CLN8

Chr 8AR

CLN8 transmembrane ER and ERGIC protein

Also known as: C8orf61, EPMR, TLCD6

NCBI Gene: 2055ENSG00000182372UniProt: Q9UBY8

This gene encodes a transmembrane protein belonging to a family of proteins containing TLC domains, which are postulated to function in lipid synthesis, transport, or sensing. The protein localizes to the endoplasmic reticulum (ER), and may recycle between the ER and ER-Golgi intermediate compartment. Mutations in this gene are associated with a disorder characterized by progressive epilepsy with cognitive disabilities (EPMR), which is a subtype of neuronal ceroid lipofuscinoses (NCL). Patients with mutations in this gene have altered levels of sphingolipid and phospholipids in the brain. [provided by RefSeq, Jul 2017]

Primary Disease Associations & Inheritance

Ceroid lipofuscinosis, neuronal, 8MIM #600143
AR
Ceroid lipofuscinosis, neuronal, 8, Northern epilepsy variantMIM #610003
AR
Ceroid lipofuscinosis, neuronal, 8MIM #600143
AR
195
ClinVar variants
49
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— CLN8
🧬
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
49 Pathogenic / Likely Pathogenic· 78 VUS of 195 total submissions
💊
Clinical Trials
1 active or recruiting trial — 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.
1.17LOEUF
pLI 0.004
Z-score 1.22
OE 0.56 (0.29–1.17)
Tolerant

Highly tolerant — LoF variants common in population

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.
-0.77Z-score
OE missense 1.16 (1.04–1.31)
200 obs / 171.7 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.0.56 (0.29–1.17)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.16 (1.04–1.31)
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.1.34
0≤1.21.6
LoF obs/exp: 5 / 8.9Missense obs/exp: 200 / 171.7Syn Z: -2.34

ClinVar Variant Classifications

195 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic40
Likely Pathogenic9
VUS78
Likely Benign64
Benign1
Conflicting3
40
Pathogenic
9
Likely Pathogenic
78
VUS
64
Likely Benign
1
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
9
2
29
0
40
Likely Pathogenic
2
5
2
0
9
VUS
2
62
12
2
78
Likely Benign
0
0
11
53
64
Benign
0
0
1
0
1
Conflicting
—3
Total13695555195

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

View in ClinVar →

Protein Context — Lollipop Plot

CLN8 · protein map & ClinVar variants

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

Gene2Phenotype Curations

CLN8-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, 8

MIM #600143

Molecular basis of disorder known

Autosomal recessive

Ceroid lipofuscinosis, neuronal, 8, Northern epilepsy variant

MIM #610003

Molecular basis of disorder known

Autosomal recessive

Ceroid lipofuscinosis, neuronal, 8

MIM #600143

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — CLN8
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
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
8p23.2-pter Microdeletions: Seven New Cases Narrowing the Candidate Region and Review of the Literature.
Catusi I et al.·Genes (Basel)
2021Review
Studies of homogenous populations: CLN5 and CLN8.
Ranta S et al.·Adv Genet
2001Review
The Neuronal Ceroid Lipofuscinoses-Linked Loss of Function CLN5 and CLN8 Variants Disrupt Normal Lysosomal Function.
Parvin S et al.·Neuromolecular Med
2019Case report
Neuronal Ceroid Lipofuscinosis: Potential for Targeted Therapy.
Specchio N et al.·Drugs
2021Review
Neuronal ceroid lipofuscinoses: classification and diagnosis.
Wisniewski KE et al.·Adv Genet
2001Review
CLN8 Gene Compound Heterozygous Variants: A New Case and Protein Bioinformatics Analyses.
Sharkia R et al.·Genes (Basel)
2022Case report
NCLs and ER: A stressful relationship.
Marotta D et al.·Biochim Biophys Acta Mol Basis Dis
2017Review
CLN5 and CLN8 protein association with ceramide synthase: biochemical and proteomic approaches.
Haddad SE et al.·Electrophoresis
2012
Correlations between genotype, ultrastructural morphology and clinical phenotype in the neuronal ceroid lipofuscinoses.
Mole SE et al.·Neurogenetics
2005Review
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
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

External Resources

Links to major genomics databases and tools