8 — [methionine synthase] reductase (BRENDA: 3 organisms, 22 substrates, 5 inhibitors, 20 Km, 9 kcat entries)

Substrate kinetics (BRENDA)

6 substrates with measured Km, best-characterized 6. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
NADPH	0.0024–0.015	5
2,6-DICHLOROPHENOLINDOPHENOL	0.0023–0.0038	2
3-ACETYLPYRIDINE ADENINE DINUCLEOTIDE PHOSPHATE	0.0177–0.018	2
DOXORUBICIN	0.0286–0.0366	2
FERRICYANIDE	0.663–0.774	2
MENADIONE	0.0177–0.018	2

Catalyzed reactions (Rhea), 2 shown:

• 2 cob(II)alamin + A + 2 H2O + 2 H(+) = 2 aquacob(III)alamin + AH2 (RHEA:20752)
• 2 methylcob(III)alamin-[methionine synthase] + 2 S-adenosyl-L-homocysteine + NADP(+) + H(+) = 2 cob(II)alamin-[methionine synthase] + 2 S-adenosyl-L-methionine + NADPH (RHEA:23908)

UniProt features (67 total): helix 17, sequence variant 16, strand 15, binding site 8, turn 4, domain 2, modified residue 2, chain 1, splice variant 1, region of interest 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2QTL	X-RAY DIFFRACTION	1.9
2QTZ	X-RAY DIFFRACTION	1.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UBK8-F1	85.79	0.72

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (8): 659; 697; 93–124; 291; 451–454; 487–490; 610–611; 624–626

Post-translational modifications (2): 171, 189

Function

Pathways and Gene Ontology

Reactome pathways

16 pathways

ID	Pathway
R-HSA-156581	Methylation
R-HSA-1614635	Sulfur amino acid metabolism
R-HSA-3359467	Defective MTRR causes HMAE
R-HSA-3359469	Defective MTR causes HMAG
R-HSA-9759218	Cobalamin (Cbl) metabolism
R-HSA-1430728	Metabolism
R-HSA-156580	Phase II - Conjugation of compounds
R-HSA-1643685	Disease
R-HSA-196741	Cobalamin (Cbl, vitamin B12) transport and metabolism
R-HSA-196849	Metabolism of water-soluble vitamins and cofactors
R-HSA-196854	Metabolism of vitamins and cofactors
R-HSA-211859	Biological oxidations
R-HSA-3296469	Defects in cobalamin (B12) metabolism
R-HSA-3296482	Defects in vitamin and cofactor metabolism
R-HSA-5668914	Diseases of metabolism
R-HSA-71291	Metabolism of amino acids and derivatives

MSigDB gene sets: 300 (showing top): REACTOME_BIOLOGICAL_OXIDATIONS, MIDORIKAWA_AMPLIFIED_IN_LIVER_CANCER, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOBP_AMINO_ACID_BIOSYNTHETIC_PROCESS, GOBP_ASPARTATE_FAMILY_AMINO_ACID_BIOSYNTHETIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_DICARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_HOMOCYSTEINE_METABOLIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, BACOLOD_RESISTANCE_TO_ALKYLATING_AGENTS_DN, GOBP_SULFUR_COMPOUND_BIOSYNTHETIC_PROCESS, GOBP_SULFUR_COMPOUND_CATABOLIC_PROCESS, GOBP_COBALAMIN_METABOLIC_PROCESS, GOBP_S_ADENOSYLMETHIONINE_METABOLIC_PROCESS, GOBP_PTERIDINE_CONTAINING_COMPOUND_METABOLIC_PROCESS

GO Biological Process (7): obsolete methionine biosynthetic process (GO:0009086), cobalamin metabolic process (GO:0009235), L-methionine cycle (GO:0033353), L-homocysteine catabolic process (GO:0043418), folic acid metabolic process (GO:0046655), homocysteine metabolic process (GO:0050667), amino acid biosynthetic process (GO:0008652)

GO Molecular Function (10): NADPH-hemoprotein reductase activity (GO:0003958), FMN binding (GO:0010181), oxidoreductase activity, acting on metal ions, NAD or NADP as acceptor (GO:0016723), [methionine synthase] reductase (NADPH) activity (GO:0030586), flavin adenine dinucleotide binding (GO:0050660), NADPH binding (GO:0070402), FAD binding (GO:0071949), molecular carrier activity (GO:0140104), protein binding (GO:0005515), oxidoreductase activity (GO:0016491)

GO Cellular Component (4): nucleoplasm (GO:0005654), cytosol (GO:0005829), intermediate filament cytoskeleton (GO:0045111), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
Metabolism	3
Defects in cobalamin (B12) metabolism	2
Phase II - Conjugation of compounds	1
Metabolism of amino acids and derivatives	1
Cobalamin (Cbl, vitamin B12) transport and metabolism	1
Biological oxidations	1
Metabolism of water-soluble vitamins and cofactors	1
Metabolism of vitamins and cofactors	1
Defects in vitamin and cofactor metabolism	1
Diseases of metabolism	1
Disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anion binding	3
cellular anatomical structure	3
homocysteine metabolic process	2
binding	2
tetrapyrrole metabolic process	1
L-methionine metabolic process	1
modified amino acid metabolic process	1
purine ribonucleoside metabolic process	1
S-adenosylmethionine metabolic process	1
sulfur amino acid catabolic process	1
L-amino acid catabolic process	1
non-proteinogenic amino acid catabolic process	1
folic acid-containing compound metabolic process	1
dicarboxylic acid metabolic process	1
sulfur amino acid metabolic process	1
non-proteinogenic amino acid metabolic process	1
amino acid metabolic process	1
biosynthetic process	1
oxidoreductase activity, acting on NAD(P)H, heme protein as acceptor	1
ribonucleotide binding	1
oxidoreductase activity, acting on metal ions	1
oxidoreductase activity, acting on metal ions, NAD or NADP as acceptor	1
nucleotide binding	1
NADP binding	1
flavin adenine dinucleotide binding	1
molecular_function	1
catalytic activity	1
nuclear lumen	1
cytoplasm	1
cytoskeleton	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1426 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MTRR	MTR	Q99707	993
MTRR	MTHFR	P42898	978
MTRR	MMADHC	Q9H3L0	957
MTRR	LMBRD1	Q9NUN5	944
MTRR	H7C2H4	H7C2H4	941
MTRR	MTHFD1	P11586	941
MTRR	P0DN79	P0DN79	936
MTRR	SHMT1	P34896	927
MTRR	MMAA	Q8IVH4	883
MTRR	MMAB	Q96EY8	864
MTRR	BHMT	Q93088	800
MTRR	BHMT2	Q9H2M3	795
MTRR	TCN2	P20062	788
MTRR	TYMS	P04818	787
MTRR	SLC19A1	P41440	782

IntAct

6 interactions, top by confidence:

A	B	Type	Score
FLJ13057	MTRR	psi-mi:“MI:0915”(physical association)	0.560
MTRR	FLJ13057	psi-mi:“MI:0915”(physical association)	0.560
MTR	MTRR	psi-mi:“MI:0407”(direct interaction)	0.440
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (23): GMCL1 (Two-hybrid), MTRR (Co-fractionation), MTRR (Co-fractionation), MTRR (Affinity Capture-MS), MTRR (Affinity Capture-MS), MTRR (Affinity Capture-MS), MTRR (Affinity Capture-MS), MTRR (Affinity Capture-MS), MTRR (Affinity Capture-MS), MTRR (Affinity Capture-MS), MTR (Reconstituted Complex), MTR (Co-crystal Structure), MTRR (Proximity Label-MS), MTRR (Affinity Capture-MS), MTRR (Proximity Label-MS)

ESM2 similar proteins: A2AI05, D3ZDK7, E1BNQ4, O55240, O70249, P21139, P24298, P25409, P50336, P51175, P56602, P97849, Q03426, Q1JPJ0, Q27979, Q2KJF7, Q3T0A0, Q3ZKN0, Q498R1, Q4JIJ2, Q5E9M9, Q5E9T8, Q5R7A2, Q5RK23, Q60714, Q60HD5, Q6AYG0, Q6NRG5, Q6P1M0, Q6P3E7, Q6PCB7, Q6PFP6, Q7TSA0, Q8BNV1, Q8BZG5, Q8C1A3, Q8CHP8, Q8IXI1, Q8JZN7, Q8QZR5

Diamond homologs: A0A2U1KZS6, A0A2U1LIM9, A0A7T9QPQ1, A0KTH4, A1AEV0, A2QS05, A5F3I4, A6TD49, A7MJ63, A7ZQK7, A8A3P5, A8ANX1, A8G9X6, A9LZ73, A9MF16, B1IU77, C5YJG8, O08336, O08394, O19114, O19132, O32214, O54705, O62699, P00388, P00389, P04175, P14779, P16435, P16603, P19618, P29474, P29475, P29476, P29477, P35228, P36587, P37039, P37040, P37116

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1087 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	63
Likely pathogenic	80
Uncertain significance	275
Likely benign	516
Benign	68

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068644	NM_002454.3(MTRR):c.718_719del (p.Leu240fs)	Pathogenic
1070124	NM_002454.3(MTRR):c.1652dup (p.Phe552fs)	Pathogenic
1070924	NM_002454.3(MTRR):c.1048_1049del (p.Lys350fs)	Pathogenic
1071439	NM_002454.3(MTRR):c.1339A>T (p.Lys447Ter)	Pathogenic
1072380	NM_002454.3(MTRR):c.1314_1315insCTGCCAGCCACCACTC (p.Ser439fs)	Pathogenic
1364376	NM_002454.3(MTRR):c.1476del (p.Trp492fs)	Pathogenic
1379312	NM_002454.3(MTRR):c.1612dup (p.Ile538fs)	Pathogenic
1418809	NM_002454.3(MTRR):c.1504C>T (p.Gln502Ter)	Pathogenic
1442465	NM_002454.3(MTRR):c.340del (p.Arg114fs)	Pathogenic
1452568	NM_002454.3(MTRR):c.228dup (p.Gln77fs)	Pathogenic
1453171	NM_002454.3(MTRR):c.815del (p.Pro272fs)	Pathogenic
1454375	NM_002454.3(MTRR):c.1049_1052del (p.Lys350fs)	Pathogenic
1456920	NM_002454.3(MTRR):c.1728del (p.Leu576fs)	Pathogenic
1458061	NC_000005.9:g.(?7870908)(7900171_?)del	Pathogenic
1909287	NM_002454.3(MTRR):c.495dup (p.Ala166fs)	Pathogenic
1986861	NM_002454.3(MTRR):c.645_648del (p.Gln216fs)	Pathogenic
1999085	NM_002454.3(MTRR):c.901del (p.Ser301fs)	Pathogenic
2009670	NM_002454.3(MTRR):c.930_934del (p.Asp311fs)	Pathogenic
2029285	NM_002454.3(MTRR):c.1394dup (p.Leu466fs)	Pathogenic
2035984	NM_002454.3(MTRR):c.920dup (p.Tyr307Ter)	Pathogenic
2040134	NM_002454.3(MTRR):c.1020C>A (p.Cys340Ter)	Pathogenic
2078287	NM_002454.3(MTRR):c.290del (p.Gly97fs)	Pathogenic
2089994	NM_002454.3(MTRR):c.1441dup (p.Thr481fs)	Pathogenic
2108206	NM_002454.3(MTRR):c.1643del (p.Gly548fs)	Pathogenic
2112831	NM_002454.3(MTRR):c.1631del (p.Gly544fs)	Pathogenic
2115097	NM_002454.3(MTRR):c.754del (p.Val252fs)	Pathogenic
2126896	NM_002454.3(MTRR):c.1355_1361dup (p.Cys455fs)	Pathogenic
2424450	NC_000005.9:g.(?7870908)(7871056_?)del	Pathogenic
2424451	NC_000005.9:g.(?7875361)(7875498_?)del	Pathogenic
265421	NM_002454.3(MTRR):c.1573C>T (p.Arg525Ter)	Pathogenic

SpliceAI

3897 predictions. Top by Δscore:

Variant	Effect	Δscore
5:7861143:CCGTA:C	donor_loss	1.0000
5:7861144:CGTA:C	donor_loss	1.0000
5:7861145:GTACC:G	donor_loss	1.0000
5:7861146:TACC:T	donor_loss	1.0000
5:7861147:A:AT	donor_loss	1.0000
5:7861159:TGATA:T	donor_gain	1.0000
5:7861259:CTATC:C	acceptor_gain	1.0000
5:7861260:TATC:T	acceptor_gain	1.0000
5:7861261:ATC:A	acceptor_gain	1.0000
5:7861262:TC:T	acceptor_gain	1.0000
5:7861263:CC:C	acceptor_gain	1.0000
5:7861264:C:CC	acceptor_gain	1.0000
5:7873371:A:AG	acceptor_gain	1.0000
5:7873372:G:GG	acceptor_gain	1.0000
5:7873466:G:GT	donor_gain	1.0000
5:7875253:TCTA:T	acceptor_loss	1.0000
5:7875255:TAG:T	acceptor_loss	1.0000
5:7875256:A:AG	acceptor_gain	1.0000
5:7875256:A:C	acceptor_loss	1.0000
5:7875257:G:GA	acceptor_loss	1.0000
5:7875257:G:GG	acceptor_gain	1.0000
5:7875371:GTAGG:G	donor_gain	1.0000
5:7875372:TAGGG:T	donor_loss	1.0000
5:7875373:AGGGT:A	donor_loss	1.0000
5:7875374:GG:G	donor_gain	1.0000
5:7875374:GGGT:G	donor_loss	1.0000
5:7875375:GG:G	donor_gain	1.0000
5:7875376:G:GA	donor_loss	1.0000
5:7875376:G:GG	donor_gain	1.0000
5:7875377:T:G	donor_loss	1.0000

AlphaMissense

4545 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:7877966:T:A	W142R	0.990
5:7877966:T:C	W142R	0.990
5:7875284:T:C	F104L	0.989
5:7875286:T:A	F104L	0.989
5:7875286:T:G	F104L	0.989
5:7875318:T:C	L115P	0.987
5:7875264:G:T	G97V	0.985
5:7873404:T:A	V54D	0.984
5:7870849:G:C	A19P	0.983
5:7889164:A:C	S406R	0.982
5:7889166:T:A	S406R	0.982
5:7889166:T:G	S406R	0.982
5:7889150:T:C	L401P	0.980
5:7891397:A:C	R451S	0.979
5:7891397:A:T	R451S	0.979
5:7891401:T:G	Y453D	0.979
5:7875264:G:A	G97D	0.978
5:7877968:G:C	W142C	0.978
5:7877968:G:T	W142C	0.978
5:7889159:T:C	L404P	0.978
5:7895807:G:A	G544D	0.978
5:7875360:C:A	A129E	0.977
5:7875333:C:A	A120D	0.976
5:7875362:G:C	D130H	0.975
5:7875261:T:C	L96P	0.974
5:7891396:G:C	R451T	0.974
5:7873514:T:G	Y91D	0.973
5:7877958:T:A	V139D	0.973
5:7895825:C:A	A550D	0.973
5:7892823:T:G	C489W	0.972

dbSNP variants (sampled 300 via entrez): RS1000037037 (5:7872202 AAAGTT>A), RS1000038133 (5:7876510 T>G), RS1000070228 (5:7868253 C>A,T), RS1000109955 (5:7872515 T>C), RS1000189260 (5:7855371 T>C), RS1000241404 (5:7870983 T>A,G), RS1000297484 (5:7878238 A>C), RS1000323683 (5:7881889 C>A), RS1000340924 (5:7864883 G>A,T), RS1000390070 (5:7865170 C>T), RS1000599722 (5:7861362 T>C), RS1000677622 (5:7866762 T>C), RS1000783122 (5:7859982 T>C,G), RS1000789327 (5:7885027 T>C), RS1000808407 (5:7894769 A>G)

Disease associations

OMIM: gene MIM:602568 | disease phenotypes: MIM:236270, MIM:601634, MIM:606764, MIM:250940, MIM:117000

GenCC curated gene-disease

Disease	Classification	Inheritance
methylcobalamin deficiency type cblE	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
methylcobalamin deficiency type cblE	Definitive	AR

Mondo (6): methylcobalamin deficiency type cblE (MONDO:0009354), neural tube defects, folate-sensitive (MONDO:0011120), gastrointestinal stromal tumor (MONDO:0011719), methylcobalamin deficiency type cblG (MONDO:0009609), congenital myopathy (MONDO:0019952), homocystinuria without methylmalonic aciduria (MONDO:0018964)

Orphanet (6): Methylcobalamin deficiency type cblE (Orphanet:2169), Homocystinuria without methylmalonic aciduria (Orphanet:622), Spina bifida and other spinal dysraphisms (Orphanet:823), Gastrointestinal stromal tumor (Orphanet:44890), Methylcobalamin deficiency type cblG (Orphanet:2170), Congenital myopathy (Orphanet:97245)

HPO phenotypes

68 total (30 of 68 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000365	Hearing impairment
HP:0000478	Abnormality of the eye
HP:0000505	Visual impairment
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000708	Atypical behavior
HP:0000822	Hypertension
HP:0000924	Abnormality of the skeletal system
HP:0000939	Osteoporosis
HP:0001159	Syndactyly
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001262	Excessive daytime somnolence
HP:0001263	Global developmental delay
HP:0001276	Hypertonia
HP:0001288	Gait disturbance
HP:0001392	Abnormality of the liver
HP:0001508	Failure to thrive
HP:0001511	Intrauterine growth retardation
HP:0001626	Abnormality of the cardiovascular system
HP:0001875	Decreased total neutrophil count
HP:0001876	Pancytopenia
HP:0001889	Megaloblastic anemia
HP:0001897	Normocytic anemia
HP:0001907	Thromboembolism

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST001368_19	Capecitabine sensitivity	5.000000e-08
GCST001368_5	Capecitabine sensitivity	6.000000e-07
GCST002701_4	Verbal declarative memory	3.000000e-06
GCST002701_40	Verbal declarative memory	3.000000e-06
GCST007771_1	Hyperinsulinemia in lower physical activity	4.000000e-09
GCST009391_13	Metabolite levels	6.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004874	memory performance
EFO:0006806	paragraph delayed recall measurement
EFO:0007813	cotinine measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D046152	Gastrointestinal Stromal Tumors	C04.557.450.565.370; C06.301.371.308; C06.405.249.308
C565510	Homocystinuria-Megaloblastic Anemia due to Defect in Cobalamin Metabolism, CblE Complementation Type (supp.)
C536409	Neural tube defect, folate-sensitive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

9 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1801394	Efficacy	3	sevoflurane	sedation
rs1801394	Other	3	sevoflurane
rs1801394	Toxicity	4	methotrexate	Juvenile Rheumatoid Arthritis;Rheumatoid arthritis
rs1801394	Efficacy	3	folic acid;vitamin b-complex;plain	Migraine with Aura
rs1801394	Efficacy	3	methotrexate	Juvenile Rheumatoid Arthritis;Rheumatoid arthritis
rs1801394	Toxicity	3	methotrexate	Acute lymphoblastic leukemia;Drug Toxicity;Lymphoma;Osteosarcoma
rs2307116	Other	3	sevoflurane
rs2307116	Efficacy	3	sevoflurane
rs3733784	Efficacy	3	sevoflurane

PharmGKB variants

7 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs10380	MTRR		0.00	0
rs162036	MTRR		0.00	0
rs1532268	MTRR		0.00	0
rs1801394	FASTKD3, MTRR	3	4.75	6	folic acid;vitamin b-complex;plain;methotrexate;sevoflurane
rs162040	MTRR		0.00	0
rs3733784	FASTKD3, MTRR	3	2.50	1	sevoflurane
rs2307116	FASTKD3, MTRR	3	2.00	2	sevoflurane

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bufotalin	increases expression	1
triphenyl phosphate	affects expression	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
potassium chromate(VI)	increases expression	1
pentanal	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
Sunitinib	increases expression	1
Acetaminophen	decreases expression	1
Aldehydes	decreases expression	1
Arsenic	affects metabolic processing	1
Caffeine	decreases phosphorylation	1
Doxorubicin	decreases expression	1
Estradiol	increases expression	1
Folic Acid	affects expression	1
Hydrogen Peroxide	affects expression	1
Ivermectin	decreases expression	1
Nickel	increases expression	1
Silicon Dioxide	decreases expression	1
Valproic Acid	affects expression	1
Vanadates	decreases expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	decreases expression	1

Cellosaurus cell lines

10 cell lines: 9 finite cell line, 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E0UK	Ubigene Hep G2 MTRR KO	Cancer cell line	Male
CVCL_QZ18	WG0788	Finite cell line	Male
CVCL_QZ19	WG1146	Finite cell line	Male
CVCL_QZ22	WG1296	Finite cell line	Male
CVCL_QZ25	WG1384	Finite cell line	Male
CVCL_QZ27	WG1401	Finite cell line	Male
CVCL_QZ30	WG1575	Finite cell line	Male
CVCL_QZ38	WG2366	Finite cell line
CVCL_QZ39	WG2317	Finite cell line
CVCL_QZ42	WG1836	Finite cell line	Female

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00171977	PHASE4	COMPLETED	Post-Marketing Clinical Study of Postoperative Adjuvant Therapy With Imatinib Mesylate in Patients With Gastrointestinal Stromal Tumors (GIST)
NCT00510354	PHASE4	COMPLETED	Treatment of Patients With Everolimus and Imatinib Mesylate Who Have Progressive Gastro Intestinal Stromal Tumors (GIST) and Are Resistant to Imatinib Mesylate
NCT00756509	PHASE4	COMPLETED	Treatment of Patients With Metastatic or Unresectable Gastrointestinal Stromal Tumors in First Line With Nilotinib
NCT00777504	PHASE4	UNKNOWN	Study to the Optimal Duration of Therapy With Oral Angiogenesis Inhibitors
NCT02800330	PHASE4	COMPLETED	The Effects of the Proton Pump Inhibitor Esomeprazole on the Bioavailability of Regorafenib
NCT04825574	PHASE4	COMPLETED	Study for Patients Previously Treated in Avapritinib Clinical Trials
NCT00009906	PHASE3	TERMINATED	Comparison of Two Different Doses of STI571 in Treating Patients With Metastatic or Unresectable Gastrointestinal Stromal Tumor
NCT00041197	PHASE3	COMPLETED	Imatinib Mesylate in Treating Patients With Primary Gastrointestinal Stromal Tumor That Has Been Completely Removed By Surgery
NCT00075218	PHASE3	COMPLETED	A Study To Assess The Safety And Efficacy Of SU11248 In Patients With Gastrointestinal Stromal Tumor(GIST)
NCT00103168	PHASE3	COMPLETED	Imatinib Mesylate or Observation Only in Treating Patients Who Have Undergone Surgery for Localized Gastrointestinal Stromal Tumor
NCT00293124	PHASE3	COMPLETED	Open-label Trial of GlivecWith Unresectable or Metastatic Malignant Gastrointestinal Stromal Tumors
NCT00324987	PHASE3	TERMINATED	Imatinib Mesylate With or Without Bevacizumab in Treating Patients With Metastatic or Unresectable Gastrointestinal Stromal Tumor
NCT00372567	PHASE3	TERMINATED	Safety And Effectiveness Of Daily Dosing With Sunitinib Or Imatinib In Patients With Gastrointestinal Stromal Tumors
NCT00471328	PHASE3	COMPLETED	Efficacy and Safety of Nilotinib (AMN107) Compared With Current Treatment Options in Patients With GIST Who Have Failed Both Imatinib and Sunitinib
NCT00685828	PHASE3	UNKNOWN	Imatinib Mesylate in Treating Patients With Unresectable or Metastatic Gastrointestinal Stromal Tumor
NCT00688766	PHASE3	TERMINATED	Study Evaluating IPI-504 in Patients With Gastrointestinal Stromal Tumors (GIST) Following Failure of at Least Imatinib and Sunitinib
NCT00751036	PHASE3	TERMINATED	Nilotinib 800 Mg And Imatinib 800 Mg For The Treatment Of Patients With Gastrointestinal Stromal Tumors (Gist) Refractory To Imatinib 400 Mg
NCT00785785	PHASE3	COMPLETED	A Study of Nilotinib Versus Imatinib in GIST Patients
NCT00812240	PHASE3	TERMINATED	Masitinib in First Line Treatment of Gastro-Intestinal Stromal Tumor (GIST)
NCT00956072	PHASE3	TERMINATED	Imatinib Mesylate With or Without Surgery in Treating Patients With Metastatic Gastrointestinal Stromal Tumor That is Responding to Imatinib Mesylate
NCT01031628	PHASE3	TERMINATED	Study of Dose Escalation Versus no Dose Escalation of Imatinib in Metastatic Gastrointestinal Stromal Tumors (GIST) Patients
NCT01151852	PHASE3	COMPLETED	Rechallenge of Imatinib in GIST Having no Effective Treatment: RIGHT
NCT01265810	PHASE3	COMPLETED	Caphosol in Oral Mucositis Due to Targeted Therapy
NCT01271712	PHASE3	COMPLETED	Study of Regorafenib as a 3rd-line or Beyond Treatment for Gastrointestinal Stromal Tumors (GIST)
NCT01289028	PHASE3	COMPLETED	Efficacy of Nilotinib in Adult Patients With Gastrointestinal Stromal Tumors Resistant to Imatinib and Sunitinib.
NCT01462994	PHASE3	COMPLETED	Detection of CF-DNA in Patients With Gastrointestinal Stromal Tumors (GIST)
NCT01694277	PHASE3	COMPLETED	Masitinib in Patients With Gastrointestinal Stromal Tumour After Progression With Imatinib
NCT02260505	PHASE3	COMPLETED	Efficiency of Imatinib Treatment Maintenance or Interruption After 3 Years of Adjuvant Treatment in Patients With Gastrointestinal Stromal Tumours (GIST)
NCT02576080	PHASE3	UNKNOWN	Efficacy of Imatinib in Patients With Intermediate-risk Gastrointestinal Stromal Tumor With a High-risk Genomic Grade Index
NCT02866045	PHASE3	UNKNOWN	EUS-FNB vs. Single-incision Needle-knife (SINK) Biopsy for Gastrointestinal SELs
NCT03353753	PHASE3	COMPLETED	Phase 3 Study of DCC-2618 vs Placebo in Advanced GIST Patients Who Have Been Treated With Prior Anticancer Therapies
NCT03426722	PHASE3	COMPLETED	L-carnitine vs Placebo for the Treatment of Muscle Cramps After Imatinib in Gastrointestinal Stromal Tumors
NCT03465722	PHASE3	COMPLETED	(VOYAGER) Study of Avapritinib vs Regorafenib in Patients With Locally Advanced Unresectable or Metastatic GIST
NCT03673501	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Ripretinib vs Sunitinib in Advanced GIST Patients After Treatment With Imatinib
NCT04409223	PHASE3	TERMINATED	Efficacy and Safety of Famitinib Versus Sunitinib in the Treatment of Advanced Gastrointestinal Stromal Tumour Patients After Failure of Imatinib
NCT05208047	PHASE3	ACTIVE_NOT_RECRUITING	(Peak) A Phase 3 Randomized Trial of CGT9486+Sunitinib vs. Sunitinib in Subjects With Gastrointestinal Stromal Tumors
NCT05734105	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Ripretinib vs Sunitinib in Patients With Advanced GIST With Specific KIT Exon Mutations Who Were Previously Treated With Imatinib
NCT06640361	PHASE3	RECRUITING	A Study of Olverembatinib in SDH-deficient GIST.
NCT07585266	PHASE3	NOT_YET_RECRUITING	A Study to Investigate Velzatinib Compared With Imatinib in Adult Participants With Previously Untreated Metastatic and/or Unresectable Gastrointestinal Stromal Tumors (StrateGIST Frontline)
NCT00003939	PHASE2	COMPLETED	Ecteinascidin 743 in Treating Patients With Advanced Soft Tissue Sarcoma