MTR

protein-coding

5-methyltetrahydrofolate-homocysteine methyltransferase, the group of Homocysteine methyltransferases|Methyltransferase families

Gene summary

This gene encodes the 5-methyltetrahydrofolate-homocysteine methyltransferase. This enzyme, also known as cobalamin-dependent methionine synthase, catalyzes the final step in methionine biosynthesis. Mutations in MTR have been identified as the underlying cause of methylcobalamin deficiency complementation group G. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, May 2014]

MANE transcript

NM_000254.3

Inheritance

ClinVar variants

P:112U:307B:377

Top phenotype

Homocystinuria-megaloblastic anemia, cblG type

gnomAD constraint

pLI —, LoF o/e 0.46

Max pathogenic AF

—

Genomic locus

chr1:236,795,260-236,921,278

External References & Databases

Ensembl (ENSG00000116984)

Transcript & Mutation Effects

hg38 • Region Span ~126.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

methylcobalamin deficiency type cblGSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009609

Submitter: Orphanet

methylcobalamin deficiency type cblGDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009609

Submitter: G2P

methylcobalamin deficiency type cblGDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009609

Submitter: ClinGen

The relationship between MTR and methylcobalamin deficiency type cblG, an autosomal recessive disorder of cobalamin metabolism, was evaluated using the ClinGen Clinical Validity Framework as of April 30, 2021. MTR encodes methionine synthase (5-methyltetrahydrofolate-homocystine S-methyltransferase) which catalyzes the transmethylation of homocysteine by 5-methyltetrahydrofolate to give methionine and tetrahydrofolate. Individuals with bilalleic variants in MTR, resulting in loss of function of methionine synthase, usually present in infancy with hematological abnormalities, muscular hypotonia, and neurocognitive impairment. Some patients present with impaired consciousness, seizures, or visual impairment (Huemer et al, 2015, PMID 25526710; Sloan et al, 2018, PMID 20301503). Variants in MTR were first reported in patients with methylcobalamin deficiency type cblG in 1996 (Gulati et al, PMID 8968736; Leclerc et al, PMID 8968737). Data from 23 probands, who are homozygous or compound heterozygous for MTR variants, were curated. This curation includes 30 unique variants (missense, frameshift, nonsense, splice site, intronic) from 8 publications (Gulati et al, 1996, PMID 8968736; Wilson et al, 1998, PMID 9683607; Watkins et al, 2002, PMID 12068375; Fofou-Caillierez et al, 2013, PMID 23825108; Huemer et al, 2015, PMID 25526710; Vaisbich et al, 2017, PMID 28210839; Kasapkara et al, 2019, PMID 31951343; Liu et al, 2019, PMID 30651581). One variant, p.Pro1173Leu, was found in 66% of alleles in 24 patients in one study, with evidence showing that the variant has arisen more than once (PMID: 12068375). More data is available in the literature but the maximum points for genetic evidence (12 points) has been reached. The gene-disease relationship is supported by the biochemical function of the product of MTR, methionine synthase, which is consistent with the biochemical features in patients with methylcobalamin deficiency type cblG (Loughlin et al, 1964, PMID 14216440; Banerjee et al, 1990, PMID 2407589; Watkins et al, 2011, PMID 21312325); evidence supporting interaction with other proteins involved in cobalamin metabolism and associated with homocystinuria when deficient, including MMACHC, MMADHC, and MTRR (Fofou-Caillierez et al, 2013, PMID 23825108; Bassila et al, 2017, PMID 27771510), and the findings in an Mtr knock-out mouse model (Swanson et al, PMID 11158293) In summary, MTR is definitively associated with methylcobalamin deficiency type cblG. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This clinical validity classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel on July 2, 2021.

methylcobalamin deficiency type cblGSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009609

Submitter: PanelApp Australia

methylcobalamin deficiency type cblGSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009609

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Homocystinuria-megaloblastic anemia, cblG typeAR

Manifestation: Biochemical; Cardiovascular; Hematologic; Neurologic; Renal

Intervention: Biochemical

Rationale: Medical treatment may be beneficial (while hydroxycobalamin may not be as effective as in other MMA types, other treatments, such as betaine, methylfolate, and even methionine supplements may be attempted)

Refs: 2897628; 2203337; 8968736; 8968737; 12068375; 20301503; 22108709

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MTR variants in ClinVar

14 Conditions Cataloged

Methylcobalamin deficiency type cblGTotal: 1011

not providedTotal: 147

Inborn genetic diseasesTotal: 119

not specifiedTotal: 92

Disorders of Intracellular Cobalamin MetabolismTotal: 66

MTR-related disorderTotal: 33

Neural tube defects, folate-sensitiveTotal: 22

Intellectual disabilityTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000254.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			10 clinvar	344 clinvar	4 clinvar	358
missense	3 clinvar	12 clinvar	282 clinvar	24 clinvar	3 clinvar	324
nonsense	16 clinvar	8 clinvar	3 clinvar			27
start loss		1 clinvar	1 clinvar			2
frameshift	32 clinvar	9 clinvar	1 clinvar			42
splice donor/acceptor (+/-2bp)	5 clinvar	26 clinvar	10 clinvar	2 clinvar		43
Total	56	56	307	370	7	796

Highest pathogenic variant AF is 0.0005113246

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 30 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000254.3	RefSeq	NP_000245.2	33	MANE Select
ENST00000366577.10	Ensembl	ENSP00000355536.5	33	MANE Select
NM_001291939.1	RefSeq	NP_001278868.1	32	Standard
NM_001291940.2	RefSeq	NP_001278869.1	20	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Antimetabolite Pathway - Folate Cycle, Pharmacodynamics
One carbon pool by folate - Homo sapiens (human)
Cysteine and methionine metabolism - Homo sapiens (human)
Selenocompound metabolism - Homo sapiens (human)
Methotrexate Pathway (Cancer Cell), Pharmacodynamics

Biological Process

nervous system development
methionine biosynthetic process
cobalamin metabolic process
axon regeneration
methylation

Molecular Function

protein binding
zinc ion binding
methionine synthase activity
cobalamin binding

Cellular Component

cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000366577
Coding exons: 33
Length: 108672
Individuals with no LoFs: 125655
Homozygous LoFs: 0
Heterozygous LoFs: 93
Defined: 125748
p: 0.000370

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.04	527	677	0.779	0.0000371	8317
Missense (PolyPhen)		171	297.93	0.57395		3623
Synonymous	-0.582	259	247	1.05	0.0000145	2384
Loss of Function	4.05	31	66.7	0.465	0.00000350	852

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00029	0.00029	rare
Ashkenazi Jewish	0.00061	0.00060	rare
East Asian	0.00054	0.00054	rare
Finnish	0.00019	0.00018	rare
European (Non-Finnish)	0.00038	0.00038	rare
South Asian	0.00041	0.00039	rare
Other	0.00065	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the transfer of a methyl group from methyl- cobalamin to homocysteine, yielding enzyme-bound cob(I)alamin and methionine. Subsequently, remethylates the cofactor using methyltetrahydrofolate (By similarity). {ECO:0000250}.;
Disease: DISEASE: Homocystinuria-megaloblastic anemia, cblG complementation type (HMAG) [MIM:250940]: 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. {ECO:0000269|PubMed:8968736, ECO:0000269|PubMed:8968737}. Note=The disease is caused by mutations 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:12375236}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.687

Intolerance Scores

LoFtool: 0.507
RVIS EVS: 0.25
RVIS percentile EVS: 69.7

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.965

Gene Damage Prediction

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