methylmalonic aciduria and homocystinuria type cblF

Summary

methylmalonic aciduria and homocystinuria type cblF (MONDO:0010183) is a disease caused by LMBRD1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: LMBRD1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 441
• Phenotypes (HPO): 28

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		15	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

28 HPO clinical features (Orphanet curated; top 28 by frequency):

HPO ID	Term	Frequency
HP:0001889	Megaloblastic anemia	Very frequent (80-99%)
HP:0002160	Hyperhomocystinemia	Very frequent (80-99%)
HP:0003145	Decreased adenosylcobalamin	Very frequent (80-99%)
HP:0003223	Decreased methylcobalamin	Very frequent (80-99%)
HP:0012120	Methylmalonic aciduria	Very frequent (80-99%)
HP:0031544	Elevated propionylcarnitine level	Very frequent (80-99%)
HP:0100502	Decreased circulating vitamin B12 concentration	Very frequent (80-99%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001254	Lethargy	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0001511	Intrauterine growth retardation	Frequent (30-79%)
HP:0001627	Abnormal heart morphology	Frequent (30-79%)
HP:0001999	Abnormal facial shape	Frequent (30-79%)
HP:0002719	Recurrent infections	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0012758	Neurodevelopmental delay	Frequent (30-79%)
HP:0000122	Unilateral renal agenesis	Occasional (5-29%)
HP:0000175	Cleft palate	Occasional (5-29%)
HP:0000206	Glossitis	Occasional (5-29%)
HP:0000988	Skin rash	Occasional (5-29%)
HP:0001875	Decreased total neutrophil count	Occasional (5-29%)
HP:0006571	Reduced number of intrahepatic bile ducts	Occasional (5-29%)
HP:0010280	Stomatitis	Occasional (5-29%)
HP:0030746	Intraventricular hemorrhage	Occasional (5-29%)
HP:0003658	Hypomethioninemia	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	methylmalonic aciduria and homocystinuria type cblF
Mondo ID	MONDO:0010183
MeSH	C564747
OMIM	277380
Orphanet	79284
DOID	DOID:0050717
SNOMED CT	80887004
UMLS	C1848578
MedGen	336373
GARD	0003584
Is cancer (heuristic)	no

Also known as: cblF defect · cobalamin F defect · combined defect in adenosylcobalamin and methylcobalamin synthesis, type cblF · inherited methylmalonic acidemia and homocystinuria · lysosomal membrane cobalamin transporter deficiency · MAHCF · methylmalonic aciduria and homocystinuria type cblF · methylmalonic aciduria with homocystinuria, type cblF

Data availability: 441 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: 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 › inborn organic aciduria › methylmalonic acidemia › methylmalonic aciduria and homocystinuria › methylmalonic aciduria and homocystinuria type cblF

Related subtypes (5): methylmalonic aciduria and homocystinuria type cblC, methylmalonic aciduria and homocystinuria type cblD, methylmalonic acidemia with homocystinuria, type cblX, methylmalonic acidemia with homocystinuria, type cblJ, methylmalonic aciduria and homocystinuria, cb1L 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

441 retrieved; paginated sample, class counts are floors:

244 likely benign, 106 uncertain significance, 28 pathogenic, 26 likely pathogenic, 16 benign, 9 conflicting classifications of pathogenicity, 8 benign/likely benign, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1456629	NC_000006.11:g.(?70386050)(71012627_?)del	COL19A1	Pathogenic	criteria provided, single submitter
1070033	NM_018368.4(LMBRD1):c.967_970del (p.Leu323fs)	LMBRD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323238	NM_018368.4(LMBRD1):c.1339-1G>T	LMBRD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1371786	NM_018368.4(LMBRD1):c.399del (p.Lys133fs)	LMBRD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1459108	NC_000006.11:g.(?70459213)(70462268_?)del	LMBRD1	Pathogenic	criteria provided, single submitter
1687319	NM_018368.4(LMBRD1):c.1094_1095del (p.Leu365fs)	LMBRD1	Pathogenic	criteria provided, single submitter
1963521	NC_000006.12:g.69780555del	LMBRD1	Pathogenic	criteria provided, single submitter
225048	NM_018368.4(LMBRD1):c.1056del (p.Asn353fs)	LMBRD1	Pathogenic	criteria provided, multiple submitters, no conflicts
2706238	NM_018368.4(LMBRD1):c.741_742del (p.Ile248fs)	LMBRD1	Pathogenic	criteria provided, single submitter
2712623	NM_018368.4(LMBRD1):c.358del (p.Tyr120fs)	LMBRD1	Pathogenic	criteria provided, single submitter
2726203	NM_018368.4(LMBRD1):c.376A>T (p.Lys126Ter)	LMBRD1	Pathogenic	criteria provided, single submitter
2734911	NM_018368.4(LMBRD1):c.848_851del (p.Glu283fs)	LMBRD1	Pathogenic	criteria provided, single submitter
2745402	NM_018368.4(LMBRD1):c.1172G>A (p.Trp391Ter)	LMBRD1	Pathogenic	criteria provided, single submitter
2748820	NM_018368.4(LMBRD1):c.528del (p.Lys176_Val177insTer)	LMBRD1	Pathogenic	criteria provided, single submitter
2761830	NM_018368.4(LMBRD1):c.229C>T (p.Gln77Ter)	LMBRD1	Pathogenic	criteria provided, single submitter
2780339	NM_018368.4(LMBRD1):c.614del (p.Met205fs)	LMBRD1	Pathogenic	criteria provided, single submitter
2800010	NM_018368.4(LMBRD1):c.1321C>T (p.Gln441Ter)	LMBRD1	Pathogenic	criteria provided, single submitter
2838155	NM_018368.4(LMBRD1):c.481_484del (p.Val161fs)	LMBRD1	Pathogenic	criteria provided, single submitter
2896786	NM_018368.4(LMBRD1):c.63dup (p.Leu22fs)	LMBRD1	Pathogenic	criteria provided, single submitter
2914710	NM_018368.4(LMBRD1):c.1443C>A (p.Tyr481Ter)	LMBRD1	Pathogenic	criteria provided, single submitter
2986617	NM_018368.4(LMBRD1):c.829C>T (p.Arg277Ter)	LMBRD1	Pathogenic	criteria provided, single submitter
3002392	NM_018368.4(LMBRD1):c.373G>T (p.Glu125Ter)	LMBRD1	Pathogenic	criteria provided, single submitter
3003435	NM_018368.4(LMBRD1):c.775C>T (p.Arg259Ter)	LMBRD1	Pathogenic	criteria provided, single submitter
3010436	NM_018368.4(LMBRD1):c.1251dup (p.Leu418fs)	LMBRD1	Pathogenic	criteria provided, single submitter
3016240	NM_018368.4(LMBRD1):c.317_318del (p.Ser106fs)	LMBRD1	Pathogenic	criteria provided, single submitter
3594091	NM_018368.4(LMBRD1):c.916-1G>T	LMBRD1	Pathogenic	criteria provided, single submitter
3625107	NM_018368.4(LMBRD1):c.690del (p.Ala231fs)	LMBRD1	Pathogenic	criteria provided, single submitter
3663395	NC_000006.12:g.69697707_69697708insTATCAGATTATCAGAAGTTATATTAGTCTGAAAGATAAAAATACAGTTAAAATATAAAAACCGCATTAATAAATACATTTGGATTTAAAAAGT	LMBRD1	Pathogenic	criteria provided, single submitter
4731228	NM_018368.4(LMBRD1):c.1067del (p.Leu356fs)	LMBRD1	Pathogenic	criteria provided, single submitter
517	NM_018368.4(LMBRD1):c.515_516del (p.Thr172fs)	LMBRD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · 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
LMBRD1	Definitive	Autosomal recessive	methylmalonic aciduria and homocystinuria type cblF	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LMBRD1	Orphanet:79284	Methylmalonic acidemia with homocystinuria type cblF

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
LMBRD1	HGNC:23038	ENSG00000168216	Q9NUN5	Lysosomal cobalamin transport escort protein LMBD1	gencc,clinvar
COL19A1	HGNC:2196	ENSG00000082293	Q14993	Collagen alpha-1(XIX) chain	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LMBRD1	Lysosomal cobalamin transport escort protein LMBD1	Lysosomal membrane chaperone required to export cobalamin (vitamin B12) from the lysosome to the cytosol, allowing its conversion to cofactors.
COL19A1	Collagen alpha-1(XIX) chain	May act as a cross-bridge between fibrils and other extracellular matrix molecules.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LMBRD1	Other/Unknown	no		LMBR1-like_membr_prot, LMBD1_LysCbl_Transport
COL19A1	Other/Unknown	no		Collagen, ConA-like_dom_sf, TSPN-like_N

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
oocyte	1
pigmented layer of retina	1
secondary oocyte	1
male germ line stem cell (sensu Vertebrata) in testis	1
mucosa of stomach	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LMBRD1	288	ubiquitous	marker	secondary oocyte, oocyte, pigmented layer of retina
COL19A1	153	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, mucosa of stomach

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COL19A1	984
LMBRD1	609

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LMBRD1	Q9NUN5	84.17
COL19A1	Q14993	55.83

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. 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 ABCD4 causes MAHCJ	1	2855.0×	0.006	LMBRD1
Transport of RCbl within the body	1	713.8×	0.009	LMBRD1
Uptake of dietary cobalamins into enterocytes	1	571.0×	0.009	LMBRD1
Defects in cobalamin (B12) metabolism	1	407.9×	0.009	LMBRD1
Cobalamin (Cbl, vitamin B12) transport and metabolism	1	317.2×	0.009	LMBRD1
Defects in vitamin and cofactor metabolism	1	300.5×	0.009	LMBRD1
ABC transporter disorders	1	219.6×	0.010	LMBRD1
Collagen chain trimerization	1	129.8×	0.015	COL19A1
Metabolism of water-soluble vitamins and cofactors	1	90.6×	0.017	LMBRD1
Collagen degradation	1	87.8×	0.017	COL19A1
Collagen biosynthesis and modifying enzymes	1	85.2×	0.017	COL19A1
Disorders of transmembrane transporters	1	69.6×	0.019	LMBRD1
Metabolism of vitamins and cofactors	1	58.3×	0.021	LMBRD1
Diseases of metabolism	1	40.2×	0.028	LMBRD1
Disease	1	6.5×	0.157	LMBRD1
Metabolism	1	5.8×	0.165	LMBRD1

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
insulin receptor internalization	1	2808.7×	0.004	LMBRD1
protein localization to lysosome	1	526.6×	0.009	LMBRD1
gastrulation	1	351.1×	0.009	LMBRD1
clathrin-dependent endocytosis	1	290.6×	0.009	LMBRD1
skeletal muscle tissue development	1	145.3×	0.014	COL19A1
skeletal system development	1	62.9×	0.023	COL19A1
extracellular matrix organization	1	61.1×	0.023	COL19A1
cell-cell adhesion	1	50.8×	0.025	COL19A1
cell adhesion	1	18.7×	0.059	COL19A1
cell differentiation	1	14.6×	0.068	COL19A1

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
LMBRD1	0	0
COL19A1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	LMBRD1, COL19A1

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)
LMBRD1	0	—
COL19A1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.