Methylmalonic acidemia due to transcobalamin receptor defect

Summary

Methylmalonic acidemia due to transcobalamin receptor defect (MONDO:0013341) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 163

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	methylmalonic acidemia due to transcobalamin receptor defect
Mondo ID	MONDO:0013341
OMIM	613646
Orphanet	280183
DOID	DOID:0060741
UMLS	C4749905
MedGen	1670056
GARD	0016481
Is cancer (heuristic)	no

Also known as: CD320 methylmalonic acidemia · methylmalonic acidemia caused by mutation in CD320 · methylmalonic acidemia, TCb1R type · methylmalonic acidemia, TCbIR type · methylmalonic aciduria due to transcobalamin receptor defect

Data availability: 163 ClinVar variants · 4 GenCC gene-disease records · 1 cell line.

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 › inborn organic aciduria › methylmalonic acidemia › methylmalonic acidemia due to transcobalamin receptor defect

Related subtypes (6): methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency, methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency, combined malonic and methylmalonic acidemia, methylmalonic aciduria and homocystinuria, vitamin B12-responsive methylmalonic acidemia, isolated methylmalonic aciduria 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

163 retrieved; paginated sample, class counts are floors:

91 uncertain significance, 51 likely benign, 13 benign, 5 benign/likely benign, 2 conflicting classifications of pathogenicity, 1 conflicting classifications of pathogenicity; other

ClinVar	Variant (HGVS)	Gene	Classification	Review
1421005	NM_016579.4(CD320):c.7G>A (p.Gly3Ser)	CD320	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
203643	NM_016579.4(CD320):c.256GAG[2] (p.Glu88del)	CD320	Conflicting classifications of pathogenicity; other	criteria provided, conflicting classifications
2064661	NM_016579.4(CD320):c.337G>A (p.Val113Ile)	CD320	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1018004	NM_016579.4(CD320):c.451C>T (p.Arg151Cys)	CD320	Uncertain significance	criteria provided, single submitter
1024024	NM_016579.4(CD320):c.305C>T (p.Pro102Leu)	CD320	Uncertain significance	criteria provided, single submitter
1054168	NM_016579.4(CD320):c.412C>A (p.Arg138Ser)	CD320	Uncertain significance	criteria provided, multiple submitters, no conflicts
1055816	NM_016579.4(CD320):c.634G>T (p.Gly212Trp)	CD320	Uncertain significance	criteria provided, single submitter
1060439	NM_016579.4(CD320):c.88G>C (p.Gly30Arg)	CD320	Uncertain significance	criteria provided, multiple submitters, no conflicts
1063339	NM_016579.4(CD320):c.760C>T (p.Arg254Ter)	CD320	Uncertain significance	criteria provided, single submitter
1298738	NM_016579.4(CD320):c.731C>T (p.Thr244Ile)	CD320	Uncertain significance	criteria provided, multiple submitters, no conflicts
1383199	NM_016579.4(CD320):c.167C>T (p.Pro56Leu)	CD320	Uncertain significance	criteria provided, single submitter
1416159	NM_016579.4(CD320):c.386G>T (p.Arg129Leu)	CD320	Uncertain significance	criteria provided, multiple submitters, no conflicts
1432781	NM_016579.4(CD320):c.679A>G (p.Thr227Ala)	CD320	Uncertain significance	criteria provided, single submitter
1439352	NM_016579.4(CD320):c.773G>A (p.Arg258His)	CD320	Uncertain significance	criteria provided, multiple submitters, no conflicts
1439701	NM_016579.4(CD320):c.32C>A (p.Ala11Glu)	CD320	Uncertain significance	criteria provided, single submitter
1475517	NM_016579.4(CD320):c.178C>T (p.Gln60Ter)	CD320	Uncertain significance	criteria provided, single submitter
1523982	NM_016579.4(CD320):c.32C>T (p.Ala11Val)	CD320	Uncertain significance	criteria provided, single submitter
1714587	NM_016579.4(CD320):c.242G>A (p.Ser81Asn)	CD320	Uncertain significance	criteria provided, single submitter
1718921	NM_016579.4(CD320):c.139G>C (p.Ala47Pro)	CD320	Uncertain significance	criteria provided, single submitter
1946206	NM_016579.4(CD320):c.839C>T (p.Ser280Leu)	CD320	Uncertain significance	criteria provided, single submitter
1998831	NM_016579.4(CD320):c.142+4A>G	CD320	Uncertain significance	criteria provided, single submitter
2006693	NM_016579.4(CD320):c.179A>T (p.Gln60Leu)	CD320	Uncertain significance	criteria provided, single submitter
2006695	NM_016579.4(CD320):c.96G>C (p.Glu32Asp)	CD320	Uncertain significance	criteria provided, single submitter
2008266	NM_016579.4(CD320):c.168_171del (p.Thr57fs)	CD320	Uncertain significance	criteria provided, single submitter
2017815	NM_016579.4(CD320):c.622_624del (p.Val208del)	CD320	Uncertain significance	criteria provided, single submitter
2060586	NM_016579.4(CD320):c.521C>T (p.Pro174Leu)	CD320	Uncertain significance	criteria provided, single submitter
2062092	NM_016579.4(CD320):c.314G>T (p.Gly105Val)	CD320	Uncertain significance	criteria provided, single submitter
2071104	NM_016579.4(CD320):c.509A>G (p.Asn170Ser)	CD320	Uncertain significance	criteria provided, multiple submitters, no conflicts
2089940	NM_016579.4(CD320):c.229G>A (p.Asp77Asn)	CD320	Uncertain significance	criteria provided, single submitter
2106444	NM_016579.4(CD320):c.302C>G (p.Pro101Arg)	CD320	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
CD320	Supportive	Autosomal recessive	methylmalonic acidemia due to transcobalamin receptor defect	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CD320	Orphanet:280183	Methylmalonic aciduria due to transcobalamin receptor defect

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CD320	HGNC:16692	ENSG00000167775	Q9NPF0	CD320 antigen	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CD320	CD320 antigen	Receptor for transcobalamin saturated with cobalamin (TCbl).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CD320	Other/Unknown	no		LDrepeatLR_classA_rpt, LDLR_class-A_CS, LDL_receptor-like_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
left testis	1
mucosa of transverse colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CD320	256	ubiquitous	marker	mucosa of transverse colon, apex of heart, left testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CD320	708

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CD320	Q9NPF0	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective CD320 causes MMATC	1	5710.0×	0.002	CD320
Transport of RCbl within the body	1	1427.5×	0.003	CD320
Defects in cobalamin (B12) metabolism	1	815.7×	0.003	CD320
Cobalamin (Cbl, vitamin B12) transport and metabolism	1	634.4×	0.003	CD320
Defects in vitamin and cofactor metabolism	1	601.0×	0.003	CD320
Metabolism of water-soluble vitamins and cofactors	1	181.3×	0.009	CD320
Metabolism of vitamins and cofactors	1	116.5×	0.012	CD320
Diseases of metabolism	1	80.4×	0.016	CD320
Disease	1	13.1×	0.085	CD320
Metabolism	1	11.6×	0.086	CD320

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of vitamin metabolic process	1	16852.0×	2e-04	CD320
B cell costimulation	1	5617.3×	4e-04	CD320
cobalamin transport	1	1872.4×	7e-04	CD320
positive regulation of B cell proliferation	1	343.9×	0.003	CD320

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
CD320	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	CD320

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)
CD320	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.