methylcobalamin deficiency type cblE

Summary

methylcobalamin deficiency type cblE (MONDO:0009354) is a disease caused by MTRR (GenCC Definitive), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MTRR (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 886
• Phenotypes (HPO): 50
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		27	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

50 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001980	Megaloblastic bone marrow	Very frequent (80-99%)
HP:0002160	Hyperhomocystinemia	Very frequent (80-99%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000478	Abnormality of the eye	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001511	Intrauterine growth retardation	Frequent (30-79%)
HP:0001972	Macrocytic anemia	Frequent (30-79%)
HP:0002013	Vomiting	Frequent (30-79%)
HP:0002167	Abnormality of speech or vocalization	Frequent (30-79%)
HP:0002329	Drowsiness	Frequent (30-79%)
HP:0002500	Abnormal cerebral white matter morphology	Frequent (30-79%)
HP:0003658	Hypomethioninemia	Frequent (30-79%)
HP:0005518	Increased mean corpuscular volume	Frequent (30-79%)
HP:0007185	Loss of consciousness	Frequent (30-79%)
HP:0008897	Postnatal growth retardation	Frequent (30-79%)
HP:0011344	Severe global developmental delay	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0012444	Brain atrophy	Frequent (30-79%)
HP:0100022	Abnormality of movement	Frequent (30-79%)
HP:0000238	Hydrocephalus	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000505	Visual impairment	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000708	Atypical behavior	Occasional (5-29%)
HP:0000822	Hypertension	Occasional (5-29%)
HP:0000924	Abnormality of the skeletal system	Occasional (5-29%)
HP:0000939	Osteoporosis	Occasional (5-29%)
HP:0001159	Syndactyly	Occasional (5-29%)
HP:0001254	Lethargy	Occasional (5-29%)
HP:0001262	Excessive daytime somnolence	Occasional (5-29%)
HP:0001392	Abnormality of the liver	Occasional (5-29%)
HP:0001626	Abnormality of the cardiovascular system	Occasional (5-29%)
HP:0001875	Decreased total neutrophil count	Occasional (5-29%)
HP:0001876	Pancytopenia	Occasional (5-29%)
HP:0001907	Thromboembolism	Occasional (5-29%)
HP:0002119	Ventriculomegaly	Occasional (5-29%)
HP:0002365	Hypoplasia of the brainstem	Occasional (5-29%)
HP:0002625	Deep venous thrombosis	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0005575	Hemolytic-uremic syndrome	Occasional (5-29%)
HP:0006895	Lower limb hypertonia	Occasional (5-29%)
HP:0009830	Peripheral neuropathy	Occasional (5-29%)
HP:0012448	Delayed myelination	Occasional (5-29%)
HP:0012704	Widened subarachnoid space	Occasional (5-29%)
HP:0030084	Clinodactyly	Occasional (5-29%)
HP:0100820	Glomerulopathy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	methylcobalamin deficiency type cblE
Mondo ID	MONDO:0009354
MeSH	C565510
OMIM	236270
Orphanet	2169
DOID	DOID:0050732, DOID:0112255
NCIT	C142173
UMLS	C1856057
MedGen	344640
GARD	0003576
Is cancer (heuristic)	no

Also known as: functional methionine synthase deficiency type cblE · HMAE · homocystinuria due to defect in methylation Cbl e · homocystinuria-megaloblastic Anaemia due to defect in cobalamin metabolism, cblE complementation type · homocystinuria-megaloblastic anemia, cbl e type · homocystinuria-megaloblastic anemia, cblE complementation type · methylcobalamin deficiency type cblE

Data availability: 886 ClinVar variants · 4 GenCC gene-disease records · 12 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 cblE

Related subtypes (3): methylcobalamin deficiency type cblG, 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:

378 likely benign, 115 uncertain significance, 37 pathogenic, 27 benign, 21 likely pathogenic, 13 pathogenic/likely pathogenic, 6 conflicting classifications of pathogenicity, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1068644	NM_002454.3(MTRR):c.718_719del (p.Leu240fs)	MTRR	Pathogenic	criteria provided, single submitter
1068647	NM_002454.3(MTRR):c.1156C>T (p.Arg386Ter)	MTRR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070124	NM_002454.3(MTRR):c.1652dup (p.Phe552fs)	MTRR	Pathogenic	criteria provided, single submitter
1070924	NM_002454.3(MTRR):c.1048_1049del (p.Lys350fs)	MTRR	Pathogenic	criteria provided, single submitter
1071439	NM_002454.3(MTRR):c.1339A>T (p.Lys447Ter)	MTRR	Pathogenic	criteria provided, single submitter
1072380	NM_002454.3(MTRR):c.1314_1315insCTGCCAGCCACCACTC (p.Ser439fs)	MTRR	Pathogenic	criteria provided, single submitter
1176807	NM_002454.3(MTRR):c.166G>A (p.Val56Met)	MTRR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1364376	NM_002454.3(MTRR):c.1476del (p.Trp492fs)	MTRR	Pathogenic	criteria provided, single submitter
1379312	NM_002454.3(MTRR):c.1612dup (p.Ile538fs)	MTRR	Pathogenic	criteria provided, single submitter
1418809	NM_002454.3(MTRR):c.1504C>T (p.Gln502Ter)	MTRR	Pathogenic	criteria provided, single submitter
1432431	NM_002454.3(MTRR):c.763C>T (p.Gln255Ter)	MTRR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1442465	NM_002454.3(MTRR):c.340del (p.Arg114fs)	MTRR	Pathogenic	criteria provided, single submitter
1451191	NM_002454.3(MTRR):c.1123G>T (p.Glu375Ter)	MTRR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452568	NM_002454.3(MTRR):c.228dup (p.Gln77fs)	MTRR	Pathogenic	criteria provided, single submitter
1452948	NM_002454.3(MTRR):c.354_358del (p.Gly119fs)	MTRR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453171	NM_002454.3(MTRR):c.815del (p.Pro272fs)	MTRR	Pathogenic	criteria provided, single submitter
1454375	NM_002454.3(MTRR):c.1049_1052del (p.Lys350fs)	MTRR	Pathogenic	criteria provided, single submitter
1456920	NM_002454.3(MTRR):c.1728del (p.Leu576fs)	MTRR	Pathogenic	criteria provided, single submitter
1458061	NC_000005.9:g.(?7870908)(7900171_?)del	MTRR	Pathogenic	criteria provided, single submitter
1466138	NM_002454.3(MTRR):c.1554_1557+3del	MTRR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1909287	NM_002454.3(MTRR):c.495dup (p.Ala166fs)	MTRR	Pathogenic	criteria provided, single submitter
1958969	NM_002454.3(MTRR):c.1129C>T (p.Arg377Ter)	MTRR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1986861	NM_002454.3(MTRR):c.645_648del (p.Gln216fs)	MTRR	Pathogenic	criteria provided, single submitter
1999085	NM_002454.3(MTRR):c.901del (p.Ser301fs)	MTRR	Pathogenic	criteria provided, single submitter
2009670	NM_002454.3(MTRR):c.930_934del (p.Asp311fs)	MTRR	Pathogenic	criteria provided, single submitter
2029285	NM_002454.3(MTRR):c.1394dup (p.Leu466fs)	MTRR	Pathogenic	criteria provided, single submitter
2035984	NM_002454.3(MTRR):c.920dup (p.Tyr307Ter)	MTRR	Pathogenic	criteria provided, single submitter
2040134	NM_002454.3(MTRR):c.1020C>A (p.Cys340Ter)	MTRR	Pathogenic	criteria provided, single submitter
2078287	NM_002454.3(MTRR):c.290del (p.Gly97fs)	MTRR	Pathogenic	criteria provided, single submitter
2089994	NM_002454.3(MTRR):c.1441dup (p.Thr481fs)	MTRR	Pathogenic	criteria provided, single submitter

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
MTRR	Definitive	Autosomal recessive	methylcobalamin deficiency type cblE	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MTRR	Orphanet:2169	Methylcobalamin deficiency type cblE
PER3	Orphanet:164736	Familial advanced sleep-phase syndrome

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
MTRR	HGNC:7473	ENSG00000124275	Q9UBK8	Methionine synthase reductase	gencc,clinvar
PER3	HGNC:8847	ENSG00000049246	P56645	Period circadian protein homolog 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
PER3	Period circadian protein homolog 3	Originally described as a core component of the circadian clock.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

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)	1	6.0×	0.228
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MTRR	Enzyme (other)	yes	1.16.1.8	Flavdoxin-like, OxRdtase_FAD/NAD-bd, Flavoprot_Pyr_Nucl_cyt_Rdtase
PER3	Transcription factor	no		PAS, PAS_fold_3, Period_circadian-like_C

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
choroid plexus epithelium	1
endothelial cell	1
pancreatic ductal cell	1
cerebellar vermis	1
parietal pleura	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MTRR	291	ubiquitous	marker	endothelial cell, pancreatic ductal cell, choroid plexus epithelium
PER3	278	ubiquitous	marker	sural nerve, parietal pleura, cerebellar vermis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MTRR	1,455
PER3	898

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MTRR	Q9UBK8	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PER3	P56645	54.62

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	1	2855.0×	0.004	MTRR
Defective MTR causes HMAG	1	2855.0×	0.004	MTRR
Cobalamin (Cbl) metabolism	1	634.4×	0.007	MTRR
Phosphorylation of CLOCK, acetylation of BMAL1 (ARNTL) at target gene promoters	1	439.2×	0.007	PER3
Methylation	1	407.9×	0.007	MTRR
Defects in cobalamin (B12) metabolism	1	407.9×	0.007	MTRR
Phosphorylation and nuclear translocation of the CRY:PER:kinase complex	1	407.9×	0.007	PER3
The CRY:PER:kinase complex represses transactivation by the BMAL:CLOCK (ARNTL:CLOCK) complex	1	356.9×	0.007	PER3
Cobalamin (Cbl, vitamin B12) transport and metabolism	1	317.2×	0.007	MTRR
Defects in vitamin and cofactor metabolism	1	300.5×	0.007	MTRR
Sulfur amino acid metabolism	1	285.5×	0.007	MTRR
Phosphorylated BMAL1:CLOCK (ARNTL:CLOCK) activates expression of core clock genes	1	237.9×	0.007	PER3
Phase II - Conjugation of compounds	1	139.3×	0.012	MTRR
Degradation of CRY and PER proteins	1	109.8×	0.014	PER3
Metabolism of water-soluble vitamins and cofactors	1	90.6×	0.015	MTRR
Biological oxidations	1	64.9×	0.020	MTRR
Metabolism of vitamins and cofactors	1	58.3×	0.021	MTRR
Diseases of metabolism	1	40.2×	0.029	MTRR
Metabolism of amino acids and derivatives	1	33.8×	0.032	MTRR
Disease	1	6.5×	0.154	MTRR
Metabolism	1	5.8×	0.165	MTRR

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
L-homocysteine catabolic process	1	2808.7×	0.002	MTRR
L-methionine cycle	1	2106.5×	0.002	MTRR
obsolete methionine biosynthetic process	1	1685.2×	0.002	MTRR
regulation of circadian sleep/wake cycle, sleep	1	1203.7×	0.002	PER3
homocysteine metabolic process	1	936.2×	0.002	MTRR
cobalamin metabolic process	1	766.0×	0.002	MTRR
folic acid metabolic process	1	561.7×	0.003	MTRR
entrainment of circadian clock by photoperiod	1	366.4×	0.004	PER3
circadian regulation of gene expression	1	117.0×	0.010	PER3
protein stabilization	1	33.4×	0.033	PER3
negative regulation of transcription by RNA polymerase II	1	8.9×	0.110	PER3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MTRR	0	0
PER3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
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

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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	1	PER3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MTRR	0	—
PER3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns