MTRR

protein-coding

5-methyltetrahydrofolate-homocysteine methyltransferase reductase

Gene summary

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. [provided by RefSeq, Dec 2015]

MANE transcript

NM_002454.3

Inheritance

ClinVar variants

P:162U:245B:358

Top phenotype

Homocystinuria-megaloblastic anemia, cobalamin E type

gnomAD constraint

pLI —, LoF o/e 0.71

Max pathogenic AF

—

Genomic locus

chr5:7,851,186-7,906,025

External References & Databases

Ensembl (ENSG00000124275)

Transcript & Mutation Effects

hg38 • Region Span ~54.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

methylcobalamin deficiency type cblESTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009354

Submitter: PanelApp Australia

methylcobalamin deficiency type cblESUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009354

Submitter: Orphanet

methylcobalamin deficiency type cblESTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009354

Submitter: Labcorp Genetics (formerly Invitae)

methylcobalamin deficiency type cblEDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009354

Submitter: Natera

methylcobalamin deficiency type cblEDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009354

Submitter: ClinGen

The relationship between MTRR and methylcobalamin deficiency type cblE, an autosomal recessive disorder of cobalamin metabolism, was evaluated using the ClinGen Clinical Validity Framework as of May 4, 2021. MTRR encodes methionine synthase reductase. This enzyme reactivates methionine synthase by reductive methylation of its cobalamin cofactor. Individuals with methylcobalamin deficiency type cblE usually present early childhood with failure to thrive, megaloblastic anemia, developmental delay, and cerebral atrophy with white matter abnormalities. Biochemical characteristics include homocystinuria, hyperhomocysteinemia, and often hypomethioninemia (Zavadakova et al, 2005, PMID 15714522). Variants in MTRR were first reported in patients with methylcobalamin deficiency type cblE in 1998 (LeClerc et al, PMID 9501215). Data from 9 probands, who are homozygous or compound heterozygous for MTRR variants were curated. This curation includes 11 unique variants (missense, frameshift, nonsense, intronic) from 3 publications (Wilson et al, 1999, PMID 10484769; Zavadakova et al, 2002, PMID 12555939, Zavadakova et al, 2005, PMID 15714522). 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 MTRR, methionine synthase reductase, which is consistent with the biochemical features in patients with methylcobalamin deficiency type cblE (Olteanu et al, 2001, PMID 11466310; Yamada et al, 2006, PMID 16769880; Wolthers et al, 2009, PMID 19243433; Watkins and Rosenblatt, 2012, PMID 22108709); evidence supporting interaction with other proteins involved in cobalamin metabolism and associated with homocystinuria including MMACHC and methionine synthase (Wolthers et al, 2007, PMID; 17477549; Bassila et al, 2017, PMID 27771510); rescue of MSR function in cblE cells (Zavadáková et al, 2005, PMID 15714522; Palhais et al, 2015, PMID 25878036); and the findings reported in a hypomorphic mouse model (Elmore et al, 2007, PMID 17369066). More evidence is available in the literature but the maximum score for experimental evidence (6 points) has been reached. In summary, MTRR is definitively associated with methylcobalamin deficiency type cblE. 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 cblEDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009354

Submitter: G2P

Clinical Genomic Database (CGD)

Homocystinuria-megaloblastic anemia, cobalamin E typeAR

Manifestation: Biochemical; Hematologic; Neurologic; Renal

Intervention: Biochemical

Rationale: Treatment (eg, with hydroxycobalamin, folate, methylcobalamin) has been reported as effective

Refs: 6700644; 2860337; 3812589; 9427140; 10444342; 15060097; 15979034; 15714522

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MTRR variants in ClinVar

10 Conditions Cataloged

Methylcobalamin deficiency type cblETotal: 852

Inborn genetic diseasesTotal: 108

not providedTotal: 83

Neural tube defects, folate-sensitiveTotal: 79

Disorders of Intracellular Cobalamin MetabolismTotal: 58

not specifiedTotal: 50

MTRR-related disorderTotal: 26

Congenital myopathyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002454.3. 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			4 clinvar	333 clinvar	4 clinvar	341
missense		6 clinvar	233 clinvar	19 clinvar	1 clinvar	259
nonsense	16 clinvar	24 clinvar	2 clinvar			42
start loss	1 clinvar	1 clinvar				2
frameshift	37 clinvar	38 clinvar	2 clinvar			77
splice donor/acceptor (+/-2bp)	1 clinvar	38 clinvar	4 clinvar	1 clinvar		44
Total	55	107	245	353	5	765

Highest pathogenic variant AF is 0.0000799307

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 62 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002454.3	RefSeq	NP_002445.2	14	MANE Select
ENST00000440940.7	Ensembl	ENSP00000402510.2	14	MANE Select
NM_001364440.2	RefSeq	NP_001351369.1	14	Standard
NM_001364441.2	RefSeq	NP_001351370.1	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Antimetabolite Pathway - Folate Cycle, Pharmacodynamics
Methotrexate Pathway (Cancer Cell), Pharmacodynamics
Thiopurine Pathway, Pharmacokinetics/Pharmacodynamics
Vitamin B12 Metabolism
Folate Metabolism

Biological Process

DNA methylation
methionine metabolic process
methionine biosynthetic process
cobalamin metabolic process
S-adenosylmethionine cycle

Molecular Function

NADPH-hemoprotein reductase activity
protein binding
FMN binding
oxidoreductase activity
oxidoreductase activity, oxidizing metal ions, NAD or NADP as acceptor

Cellular Component

cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000264668
Coding exons: 15
Length: 54840
Individuals with no LoFs: 125636
Homozygous LoFs: 0
Heterozygous LoFs: 112
Defined: 125748
p: 0.000445

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.665	423	386	1.10	0.0000210	4699
Missense (PolyPhen)		142	152.51	0.93111		1858
Synonymous	-1.38	172	150	1.14	0.00000864	1447
Loss of Function	1.64	27	37.9	0.713	0.00000207	439

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00038	0.00037	rare
Latino/Admixed American	0.00032	0.00032	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00011	0.00011	rare
Finnish	0.00028	0.00028	rare
European (Non-Finnish)	0.00053	0.00053	rare
South Asian	0.00062	0.00062	rare
Other	0.0011	0.0011	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the reductive regeneration of cob(I)alamin (vitamin B12) cofactor required for the maintenance of methionine synthase in a functional state. Necessary for utilization of methylgroups from the folate cycle, thereby affecting transgenerational epigenetic inheritance. Folate pathway donates methyl groups necessary for cellular methylation and affects different pathways such as DNA methylation, possibly explaining the transgenerational epigenetic inheritance effects. {ECO:0000269|PubMed:17892308}.;
Disease: DISEASE: Neural tube defects, folate-sensitive (NTDFS) [MIM:601634]: The most common NTDs are open spina bifida (myelomeningocele) and anencephaly. {ECO:0000269|PubMed:10444342, ECO:0000269|PubMed:12375236}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.305

Intolerance Scores

LoFtool: 0.510
RVIS EVS: 1.43
RVIS percentile EVS: 95

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.108

Gene Damage Prediction

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