methylcobalamin deficiency type cblG

Summary

methylcobalamin deficiency type cblG (MONDO:0009609) is a disease caused by MTR (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MTR (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 1,028

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		33	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	methylcobalamin deficiency type cblG
Mondo ID	MONDO:0009609
OMIM	250940
Orphanet	2170
DOID	DOID:0050733, DOID:0112256
SNOMED CT	721187005
UMLS	C1855128
MedGen	344426
GARD	0003577
Is cancer (heuristic)	no

Also known as: cblG · functional methionine synthase deficiency type cblG · HMAG · homocystinuria due to defect in methylation Cbl g · homocystinuria-megaloblastic Anaemia due to defect in cobalamin metabolism, cblG complementation type · homocystinuria-megaloblastic anemia, cblG complementation type · methylcobalamin deficiency Cbl G type · methylcobalamin deficiency type cblG

Data availability: 1,028 ClinVar variants · 4 GenCC gene-disease records · 17 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › homocystinuria › homocystinuria without methylmalonic aciduria › methylcobalamin deficiency type cblG

Related subtypes (3): methylcobalamin deficiency type cblE, methylcobalamin deficiency type cblDv1, homocystinuria-megaloblastic anemia cblD type

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

360 likely benign, 147 uncertain significance, 36 pathogenic, 21 benign, 15 likely pathogenic, 11 conflicting classifications of pathogenicity, 5 benign/likely benign, 5 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2769519	NM_000254.3(MTR):c.12_13del (p.Leu5fs)	LOC129932886	Pathogenic	criteria provided, single submitter
1048517	NM_000254.3(MTR):c.609+1088G>A	MTR	Pathogenic	criteria provided, multiple submitters, no conflicts
1048518	NM_000254.3(MTR):c.2788_2791del (p.Leu930fs)	MTR	Pathogenic	criteria provided, single submitter
1339164	NM_000254.3(MTR):c.2404C>T (p.Arg802Ter)	MTR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14278	NM_000254.3(MTR):c.3518C>T (p.Pro1173Leu)	MTR	Pathogenic	criteria provided, multiple submitters, no conflicts
14280	NM_000254.3(MTR):c.2758C>G (p.His920Asp)	MTR	Pathogenic	criteria provided, single submitter
14281	NM_000254.3(MTR):c.340-166A>G	MTR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14282	NM_000254.3(MTR):c.2114_2115del (p.Leu705fs)	MTR	Pathogenic	no assertion criteria provided
14283	MTR, IVS6AS, G-A, LYS203	MTR	Pathogenic	no assertion criteria provided
14284	NM_000254.3(MTR):c.3380dup (p.Ala1128fs)	MTR	Pathogenic	no assertion criteria provided
14286	NM_000254.3(MTR):c.1753C>T (p.Arg585Ter)	MTR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14287	NM_000254.3(MTR):c.3613G>T (p.Glu1205Ter)	MTR	Pathogenic	criteria provided, single submitter
1447405	NM_000254.3(MTR):c.2101del (p.Tyr701fs)	MTR	Pathogenic	criteria provided, single submitter
1685963	NM_000254.3(MTR):c.2059_2060del (p.Ile687fs)	MTR	Pathogenic	criteria provided, single submitter
1905103	NM_000254.3(MTR):c.1200dup (p.Val401fs)	MTR	Pathogenic	criteria provided, single submitter
195849	NM_000254.3(MTR):c.2669_2670del (p.Val890fs)	MTR	Pathogenic	criteria provided, multiple submitters, no conflicts
2025555	NM_000254.3(MTR):c.2472dup (p.Asp825fs)	MTR	Pathogenic	criteria provided, single submitter
2091459	NM_000254.3(MTR):c.2100dup (p.Tyr701fs)	MTR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2093880	NM_000254.3(MTR):c.1330-2A>T	MTR	Pathogenic	criteria provided, single submitter
2570756	NM_000254.3(MTR):c.1941dup (p.Arg648fs)	MTR	Pathogenic	criteria provided, multiple submitters, no conflicts
2582874	NM_000254.3(MTR):c.920dup (p.His307fs)	MTR	Pathogenic	criteria provided, multiple submitters, no conflicts
2636752	NM_000254.3(MTR):c.2799_2803del (p.Ala935fs)	MTR	Pathogenic	criteria provided, multiple submitters, no conflicts
2693476	NM_000254.3(MTR):c.3570G>A (p.Trp1190Ter)	MTR	Pathogenic	criteria provided, single submitter
2694577	NM_000254.3(MTR):c.610-1_613dup	MTR	Pathogenic	criteria provided, single submitter
2696262	NM_000254.3(MTR):c.313C>T (p.Gln105Ter)	MTR	Pathogenic	criteria provided, single submitter
2697612	NM_000254.3(MTR):c.1636G>T (p.Gly546Ter)	MTR	Pathogenic	criteria provided, single submitter
2709023	NM_000254.3(MTR):c.2730_2731delinsCT (p.Met910_Glu911delinsIleTer)	MTR	Pathogenic	criteria provided, single submitter
2714103	NM_000254.3(MTR):c.899dup (p.Pro301fs)	MTR	Pathogenic	criteria provided, single submitter
2734111	NM_000254.3(MTR):c.381del (p.Ala128fs)	MTR	Pathogenic	criteria provided, single submitter
2734112	NM_000254.3(MTR):c.866-2A>C	MTR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
MTR	Definitive	Autosomal recessive	methylcobalamin deficiency type cblG	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MTR	Orphanet:2170	Methylcobalamin deficiency type cblG
MTRR	Orphanet:2169	Methylcobalamin deficiency type cblE

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MTR	HGNC:7468	ENSG00000116984	Q99707	Methionine synthase	gencc,clinvar
MTRR	HGNC:7473	ENSG00000124275	Q9UBK8	Methionine synthase reductase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MTR	Methionine synthase	Catalyzes the transfer of a methyl group from methylcob(III)alamin (MeCbl) to homocysteine, yielding enzyme-bound cob(I)alamin and methionine in the cytosol.
MTRR	Methionine synthase reductase	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.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	2	12.0×	0.007

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MTR	Enzyme (other)	yes	2.1.1.13	Pterin-binding_dom, HCY_dom, Cbl-bd_cap
MTRR	Enzyme (other)	yes	1.16.1.8	Flavdoxin-like, OxRdtase_FAD/NAD-bd, Flavoprot_Pyr_Nucl_cyt_Rdtase

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
caput epididymis	1
corpus epididymis	1
decidua	1
choroid plexus epithelium	1
endothelial cell	1
pancreatic ductal cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MTR	294	ubiquitous	marker	caput epididymis, corpus epididymis, decidua
MTRR	291	ubiquitous	marker	endothelial cell, pancreatic ductal cell, choroid plexus epithelium

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MTR	2,607
MTRR	1,455

Intra-cohort edges

A	B	Sources
MTR	MTRR	biogrid_interaction, intact, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MTR	Q99707	9
MTRR	Q9UBK8	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 21. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective MTRR causes HMAE	2	5710.0×	2e-07	MTR, MTRR
Defective MTR causes HMAG	2	5710.0×	2e-07	MTR, MTRR
Cobalamin (Cbl) metabolism	2	1268.9×	4e-06	MTR, MTRR
Methylation	2	815.7×	6e-06	MTR, MTRR
Defects in cobalamin (B12) metabolism	2	815.7×	6e-06	MTR, MTRR
Cobalamin (Cbl, vitamin B12) transport and metabolism	2	634.4×	8e-06	MTR, MTRR
Defects in vitamin and cofactor metabolism	2	601.0×	8e-06	MTR, MTRR
Sulfur amino acid metabolism	2	571.0×	8e-06	MTR, MTRR
Phase II - Conjugation of compounds	2	278.5×	3e-05	MTR, MTRR
Metabolism of water-soluble vitamins and cofactors	2	181.3×	6e-05	MTR, MTRR
Biological oxidations	2	129.8×	1e-04	MTR, MTRR
Metabolism of vitamins and cofactors	2	116.5×	1e-04	MTR, MTRR
Diseases of metabolism	2	80.4×	2e-04	MTR, MTRR
Metabolism of amino acids and derivatives	2	67.6×	3e-04	MTR, MTRR
Disease	2	13.1×	0.008	MTR, MTRR
RHOH GTPase cycle	1	154.3×	0.008	MTR
Metabolism	2	11.6×	0.009	MTR, MTRR
RHO GTPase cycle	1	30.1×	0.038	MTR
Signaling by Rho GTPases	1	17.1×	0.062	MTR
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	16.7×	0.062	MTR
Signal Transduction	1	5.1×	0.187	MTR

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete methionine biosynthetic process	2	3370.4×	9e-07	MTR, MTRR
homocysteine metabolic process	2	1872.4×	2e-06	MTR, MTRR
cobalamin metabolic process	2	1532.0×	2e-06	MTR, MTRR
sulfur amino acid metabolic process	1	8426.0×	4e-04	MTR
L-homocysteine catabolic process	1	2808.7×	9e-04	MTRR
L-methionine cycle	1	2106.5×	0.001	MTRR
tetrahydrofolate metabolic process	1	1203.7×	0.002	MTR
axon regeneration	1	561.7×	0.003	MTR
folic acid metabolic process	1	561.7×	0.003	MTRR
cellular response to nitric oxide	1	468.1×	0.003	MTR
response to axon injury	1	255.3×	0.005	MTR
methylation	1	85.1×	0.013	MTR
nervous system development	1	23.0×	0.043	MTR

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
MTR	LOMITAPIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MTR	1	4
MTRR	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
LOMITAPIDE	4	MTR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
MTR	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MTR	2.1.1.13	methionine synthase
MTRR	1.16.1.8	[methionine synthase] reductase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
LOMITAPIDE	4	MTR

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MTR
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	MTRR
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
MTRR	0	MTR

Clinical trials & evidence

Clinical trials

Clinical trials: 0.