Charcot-Marie-Tooth disease axonal type 2P

Summary

Charcot-Marie-Tooth disease axonal type 2P (MONDO:0013753) is a disease caused by LRSAM1 (GenCC Strong), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: LRSAM1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 840
• Clinical trials: 1

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	Charcot-Marie-Tooth disease axonal type 2P
Mondo ID	MONDO:0013753
OMIM	608591, 614436
Orphanet	300319, 99941
DOID	DOID:0110169
SNOMED CT	719511005
UMLS	C3280797
MedGen	482427
GARD	0012435
Is cancer (heuristic)	no

Also known as: autosomal dominant Charcot-Marie-Tooth disease type 2G · Charcot Marie Tooth disease type 2G · Charcot-Marie-Tooth disease caused by mutation in LRSAM1 · Charcot-Marie-Tooth disease type 2G · Charcot-Marie-Tooth disease, axonal, type 2G · Charcot-Marie-Tooth disease, axonal, type 2P · Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, autosomal recessive · Charcot-Marie-Tooth disease, type 4A, axonal form · Charcot-Marie-Tooth neuropathy, type 2P · Charcot-Marie-Toothe disease, axonal, type 2P · CMT 2G · CMT2G · CMT2P · LRSAM1 Charcot-Marie-Tooth disease

Data availability: 840 ClinVar variants · 5 GenCC gene-disease records.

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 type 2 › Charcot-Marie-Tooth disease axonal type 2P

Related subtypes (37): Charcot-Marie-Tooth disease type 2A1, Charcot-Marie-Tooth disease type 2B, Charcot-Marie-Tooth disease type 2D, Charcot-Marie-Tooth disease type 2B1, Charcot-Marie-Tooth disease type 2B2, Charcot-Marie-Tooth disease axonal type 2C, Charcot-Marie-Tooth disease axonal type 2F, Charcot-Marie-Tooth disease type 2I, Charcot-Marie-Tooth disease type 2E, Charcot-Marie-Tooth disease axonal type 2H, Charcot-Marie-Tooth disease type 2J, Charcot-Marie-Tooth disease axonal type 2K, Charcot-Marie-Tooth disease axonal type 2L, Charcot-Marie-Tooth disease type 2A2, giant axonal neuropathy 2, Charcot-Marie-Tooth disease axonal type 2N, Charcot-Marie-Tooth disease axonal type 2O, Charcot-Marie-Tooth disease axonal type 2Q, Charcot-Marie-Tooth disease type 2R, Charcot-Marie-Tooth disease axonal type 2S, Charcot-Marie-Tooth disease axonal type 2U, Charcot-Marie-Tooth disease axonal type 2V, autosomal dominant Charcot-Marie-Tooth disease type 2W, Charcot-Marie-Tooth disease axonal type 2X, Charcot-Marie-Tooth disease type 2Y, Charcot-Marie-Tooth disease axonal type 2Z, Charcot-Marie-Tooth disease axonal type 2CC, autosomal dominant Charcot-Marie-Tooth disease type 2M, Charcot-Marie-Tooth disease type 2B5, autosomal dominant Charcot-Marie-Tooth disease type 2 due to KIF5A mutation, autosomal dominant Charcot-Marie-Tooth disease type 2 due to TFG mutation, autosomal dominant Charcot-Marie-Tooth disease type 2K, Charcot-Marie-Tooth disease, axonal, type 2EE, autosomal dominant charcot-marie-tooth disease type 2 due to DGAT2 mutation, Charcot-Marie-Tooth disease type 2T, MME-related autosomal dominant Charcot Marie Tooth disease type 2, Charcot-Marie-tooth disease, axonal, type 2DD

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:

263 uncertain significance, 220 likely benign, 32 pathogenic, 28 likely pathogenic, 27 conflicting classifications of pathogenicity, 13 benign/likely benign, 11 benign, 6 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1000445	NM_001005373.4(LRSAM1):c.382C>T (p.Gln128Ter)	LRSAM1	Pathogenic	criteria provided, single submitter
1046625	NM_001005373.4(LRSAM1):c.1956_1957dup (p.Gln653fs)	LRSAM1	Pathogenic	criteria provided, single submitter
1073788	NM_001005373.4(LRSAM1):c.988C>T (p.Gln330Ter)	LRSAM1	Pathogenic	criteria provided, single submitter
1076638	NM_001005373.4(LRSAM1):c.1144C>T (p.Arg382Ter)	LRSAM1	Pathogenic	criteria provided, single submitter
1076924	NM_001005373.4(LRSAM1):c.602dup (p.Leu201fs)	LRSAM1	Pathogenic	criteria provided, single submitter
1324683	NM_001005373.4(LRSAM1):c.517C>T (p.Arg173Ter)	LRSAM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1445717	NM_001005373.4(LRSAM1):c.1135_1136del (p.Ser379fs)	LRSAM1	Pathogenic	criteria provided, single submitter
1458236	NM_001005373.4(LRSAM1):c.2089C>T (p.Gln697Ter)	LRSAM1	Pathogenic	criteria provided, single submitter
1460311	NC_000009.11:g.(?130265033)(130265178_?)del	LRSAM1	Pathogenic	criteria provided, single submitter
1512430	NM_001005373.4(LRSAM1):c.352C>T (p.Gln118Ter)	LRSAM1	Pathogenic	criteria provided, single submitter
1762915	NM_001005373.4(LRSAM1):c.831del (p.Gln278fs)	LRSAM1	Pathogenic	criteria provided, multiple submitters, no conflicts
1810204	NM_001005373.4(LRSAM1):c.2027_2033del (p.Val676fs)	LRSAM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
204301	NM_001005373.4(LRSAM1):c.1913-1G>A	LRSAM1	Pathogenic	criteria provided, multiple submitters, no conflicts
208726	NM_001005373.4(LRSAM1):c.2120C>T (p.Pro707Leu)	LRSAM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2107035	NM_001005373.4(LRSAM1):c.2108_2114del (p.Leu703fs)	LRSAM1	Pathogenic	criteria provided, single submitter
241836	NM_001005373.4(LRSAM1):c.1279C>T (p.Arg427Ter)	LRSAM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2427228	NC_000009.11:g.(?130245209)(130245319_?)del	LRSAM1	Pathogenic	criteria provided, single submitter
2427229	NC_000009.11:g.(?130229999)(130230129_?)del	LRSAM1	Pathogenic	criteria provided, single submitter
242907	NM_001005373.4(LRSAM1):c.2068T>C (p.Cys690Arg)	LRSAM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
268046	NM_001005373.4(LRSAM1):c.2081G>A (p.Cys694Tyr)	LRSAM1	Pathogenic	no assertion criteria provided
2706775	NM_001005373.4(LRSAM1):c.428_435dup (p.Val146fs)	LRSAM1	Pathogenic	criteria provided, single submitter
2735340	NM_001005373.4(LRSAM1):c.2075_2087del (p.His692fs)	LRSAM1	Pathogenic	criteria provided, single submitter
2737762	NM_001005373.4(LRSAM1):c.940C>T (p.Gln314Ter)	LRSAM1	Pathogenic	criteria provided, single submitter
2743863	NM_001005373.4(LRSAM1):c.1717C>T (p.Gln573Ter)	LRSAM1	Pathogenic	criteria provided, single submitter
2820235	NM_001005373.4(LRSAM1):c.1911del (p.Glu638fs)	LRSAM1	Pathogenic	criteria provided, single submitter
2887131	NM_001005373.4(LRSAM1):c.1606_1609dup (p.Glu537fs)	LRSAM1	Pathogenic	criteria provided, single submitter
2913480	NM_001005373.4(LRSAM1):c.1546C>T (p.Gln516Ter)	LRSAM1	Pathogenic	criteria provided, single submitter
30859	NM_001005373.4(LRSAM1):c.1914G>A (p.Glu638=)	LRSAM1	Pathogenic	no assertion criteria provided
30860	NM_001005373.4(LRSAM1):c.2121_2122dup (p.Leu708fs)	LRSAM1	Pathogenic	no assertion criteria provided
3341092	NM_001005373.4(LRSAM1):c.1190del (p.Cys397fs)	LRSAM1	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
LRSAM1	Strong	Autosomal dominant	Charcot-Marie-Tooth disease axonal type 2P	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LRSAM1	Orphanet:300319	Charcot-Marie-Tooth disease type 2P

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
LRSAM1	HGNC:25135	ENSG00000148356	Q6UWE0	E3 ubiquitin-protein ligase LRSAM1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LRSAM1	E3 ubiquitin-protein ligase LRSAM1	E3 ubiquitin-protein ligase that mediates monoubiquitination of TSG101 at multiple sites, leading to inactivate the ability of TSG101 to sort endocytic (EGF receptors) and exocytic (HIV-1 viral proteins) cargos.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LRSAM1	Transcription factor	no		Leu-rich_rpt, SAM, Znf_RING

Expression context

Cohort genes with no expression data: 0.

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
skin of leg	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LRSAM1	192	ubiquitous	yes	apex of heart, sural nerve, skin of leg

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LRSAM1	2,095

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LRSAM1	Q6UWE0	78.47

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Class I MHC mediated antigen processing & presentation	1	70.1×	0.045	LRSAM1
Antigen processing: Ubiquitination & Proteasome degradation	1	37.2×	0.045	LRSAM1
Adaptive Immune System	1	29.8×	0.045	LRSAM1
Immune System	1	13.0×	0.077	LRSAM1

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
positive regulation of xenophagy	1	2106.5×	0.002	LRSAM1
viral budding	1	1872.4×	0.002	LRSAM1
ubiquitin-dependent endocytosis	1	1872.4×	0.002	LRSAM1
negative regulation of endocytosis	1	936.2×	0.002	LRSAM1
positive regulation of autophagosome assembly	1	802.5×	0.002	LRSAM1
protein catabolic process	1	237.3×	0.005	LRSAM1
protein autoubiquitination	1	234.1×	0.005	LRSAM1
protein polyubiquitination	1	115.4×	0.009	LRSAM1
autophagy	1	110.1×	0.009	LRSAM1

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
LRSAM1	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	LRSAM1

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)
LRSAM1	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
NCT05902351	Not specified	RECRUITING	Natural History Study for Charcot Marie Tooth Disease