CERS1

protein-coding

ceramide synthase 1, the group of CERS class homeoboxes

Gene summary

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]

Previous symbols:

LASS1

MANE transcript

NM_021267.5

Inheritance

ClinVar variants

P:3U:146B:121

Top phenotype

Epilepsy, progressive myoclonic 8

gnomAD constraint

pLI —, LoF o/e 0.3

Max pathogenic AF

—

Genomic locus

chr19:18,868,545-18,896,727

External References & Databases

Ensembl (ENSG00000223802)

Transcript & Mutation Effects

hg38 • Region Span ~28.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

progressive myoclonic epilepsy type 8LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014545

Submitter: Ambry Genetics

progressive myoclonic epilepsy type 8SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014545

Submitter: Orphanet

progressive myoclonic epilepsy type 8STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014545

Submitter: Labcorp Genetics (formerly Invitae)

progressive myoclonus epilepsyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0020074

Submitter: ClinGen

*CERS1* was first reported in relation to autosomal recessive (AR) progressive myoclonus epilepsy in 2014 (Vanni et al., PMID: 24782409). Phenotypic features in individuals with biallelic *CERS1* variants include action myoclonus, myoclonic jerks, seizures (tonic clonic and febrile), truncal and appendicular ataxia, dysarthria, nystagmus, and progressive cognitive deterioration with onset in early to late childhood (Vanni et al., PMID: 24782409; Ferlazzo et al., PMID: 27618929; Goderio Junior et al., PMID: 30800706; Courage et al., PMID: 33798445). Cerebellar and brainstem atrophy have been reported on brain MRI. Seven affected individuals from 3 families with unique homozygous variants are included in this curation (Vanni et al., PMID: 24782409; Ferlazzo et al., PMID: 27618929; Goderio Junior et al., PMID: 30800706; Courage et al., PMID: 33798445). The mechanism of pathogenicity appears to be loss of function of CerS1 activity responsible for the synthesis of C18 ceramides (Vanni et al., PMID: 24782409). This gene-disease relationship is also supported by mouse models (Zhao et al., PMID: 21625621; Ginkel et al., PMID: 23074226). A frameshift variant expected to result in nonsense mediated decay arose spontaneously in “flincher” mice at Jackson Laboratory and, although homozygous mice do not develop spontaneous seizures, they developed cerebellar ataxia and cerebellar degeneration. A second CerS1 deficient mouse model homozygous for a deletion of the catalytic domain demonstrates decreased synthesis of gangliosides, cerebellar degeneration, and behavior and locomotion defects. The genetic evidence score is 4.2 points, and the experimental evidence score is 2 points for a total of 6.2 points. This score falls between the limited and moderate classification. The GCEP elected to classify this gene as moderate as the collective evidence supports a valid gene disease relationship, but this condition appears to be very rare. In summary, there is moderate evidence supporting the relationship between *CERS1* and autosomal recessive progressive myoclonus epilepsy. This classification was approved by the ClinGen Epilepsy GCEP on the meeting date July 16, 2024 (SOP Version 10).

Clinical Genomic Database (CGD)

Epilepsy, progressive myoclonic 8AR

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 19243074; 24782409

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CERS1 variants in ClinVar

6 Conditions Cataloged

Progressive myoclonic epilepsy type 8Total: 293

not specifiedTotal: 94

not providedTotal: 30

CERS1-related disorderTotal: 9

Right atrial isomerismTotal: 1

Congenital heart defects, multiple types, 6Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_021267.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	114 clinvar	1 clinvar	116
missense	1 clinvar	1 clinvar	140 clinvar	6 clinvar		148
nonsense			2 clinvar			2
start loss						0
frameshift	1 clinvar		1 clinvar			2
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	2	1	146	120	1	270

Highest pathogenic variant AF is 0.000003825901

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 17 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_021267.5	RefSeq	NP_067090.1	7	MANE Select
ENST00000623882.4	Ensembl	ENSP00000485308.1	7	MANE Select
NM_001290265.2	RefSeq	NP_001277194.1	5	Standard
NM_001387439.1	RefSeq	NP_001374368.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Sphingolipid signaling pathway - Homo sapiens (human)
Sphingolipid metabolism - Homo sapiens (human)
Developmental Biology
Metabolism of lipids
Metabolism

Biological Process

sphingolipid biosynthetic process
cellular response to drug
cellular response to mycotoxin
ceramide biosynthetic process
negative regulation of telomerase activity

Molecular Function

molecular_function
sphingosine N-acyltransferase activity

Cellular Component

Golgi membrane
endoplasmic reticulum
endoplasmic reticulum membrane
membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000427170
Coding exons: 7
Length: 28176
Individuals with no LoFs: 123555
Homozygous LoFs: 0
Heterozygous LoFs: 7
Defined: 123562
p: 0.0000283

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.815	137	167	0.822	0.0000107	2206
Missense (PolyPhen)		39	56.45	0.69088		656
Synonymous	-0.187	75	73.0	1.03	0.00000507	702
Loss of Function	2.35	4	13.2	0.302	5.64e-7	172

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000046	0.000045	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May be either a bona fide (dihydro)ceramide synthase or a modulator of its activity. When overexpressed in cells is involved in the production of sphingolipids containing mainly one fatty acid donor (N-linked stearoyl- (C18) ceramide) in a fumonisin B1-independent manner (By similarity). {ECO:0000250|UniProtKB:P27545}.;
Disease: DISEASE: Epilepsy, progressive myoclonic 8 (EPM8) [MIM:616230]: A severe form of progressive myoclonic epilepsy characterized by myoclonus, generalized tonic-clonic seizures and moderate to severe cognitive impairment. {ECO:0000269|PubMed:24782409}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

RVIS EVS: -0.67
RVIS percentile EVS: 15.62

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium