CPT1C

protein-coding

carnitine palmitoyltransferase 1C

Gene summary

This gene encodes a member of the carnitine/choline acetyltransferase family. The encoded protein regulates the beta-oxidation and transport of long-chain fatty acids into mitochondria, and may play a role in the regulation of feeding behavior and whole-body energy homeostasis. Alternatively spliced transcript variants encoding multiple protein isoforms have been observed for this gene. [provided by RefSeq, Dec 2010]

MANE transcript

NM_001199753.2

Inheritance

AR, AD

ClinVar variants

P:17U:223B:127

Top phenotype

Spastic paraplegia 73, autosomal dominant

gnomAD constraint

pLI —, LoF o/e 0.49

Max pathogenic AF

—

Genomic locus

chr19:49,690,898-49,713,731

External References & Databases

Ensembl (ENSG00000169169)

Transcript & Mutation Effects

hg38 • Region Span ~22.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary spastic paraplegia 73LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014568

Submitter: LiferaOmics

ClinGen AD hereditary spastic paraplegia / SPG73 approved 2023. Genetic evidence – Published (AR assessment): No published CPT1C cases with confirmed autosomal recessive inheritance for hereditary spastic paraplegia / SPG73. Published AR genetic evidence total = 0/12 Genetic evidence – our case (AR assessment; treated as new entity after mechanism check): 1 proband; consanguinity; affected brother with similar nocturnal episodes (counted as segregation only; genotype not provided here); homozygous frameshift (predicted loss-of-function). Case-level (biallelic predicted null in AR model; homozygous scored once; consanguinity deduction applied) = 1.0; segregation = 0 (affected sib reported but not counted as independent proband and no segregation scoring applied without genotype/segregation details); case-control = 0. Current case contribution = 1.0/12 Total genetic evidence (published AR + our case) = 1.0/12 Experimental evidence – Published (supports CPT1C biology relevant to motor neuron/“spastic paraplegia-like” phenotype, but not AR-specific): CPT1C expression enrichment in motor neuron regions and physical interaction with ATL1 (an established AD-HSP gene) were shown in cell-based experiments (PMID: 25751282). A Cpt1c knockout mouse shows early-onset progressive motor disturbances (impaired gait/coordination, weakness, reduced locomotor activity), supporting a motor phenotype model (PMID: 23973755). Expression = 0.5; protein interaction = 0.5; non-human model organism = 2.0. Experimental evidence total = 3.0/6 Overall score (AR assessment) = 4.0/18 Mechanism check / conservatism note: The established ClinGen-curated relationship for CPT1C–hereditary spastic paraplegia is autosomal dominant (Limited; 03/20/2023), with AD evidence including a missense variant proposed to act via dominant-negative effects (PMID: 25751282). In addition, a large 2025 analysis reported no support for a causal role of CPT1C loss-of-function (LOF) variants in HSP (PMID: 41312619), which is particularly relevant to interpreting an AR LOF case and should be tracked as potential contradictory evidence.

hereditary spastic paraplegia 73LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0014568

Submitter: Ambry Genetics

hereditary spastic paraplegia 73SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014568

Submitter: Orphanet

hereditary spastic paraplegiaLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0019064

Submitter: ClinGen

CPT1C was first reported in relation to autosomal dominant pure hereditary spastic paraplegia (HSP) in 2015 (Rinaldi C et al., PMID:25751282). Phenotypes include hyperreflexia, proximal muscle weakness, muscle atrophy, decreased vibration sensation at the ankles, and mild urinary dysfunction. Evidence supporting this gene-disease relationship includes case-level, segregation, and experimental data. Three variants (missense, nonsense, and canonical splicing) reported in three probands in three publications (PMIDs: 25751282, 30911584, 30564185) are included in this curation. This gene-disease relationship is supported by the role of CPT1C as a protein involved in lipid droplet biogenesis and turnover, processes known to be impacted in HSP (PMID: 34041268). Additionally, a knockout (KO) mouse model demonstrated that KO mice presented early onset of progressive motor disturbances, including impaired gait and coordination, severe muscle weakness, and reduced locomotor activity that recapitulates the disease phenotype (Carrasco P et al., PMID: 23973755). Immunostaining in COS-7 cells expressing the R37C missense demonstrated a decrease in the number and size of lipid droplets per cell, similar to what is observed in neurons of Cpt1c−/− mice (Rinaldi C et al., PMID: 25751282). In summary, limited evidence supports the gene-disease relationship between CPT1C and AD HSP. While more evidence is needed to establish this relationship, no convincing contradictory evidence has emerged. The ClinGen Cerebral Palsy, Gene Curation Expert Panel, approved this classification on March 20, 2023 (SOP Version 9).

hereditary spastic paraplegia 73STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014568

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Spastic paraplegia 73, autosomal dominantAD

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: 25751282

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CPT1C variants in ClinVar

6 Conditions Cataloged

Hereditary spastic paraplegia 73Total: 327

not specifiedTotal: 134

not providedTotal: 50

CPT1C-related disorderTotal: 18

Hereditary spastic paraplegiaTotal: 3

Spastic paraplegiaTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001199753.2. 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			7 clinvar	101 clinvar	4 clinvar	112
missense	1 clinvar	1 clinvar	204 clinvar	20 clinvar	2 clinvar	228
nonsense	4 clinvar	4 clinvar	4 clinvar			12
start loss		1 clinvar				1
frameshift	3 clinvar		6 clinvar			9
splice donor/acceptor (+/-2bp)		3 clinvar	2 clinvar			5
Total	8	9	223	121	6	367

Highest pathogenic variant AF is 0.000011153591

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 73 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001199753.2	RefSeq	NP_001186682.1	18	MANE Select
ENST00000598293.6	Ensembl	ENSP00000473028.1	18	MANE Select
NM_001136052.3	RefSeq	NP_001129524.1	18	Standard
NM_001199752.3	RefSeq	NP_001186681.1	18	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Adipocytokine signaling pathway - Homo sapiens (human)
AMPK signaling pathway - Homo sapiens (human)
Thermogenesis - Homo sapiens (human)
Glucagon signaling pathway - Homo sapiens (human)
Fatty acid degradation - Homo sapiens (human)

Biological Process

fatty acid beta-oxidation
carnitine metabolic process
long-chain fatty acid transport
regulation of postsynaptic membrane neurotransmitter receptor levels

Molecular Function

carnitine O-palmitoyltransferase activity
protein binding

Cellular Component

mitochondrion
mitochondrial outer membrane
endoplasmic reticulum
cell junction
integral component of endoplasmic reticulum membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000392518
Coding exons: 18
Length: 22834
Individuals with no LoFs: 125687
Homozygous LoFs: 0
Heterozygous LoFs: 61
Defined: 125748
p: 0.000243

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.31	419	502	0.835	0.0000324	5177
Missense (PolyPhen)		165	197.12	0.83705		1990
Synonymous	-0.690	233	220	1.06	0.0000149	1662
Loss of Function	3.20	22	45.2	0.486	0.00000246	438

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00027	0.00027	rare
Finnish	0.00025	0.00023	rare
European (Non-Finnish)	0.00028	0.00027	rare
South Asian	0.00046	0.00046	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May play a role in lipid metabolic process. {ECO:0000269|PubMed:25751282}.;

Intolerance Scores

LoFtool: 0.0663
RVIS EVS: -0.71
RVIS percentile EVS: 14.78

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.798

Gene Damage Prediction

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