SPTLC1

Chr 9AD

serine palmitoyltransferase long chain base subunit 1

Also known as: ALS27, HSAN1, HSN1, LBC1, LCB1, SPT1, SPTI

NCBI Gene: 10558 ENSG00000090054 UniProt: O15269 OMIM: 605712

The protein is the long chain base subunit 1 of serine palmitoyltransferase, which catalyzes the initial and rate-limiting step in sphingolipid biosynthesis by condensing L-serine with activated acyl-CoA. Mutations cause hereditary sensory and autonomic neuropathy type IA and juvenile amyotrophic lateral sclerosis, both inherited in an autosomal dominant pattern. The gene shows very low constraint against loss-of-function variants (pLI near 0), suggesting the pathogenic variants likely affect protein function through other mechanisms.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the class-II pyridoxal-phosphate-dependent aminotransferase family. The encoded protein is the long chain base subunit 1 of serine palmitoyltransferase. Serine palmitoyltransferase converts L-serine and palmitoyl-CoA to 3-oxosphinganine with pyridoxal 5'-phosphate and is the key enzyme in sphingolipid biosynthesis. Mutations in this gene were identified in patients with hereditary sensory neuropathy type 1. Alternatively spliced variants encoding different isoforms have been identified. Pseudogenes of this gene have been defined on chromosomes 1, 6, 10, and 13. [provided by RefSeq, Jul 2013]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.982 OMIM phenotypes

Clinical Summary— SPTLC1

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Gene-Disease Validity (ClinGen)

neuropathy, hereditary sensory and autonomic, type 1A · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

14 unique Pathogenic / Likely Pathogenic· 301 VUS of 559 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SPTLC1

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?

0.98LOEUF

pLI 0.000

Z-score 1.65

OE 0.68 (0.48–0.98)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.13Z-score

OE missense 0.80 (0.72–0.90)

208 obs / 259.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.68 (0.48–0.98)

0≤0.351.4

Missense OE?0.80 (0.72–0.90)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 21 / 30.9Missense obs/exp: 208 / 259.2Syn Z: -0.30

This gene — mechanism propensity

0.6550th %ile

GOF

0.5269th %ile

LOF

0.3453th %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 · 100% of P/LP are missense

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

DNThese results indicate that the HSN1-associated mutations in LCB1 confer dominant negative effects on the SPT enzyme.1

GOFThis observation is consistent with the hypothesis that HSAN1 is the result of a gain-of-function mutation in SPTLC1 that leads to accumulation of a toxic metabolite.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

559 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7

Likely Pathogenic7

VUS301

Likely Benign189

Benign14

Conflicting20

Pathogenic

Likely Pathogenic

301

VUS

189

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	7	0	0	7
Likely Pathogenic	0	7	0	0	7
VUS	44	219	36	2	301
Likely Benign	0	12	95	82	189
Benign	0	1	12	1	14
Conflicting	—				20
Total	44	246	143	85	538

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

View in ClinVar →

29 pathogenic / likely-pathogenic (of 38) ClinVar copy-number / structural variants overlap SPTLC1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →