Charcot-Marie-Tooth disease, demyelinating, IIA 1H

Summary

Charcot-Marie-Tooth disease, demyelinating, IIA 1H (MONDO:0030689) is a disease caused by FBLN5 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: FBLN5 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 11

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease, demyelinating, IIA 1H
Mondo ID	MONDO:0030689
OMIM	619764
UMLS	C5676926
MedGen	1804752
GARD	0025612
Is cancer (heuristic)	no

Also known as: Charcot-Marie-Tooth disease, demyelinating, IIA 1H · Charcot-Marie-Tooth neuropathy, IIA 1H · CMT1H · hereditary motor and sensory neuropathy, 1h · neuropathy, hereditary, with or without age-related macular degeneration

Data availability: 11 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › peripheral nervous system disorder › peripheral neuropathy › hereditary peripheral neuropathy › Charcot-Marie-Tooth disease › Charcot-Marie-Tooth disease, demyelinating, IIA 1H

Related subtypes (23): Charcot-Marie-Tooth disease, Guadalajara neuronal type, Charcot-Marie-Tooth disease with ptosis and parkinsonism, Charcot-Marie-Tooth disease type 3, neuronopathy, distal hereditary motor, autosomal dominant 1, neuropathy, hereditary motor and sensory, type 6A, Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;, demyelinating hereditary motor and sensory neuropathy, intermediate Charcot-Marie-Tooth disease, Charcot-Marie-Tooth disease type 2, Charcot-Marie-Tooth disease type X, Charcot-Marie-Tooth disease type 4, Charcot-Marie-Tooth disease type 1, Charcot-Marie-Tooth disease, axonal, mitochondrial form, 1, Charcot-Marie-Tooth disease, axonal, type 2FF, Charcot-Marie-Tooth disease, axonal, Type 2HH, Charcot-Marie-Tooth disease, demyelinating, IIA 1I, Charcot-Marie-Tooth disease, axonal, IIa 2II, Charcot-Marie-Tooth disease, demyelinating, type 1G, Charcot-Marie-Tooth disease, demyelinating, type 1J, Charcot-Marie-tooth disease, axonal, type 2JJ, Charcot-Marie-Tooth disease, axonal, type 2KK, Charcot-Marie-Tooth disease, axonal, type 2LL, charcot-marie-tooth disease, axonal, type 2MM

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

11 retrieved; paginated sample, class counts are floors:

6 uncertain significance, 2 conflicting classifications of pathogenicity, 1 pathogenic, 1 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1342916	NM_006329.4(FBLN5):c.986A>T (p.Asp329Val)	FBLN5	Pathogenic	no assertion criteria provided
218358	NM_006329.4(FBLN5):c.1117C>T (p.Arg373Cys)	FBLN5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3065380	NM_006329.4(FBLN5):c.160C>T (p.Arg54Ter)	FBLN5	Likely pathogenic	criteria provided, single submitter
218359	NM_006329.4(FBLN5):c.268G>A (p.Gly90Ser)	FBLN5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
218360	NM_006329.4(FBLN5):c.376G>A (p.Val126Met)	FBLN5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1172837	NM_006329.4(FBLN5):c.245A>C (p.Asn82Thr)	FBLN5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1342917	NM_006329.4(FBLN5):c.992G>A (p.Arg331His)	FBLN5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1463161	NM_006329.4(FBLN5):c.1076G>A (p.Arg359His)	FBLN5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1519738	NM_006329.4(FBLN5):c.834C>G (p.Ile278Met)	FBLN5	Uncertain significance	criteria provided, multiple submitters, no conflicts
502499	NM_006329.4(FBLN5):c.799G>A (p.Gly267Ser)	FBLN5	Uncertain significance	criteria provided, multiple submitters, no conflicts
5481	NM_006329.4(FBLN5):c.1051C>T (p.Arg351Trp)	FBLN5	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 3 · 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
FBLN5	Strong	Autosomal dominant	Charcot-Marie-Tooth disease, demyelinating, IIA 1H	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FBLN5	Orphanet:280598	Hereditary sensorimotor neuropathy with hyperelastic skin
FBLN5	Orphanet:90348	Autosomal dominant cutis laxa
FBLN5	Orphanet:90349	Autosomal recessive cutis laxa type 1

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
FBLN5	HGNC:3602	ENSG00000140092	Q9UBX5	Fibulin-5	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FBLN5	Fibulin-5	Essential for elastic fiber formation, is involved in the assembly of continuous elastin (ELN) polymer and promotes the interaction of microfibrils and ELN.

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)
FBLN5	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom

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
ascending aorta	1
descending thoracic aorta	1
thoracic aorta	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FBLN5	261	ubiquitous	marker	thoracic aorta, ascending aorta, descending thoracic aorta

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FBLN5	2,301

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FBLN5	Q9UBX5	83.69

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Elastic fibre formation	1	335.9×	0.003	FBLN5
Molecules associated with elastic fibres	1	308.6×	0.003	FBLN5

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
intramembranous bone growth	1	16852.0×	6e-04	FBLN5
regulation of removal of superoxide radicals	1	2808.7×	0.002	FBLN5
secretion	1	2106.5×	0.002	FBLN5
elastic fiber assembly	1	1532.0×	0.002	FBLN5
positive regulation of osteoblast proliferation	1	1203.7×	0.002	FBLN5
protein localization to cell surface	1	495.6×	0.003	FBLN5
negative regulation of angiogenesis	1	168.5×	0.008	FBLN5
cell-matrix adhesion	1	163.6×	0.008	FBLN5
negative regulation of transcription by RNA polymerase II	1	17.7×	0.063	FBLN5
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	FBLN5

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
FBLN5	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	FBLN5

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)
FBLN5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.