CLN3

Chr 16AR

CLN3 lysosomal/endosomal transmembrane protein, battenin

Also known as: BTN1, BTS, JNCL, SLC29B1

NCBI Gene: 1201ENSG00000188603UniProt: Q13286

This gene encodes a protein that is involved in lysosomal function. Mutations in this, as well as other neuronal ceroid-lipofuscinosis (CLN) genes, cause neurodegenerative diseases commonly known as Batten disease or collectively known as neuronal ceroid lipofuscinoses (NCLs). Many alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Ceroid lipofuscinosis, neuronal, 3MIM #204200
AR
Ceroid lipofuscinosis, neuronal, 3MIM #204200
AR
477
ClinVar variants
75
Pathogenic / LP
0.00
pLI score
10
Active trials
Clinical Summary— CLN3
🧬
Gene-Disease Validity (ClinGen)
neuronal ceroid lipofuscinosis · ARDefinitive

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
75 Pathogenic / Likely Pathogenic· 96 VUS of 477 total submissions
💊
Clinical Trials
10 active or recruiting trials — potential therapeutic options may be available

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.
0.91LOEUF
pLI 0.000
Z-score 1.93
OE 0.59 (0.39–0.91)
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.
-0.15Z-score
OE missense 1.03 (0.93–1.14)
255 obs / 248.5 exp
Tolerant

Tolerant to missense variation

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.0.59 (0.39–0.91)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.03 (0.93–1.14)
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.1.13
0≤1.21.6
LoF obs/exp: 15 / 25.5Missense obs/exp: 255 / 248.5Syn Z: -1.08

ClinVar Variant Classifications

477 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic38
Likely Pathogenic37
VUS96
Likely Benign304
Benign1
Conflicting1
38
Pathogenic
37
Likely Pathogenic
96
VUS
304
Likely Benign
1
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
11
0
27
0
38
Likely Pathogenic
25
0
12
0
37
VUS
1
73
17
5
96
Likely Benign
0
6
160
138
304
Benign
0
0
1
0
1
Conflicting
—1
Total3779217143477

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

View in ClinVar →

Protein Context — Lollipop Plot

CLN3 · protein map & ClinVar variants

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

Gene2Phenotype Curations

CLN3-related retinal dystrophy

definitive
ARUndeterminedUncertain
Eye
G2P ↗

CLN3-related neuronal ceroid lipofuscinosis

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersEye
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

2 OMIM entries

OMIM

Ceroid lipofuscinosis, neuronal, 3

MIM #204200

Molecular basis of disorder known

Autosomal recessive

Ceroid lipofuscinosis, neuronal, 3

MIM #204200

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — CLN3
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Tagless LysoIP for immunoaffinity enrichment of native lysosomes from clinical samples.
Saarela D et al.·J Clin Invest
2024
ATF3 -activated accelerating effect of LINC00941/lncIAPF on fibroblast-to-myofibroblast differentiation by blocking autophagy depending on ELAVL1/HuR in pulmonary fibrosis.
Zhang J et al.·Autophagy
2022
Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses.
Kousi M et al.·Hum Mutat
2012Review
Repurposing of tamoxifen ameliorates CLN3 and CLN7 disease phenotype.
Soldati C et al.·EMBO Mol Med
2021
The neuronal ceroid-lipofuscinoses.
Bennett MJ et al.·Dev Disabil Res Rev
2013Review
New perspective in diagnostics of mitochondrial disorders: two years' experience with whole-exome sequencing at a national paediatric centre.
Pronicka E et al.·J Transl Med
2016
CLN3 deficiency leads to neurological and metabolic perturbations during early development.
Heins-Marroquin U et al.·Life Sci Alliance
2024
The neuronal ceroid-lipofuscinoses.
Goebel HH·Semin Pediatr Neurol
1996Review
The neuronal ceroid-lipofuscinoses.
Goebel HH·J Child Neurol
1995Review
Linking autism spectrum disorders and parkinsonism: clinical and genetic association.
Mai AS et al.·Ann Clin Transl Neurol
2023Review
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
CLN6Batten Disease

Long-Term Follow Up of CLN6 Batten Disease Subjects Following Gene Transfer

ACTIVE NOT RECRUITING
NCT04273243Emily de los ReyesStarted 2020-01-24
AT-GTX-501
Neuronal Ceroid LipofuscinosisBatten DiseaseCLN1 Disease

Natural History and Longitudinal Clinical Assessments in NCL / Batten Disease, the International DEM-CHILD Database

RECRUITING
NCT04613089Universitätsklinikum Hamburg-EppendorfStarted 2020-04-08
Natural History
Eye Diseases HereditaryRetinal DiseaseAchromatopsia

Inherited Retinal Degenerative Disease Registry

RECRUITING
NCT02435940Foundation Fighting BlindnessStarted 2014-06
Batten DiseaseCLN6

Natural History of Neuronal Ceroid Lipofuscinosis, Batten's CLN6 Diseae

ACTIVE NOT RECRUITING
NCT03285425Emily de los ReyesStarted 2017-01
Natural history
Batten DiseaseCLN2Neuronal Ceroid-Lipofuscinoses

Examining Developmental Outcomes of Children Diagnosed With CLN2 Disease

ENROLLING BY INVITATION
NCT03862274Jessica ScherrStarted 2018-12-01
CLN2 Treatment
Rare DisordersUndiagnosed DisordersDisorders of Unknown Prevalence

Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford

RECRUITING
NCT01793168Sanford HealthStarted 2010-07
CLN3Batten Disease

Gene Therapy for Children With CLN3 Batten Disease

ACTIVE NOT RECRUITING
NCT03770572Phase PHASE1, PHASE2Alcyone Therapeutics, IncStarted 2018-11-13
Low dose CLN-301High dose CLN-301
Neuronal Ceroid Lipofuscinosis Type 2

A First-in-Human, Open-Label, Dose-Escalation Study to Evaluate the Safety and Tolerability of Gene Therapy With TTX-381 for the Ocular Manifestations Associated With Neuronal Ceroid Lipofuscinosis Type 2 (CLN2) Disease

RECRUITING
NCT05791864Phase PHASE1, PHASE2Tern Therapeutics, LLCStarted 2023-05-17
TTX-381
CLN7

Study for the Treatment for CLN7 Disease

ACTIVE NOT RECRUITING
NCT04737460Phase PHASE1Benjamin GreenbergStarted 2021-05-04
AAV9/CLN7
Neuronal Ceroid Lipofuscinosis CLN5

Gene Therapy Study for Children With CLN5 Batten Disease

ACTIVE NOT RECRUITING
NCT05228145Phase PHASE1, PHASE2Neurogene Inc.Started 2022-01-31
NGN-101

External Resources

Links to major genomics databases and tools