CPT1C

Chr 19AD

carnitine palmitoyltransferase 1C

Also known as: CATL1, CPT I-C, CPT1-B, CPT1P, CPTI-B, CPTIC, SPG73

NCBI Gene: 126129 ENSG00000169169 UniProt: Q8TCG5 OMIM: 608846

The encoded protein is a palmitoyl thioesterase that regulates AMPA receptor trafficking to the plasma membrane through depalmitoylation and contributes to systemic energy homeostasis and appetite control. Mutations cause spastic paraplegia 73 with autosomal dominant inheritance. This gene is not highly constrained against loss-of-function variants (pLI near zero), suggesting the pathogenic variants may not simply eliminate protein function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.691 OMIM phenotype

Clinical Summary— CPT1C

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Gene-Disease Validity (ClinGen)

hereditary spastic paraplegia · ADLimited

Limited evidence — not for standalone diagnostic reporting

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

17 unique Pathogenic / Likely Pathogenic· 226 VUS of 436 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — CPT1C

Authoritative clinical overview · Recommended first read

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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 0.000

Z-score 3.20

OE 0.49 (0.35–0.69)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.31Z-score

OE missense 0.83 (0.77–0.91)

419 obs / 501.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.49 (0.35–0.69)

0≤0.351.4

Missense OE?0.83 (0.77–0.91)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 22 / 45.2Missense obs/exp: 419 / 501.9Syn Z: -0.69

This gene — mechanism propensity

0.7229th %ile

GOF

0.6052th %ile

LOF

0.2386th %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 · 1 literature citation

GOF1 literature citation

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.

Literature Evidence

DNWe also observed a reduction of mean (SD) lipid droplets in primary cortical neurons isolated from Cpt1câ/â mice as compared with wild-type mice (1.0 [0.12] vs 0.44 [0.05]; Pâ<â.001), suggesting a dominant negative mechanism for the mutation.1

GOFCarnitine palmitoyltransferase-1c gain-of-function in the brain results in postnatal microencephaly2

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

References

ClinVar Variant Classifications

436 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic8

Likely Pathogenic9

VUS226

Likely Benign156

Benign16

Conflicting11

Pathogenic

Likely Pathogenic

226

VUS

156

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	7	1	0	0	8
Likely Pathogenic	7	2	0	0	9
VUS	9	202	11	4	226
Likely Benign	1	12	51	92	156
Benign	0	2	6	8	16
Conflicting	—				11
Total	24	219	68	104	426

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

View in ClinVar →

12 pathogenic / likely-pathogenic (of 17) ClinVar copy-number / structural variants overlap CPT1C — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →