methylmalonic acidemia with homocystinuria, type cblX

Summary

methylmalonic acidemia with homocystinuria, type cblX (MONDO:0010657) is a disease caused by HCFC1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: HCFC1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 1,179

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		18	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	methylmalonic acidemia with homocystinuria, type cblX
Mondo ID	MONDO:0010657
MeSH	C563136
OMIM	309541
Orphanet	369962
DOID	DOID:0111814
UMLS	C0796208
MedGen	167111
GARD	0013137
Is cancer (heuristic)	no

Also known as: combined defect in adenosylcobalamin and methylcobalamin synthesis, type cblX · intellectual disability, X-linked 3 · mental retardation, X-linked 3 · methylmalonic acidemia and homocysteinemia type cblX · methylmalonic aciduria and homocysteinemia, cblx type, X-linked recessive · methylmalonic aciduria with homocystinuria, type cblX

Data availability: 1,179 ClinVar variants · 5 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 acidemia with homocystinuria, type cblX

Related subtypes (5): methylmalonic aciduria and homocystinuria type cblF, methylmalonic aciduria and homocystinuria type cblC, methylmalonic aciduria and homocystinuria type cblD, 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

600 retrieved; paginated sample, class counts are floors:

385 likely benign, 78 benign, 77 uncertain significance, 35 conflicting classifications of pathogenicity, 24 benign/likely benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
224121	NM_005334.3(HCFC1):c.5048C>G (p.Pro1683Arg)	HCFC1	Pathogenic	criteria provided, single submitter
1026537	NM_005334.3(HCFC1):c.4687G>A (p.Gly1563Ser)	HCFC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1032310	NM_005334.3(HCFC1):c.4566G>A (p.Ser1522=)	HCFC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
129220	NM_005334.3(HCFC1):c.3290A>C (p.Asn1097Thr)	HCFC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1336537	NM_005334.3(HCFC1):c.5889C>T (p.Ser1963=)	HCFC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1343602	NM_005334.3(HCFC1):c.4052C>A (p.Pro1351His)	HCFC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1448986	NM_005334.3(HCFC1):c.3604G>A (p.Gly1202Arg)	HCFC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1657821	NM_005334.3(HCFC1):c.3455C>G (p.Ala1152Gly)	HCFC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
167164	NM_005334.3(HCFC1):c.6042C>T (p.Asn2014=)	HCFC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2053803	NM_005334.3(HCFC1):c.2972C>G (p.Thr991Ser)	HCFC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2080900	NM_005334.3(HCFC1):c.5726C>G (p.Thr1909Ser)	HCFC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
208779	NM_005334.3(HCFC1):c.3356C>T (p.Thr1119Ile)	HCFC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211129	NM_005334.3(HCFC1):c.1084+8C>T	HCFC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211130	NM_005334.3(HCFC1):c.2463T>A (p.Ile821=)	HCFC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211131	NM_005334.3(HCFC1):c.2691G>A (p.Ala897=)	HCFC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211133	NM_005334.3(HCFC1):c.3126G>A (p.Gln1042=)	HCFC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211134	NM_005334.3(HCFC1):c.3492C>T (p.Ser1164=)	HCFC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211135	NM_005334.3(HCFC1):c.3690G>A (p.Ala1230=)	HCFC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211137	NM_005334.3(HCFC1):c.905-3C>T	HCFC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
211138	NM_005334.3(HCFC1):c.984C>T (p.Val328=)	HCFC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2179864	NM_005334.3(HCFC1):c.4948G>A (p.Gly1650Ser)	HCFC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
235900	NM_005334.3(HCFC1):c.1429G>A (p.Ala477Thr)	HCFC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2432376	NM_005334.3(HCFC1):c.3260C>G (p.Thr1087Ser)	HCFC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2573542	NM_005334.3(HCFC1):c.3845C>T (p.Ser1282Leu)	HCFC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2590761	NM_005334.3(HCFC1):c.3758G>A (p.Arg1253His)	HCFC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2634672	NM_005334.3(HCFC1):c.3489G>A (p.Lys1163=)	HCFC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2635816	NM_005334.3(HCFC1):c.5113G>A (p.Ala1705Thr)	HCFC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2661765	NM_005334.3(HCFC1):c.4639G>A (p.Val1547Met)	HCFC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2661768	NM_005334.3(HCFC1):c.3976G>A (p.Glu1326Lys)	HCFC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2689200	NM_005334.3(HCFC1):c.939A>G (p.Thr313=)	HCFC1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
HCFC1	Definitive	X-linked	methylmalonic acidemia with homocystinuria, type cblX	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HCFC1	Orphanet:369962	Methylmalonic acidemia with homocystinuria, type cblX
HCFC1	Orphanet:777	X-linked non-syndromic intellectual disability

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
HCFC1	HGNC:4839	ENSG00000172534	P51610	Host cell factor 1	gencc,clinvar
CENPT	HGNC:25787	ENSG00000102901	Q96BT3	Centromere protein T	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HCFC1	Host cell factor 1	Transcriptional coregulator.
CENPT	Centromere protein T	Component of the CENPA-NAC (nucleosome-associated) complex, a complex that plays a central role in assembly of kinetochore proteins, mitotic progression and chromosome segregation.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · 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
Antibody/Immunoglobulin	1	14.6×	0.135
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HCFC1	Antibody/Immunoglobulin	yes		FN3_dom, Ig-like_fold, Kelch-typ_b-propeller
CENPT	Other/Unknown	no		Histone-fold, CENP-T, CENP-T_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
parotid gland	1
skeletal muscle tissue of rectus abdominis	1
tendon of biceps brachii	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HCFC1	274	ubiquitous	marker	tendon of biceps brachii, parotid gland, skeletal muscle tissue of rectus abdominis
CENPT	181	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HCFC1	2,637
CENPT	1,010

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HCFC1	P51610	11
CENPT	Q96BT3	9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 25. 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
Nucleosome assembly	1	237.9×	0.040	CENPT
Formation of WDR5-containing histone-modifying complexes	1	132.8×	0.040	HCFC1
Chromosome Maintenance	1	105.7×	0.040	CENPT
Transcriptional activation of mitochondrial biogenesis	1	102.0×	0.040	HCFC1
Amplification of signal from the kinetochores	1	98.5×	0.040	CENPT
Deposition of new CENPA-containing nucleosomes at the centromere	1	79.3×	0.040	CENPT
Mitotic Spindle Checkpoint	1	79.3×	0.040	CENPT
UCH proteinases	1	62.1×	0.040	HCFC1
Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal	1	58.3×	0.040	CENPT
Mitotic Metaphase and Anaphase	1	48.4×	0.040	CENPT
Mitotic Anaphase	1	48.4×	0.040	CENPT
EML4 and NUDC in mitotic spindle formation	1	46.4×	0.040	CENPT
Cell Cycle Checkpoints	1	44.3×	0.040	CENPT
Resolution of Sister Chromatid Cohesion	1	43.3×	0.040	CENPT
HATs acetylate histones	1	39.6×	0.040	HCFC1
RHO GTPases Activate Formins	1	38.8×	0.040	CENPT
Mitotic Prometaphase	1	34.6×	0.040	CENPT
RHO GTPase Effectors	1	34.0×	0.040	CENPT
M Phase	1	33.0×	0.040	CENPT
Separation of Sister Chromatids	1	30.4×	0.041	CENPT
Cell Cycle, Mitotic	1	24.1×	0.049	CENPT
Cell Cycle	1	18.0×	0.061	CENPT
Signaling by Rho GTPases	1	17.1×	0.061	CENPT
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	16.7×	0.061	CENPT
Signal Transduction	1	5.1×	0.187	CENPT

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
release from viral latency	1	2808.7×	0.006	HCFC1
kinetochore assembly	1	601.9×	0.012	CENPT
regulation of protein-containing complex assembly	1	366.4×	0.012	HCFC1
chromosome organization	1	290.6×	0.012	CENPT
blastocyst hatching	1	271.8×	0.012	HCFC1
positive regulation of cell cycle	1	221.7×	0.012	HCFC1
chromosome segregation	1	86.9×	0.026	CENPT
mitotic cell cycle	1	66.9×	0.030	CENPT
chromatin remodeling	1	36.5×	0.047	HCFC1
protein stabilization	1	33.4×	0.047	HCFC1
cell division	1	23.1×	0.062	CENPT
positive regulation of gene expression	1	19.4×	0.068	HCFC1
regulation of DNA-templated transcription	1	15.8×	0.077	HCFC1
positive regulation of DNA-templated transcription	1	14.0×	0.080	HCFC1
negative regulation of transcription by RNA polymerase II	1	8.9×	0.117	HCFC1
positive regulation of transcription by RNA polymerase II	1	7.4×	0.130	HCFC1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · 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).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HCFC1	1	2
CENPT	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	HCFC1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
HCFC1	8	Binding:8

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)
MOLIBRESIB	2	HCFC1

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	1	HCFC1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CENPT

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)
CENPT	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.