CERS1

Chr 19AR

ceramide synthase 1

Also known as: EPM8, LAG1, LASS1, UOG1

NCBI Gene: 10715 ENSG00000223802 UniProt: P27544 OMIM: 606919

The ceramide synthase enzyme catalyzes the synthesis of C18 ceramide from acyl-CoA and sphingoid bases, playing a critical role in cerebellar development and Purkinje cell function in the brain. Autosomal recessive mutations cause progressive myoclonic epilepsy type 8, a neurodegenerative disorder involving seizures and dementia. This gene shows moderate constraint against loss-of-function variants (LOEUF 0.692), reflecting its importance in neuronal function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a ceramide synthase enzyme, which catalyzes the synthesis of ceramide, the hydrophobic moiety of sphingolipids. The encoded enzyme synthesizes 18-carbon (C18) ceramide in brain neurons. Elevated expression of this gene may be associated with increased longevity, while decreased expression of this gene may be associated with myoclonus epilepsy with dementia in human patients. This protein is transcribed from a monocistronic mRNA as well as a bicistronic mRNA, which also encodes growth differentiation factor 1. [provided by RefSeq, Jul 2016]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.691 OMIM phenotype

Clinical Summary— CERS1

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Gene-Disease Validity (ClinGen)

progressive myoclonus epilepsy · ARModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.30) despite low pLI — interpret in context.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.69LOEUF

pLI 0.097

Z-score 2.35

OE 0.30 (0.15–0.69)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.82Z-score

OE missense 0.82 (0.71–0.95)

137 obs / 166.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.30 (0.15–0.69)

0≤0.351.4

Missense OE?0.82 (0.71–0.95)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 4 / 13.2Missense obs/exp: 137 / 166.6Syn Z: -0.19

This gene — mechanism propensity

0.6840th %ile

GOF

0.6639th %ile

LOF

0.3162th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.