MTRR

Chr 5

5-methyltetrahydrofolate-homocysteine methyltransferase reductase

Also known as: MSR, cblE

NCBI Gene: 4552 ENSG00000124275 UniProt: Q9UBK8

The protein regenerates methionine synthase to its functional state, enabling methionine synthesis and supporting folate metabolism and cellular methylation processes. Mutations cause homocystinuria-megaloblastic anemia (cbl E type) and increase susceptibility to neural tube defects through autosomal recessive inheritance. The pathogenic mechanism involves gain-of-function effects that disrupt normal methionine synthesis pathways.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.98

Clinical Summary— MTRR

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Gene-Disease Validity (ClinGen)

methylcobalamin deficiency type cblE · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

170 unique Pathogenic / Likely Pathogenic· 338 VUS of 1189 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — MTRR

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.98LOEUF

pLI 0.000

Z-score 1.64

OE 0.71 (0.52–0.98)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.67Z-score

OE missense 1.10 (1.01–1.19)

423 obs / 386.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.71 (0.52–0.98)

0≤0.351.4

Missense OE?1.10 (1.01–1.19)

0≤0.61.4

Synonymous OE?1.14

0≤1.21.6

LoF obs/exp: 27 / 37.9Missense obs/exp: 423 / 386.2Syn Z: -1.38

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveMTRR-related homocystinuria-megaloblastic anemia, cblE typeLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6260th %ile

GOF

0.72top 25%

LOF

0.2776th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

1189 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic64

Likely Pathogenic106

VUS338

Likely Benign555

Benign73

Conflicting26

Pathogenic

106

Likely Pathogenic

338

VUS

555

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	53	2	9	0	64
Likely Pathogenic	95	7	4	0	106
VUS	4	294	37	3	338
Likely Benign	1	27	206	321	555
Benign	0	5	58	10	73
Conflicting	—				26
Total	153	335	314	334	1,162

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

104 pathogenic / likely-pathogenic (of 113) ClinVar copy-number / structural variants overlap MTRR — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →