LRSAM1

Chr 9ADAR

leucine rich repeat and sterile alpha motif containing 1

Also known as: CMT2P, RIFLE, TAL

NCBI Gene: 90678ENSG00000148356UniProt: Q6UWE0

This gene encodes a ring finger protein involved in a variety of functions, including regulation of signaling pathways and cell adhesion, mediation of self-ubiquitylation, and involvement in cargo sorting during receptor endocytosis. Mutations in this gene have been associated with Charcot-Marie-Tooth disease. Multiple transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jan 2012]

Primary Disease Associations & Inheritance

Charcot-Marie-Tooth disease, axonal, type 2PMIM #614436
ADAR
572
ClinVar variants
58
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— LRSAM1
🧬
Gene-Disease Validity (ClinGen)
Charcot-Marie-Tooth disease axonal type 2P · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
58 Pathogenic / Likely Pathogenic· 247 VUS of 572 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.75LOEUF
pLI 0.000
Z-score 3.00
OE 0.55 (0.41–0.75)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.41Z-score
OE missense 0.94 (0.87–1.03)
399 obs / 422.6 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.55 (0.41–0.75)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.94 (0.87–1.03)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.05
0≤1.21.6
LoF obs/exp: 29 / 52.4Missense obs/exp: 399 / 422.6Syn Z: -0.48

ClinVar Variant Classifications

572 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic30
Likely Pathogenic28
VUS247
Likely Benign216
Benign34
Conflicting17
30
Pathogenic
28
Likely Pathogenic
247
VUS
216
Likely Benign
34
Benign
17
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
11
0
19
0
30
Likely Pathogenic
15
0
13
0
28
VUS
3
208
35
1
247
Likely Benign
0
2
119
95
216
Benign
0
1
32
1
34
Conflicting
—17
Total2921121897572

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

LRSAM1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

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

MIM #614436

Molecular basis of disorder known

Autosomal dominantAutosomal recessive
📖
GeneReview available — LRSAM1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
LRSAM1 and the RING domain: Charcot-Marie-Tooth disease and beyond.
Palaima P et al.·Orphanet J Rare Dis
2021Review
Erianin induces ferroptosis in GSCs via REST/LRSAM1 mediated SLC40A1 ubiquitination to overcome TMZ resistance.
Mansuer M et al.·Cell Death Dis
2024
LRSAM1-mediated ubiquitylation is disrupted in axonal Charcot-Marie-Tooth disease 2P.
Hakonen JE et al.·Hum Mol Genet
2017
Charcot-Marie-Tooth disease type 2G redefined by a novel mutation in LRSAM1.
Peeters K et al.·Ann Neurol
2016
[Novel MFN2, BSCL2 and LRSAM1 variants in a cohort of Chinese patients with Charcot-Marie-Tooth disease].
Sun B et al.·Zhonghua Nei Ke Za Zhi
2022Cohort
Location matters - Genotype-phenotype correlation in LRSAM1 mutations associated with rare Charcot-Marie-Tooth neuropathy CMT2P.
Reilich P et al.·Neuromuscul Disord
2021
Further delineation of LRSAM1-related Charcot-Marie-Tooth type 2P with parkinsonism.
Ducatel P et al.·Eur J Med Genet
2025Case report
The LRR and RING domain protein LRSAM1 is an E3 ligase crucial for ubiquitin-dependent autophagy of intracellular Salmonella Typhimurium.
Huett A et al.·Cell Host Microbe
2012
LRSAM1 variants and founder effect in French families with ataxic form of Charcot-Marie-Tooth type 2.
Peretti A et al.·Eur J Hum Genet
2019
A novel missense mutation of CMT2P alters transcription machinery.
Hu B et al.·Ann Neurol
2016
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools