SPTLC1
protein-codingserine palmitoyltransferase long chain base subunit 1
Gene summary
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]
- HSN1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~115.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0008086
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0859529
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0018213
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0859529
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0008086
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0859529
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008086
Submitter: ClinGen
SPTLC1: autosomal dominant HSAN (HSAN1A). In context with an autosomal dominant, axonal Hereditary Sensory Neuropathy phenotype, SPTLC1 was first identified by linkage analysis, co-segregating in 11 families, the largest of which displaying 51 affected individuals (LOD score 6.08) (Dawkins et al., PMID: 11242114; Nicholson et al., PMID: 8673084). The same, recurrent variants located in hot-spot region p.Cys133 have been replicated in several other publications (PMIDs: 15546589, 31742231), with functional evidence showing elevated 1-deoxy sphingoid bases as a shared biomarker (PMID: 20097765) for specific gain-of-function mutations causing a shift in substrate specificity of the serine-palmitoylCoA transferase complex, the first catalytic subunit of which is encoded by SPTLC1. Interestingly, according missense variants in SPTLC2 lead to the same phenotype, underlining its pathophysiological relevance. Other than HSAN1-related variants, missense mutations affecting the transmembrane regions of SPTL1 and SPTLC2 can disrupt interaction with its main inhibitor, ORMDL3, which leads to generalized sphingolipid overproduction not selective to the 1-deoxy-sphingoid bases. This mechanism is associated with juvenile-onset amyotrophic lateral sclerosis, a different disease entity with a separate curation (split). However, missense variants in the hot-spot region around position p.Ser331 can cause a complex phenotype with sensory impairment, wound healing disturbances, and foot ulcerations (all typical for HSAN1) and additional features like generalized muscle hypotrophy and weakness as well as cataracts (PMIDs: 21618344, 24247255, 19651702, 23454272). We included these variants in the present curation due to phenotype overlap and elevated plasma 1-deoxy-sphingolipids as a shared mechanism-specific disease marker. With several unrelated reports, including both large ancestries and de-novo cases, all supported by variant-specific functional evidence, the genetic evidence alone is sufficient to establish a definitive gene-disease relationship. Additionally, data on biochemical function and functional alteration (PMID: 20097765), variant-specific mouse models (e.g. PMID: 16210380) and several demonstrations of successful rescue by L-serine (PMID: 2204557) and allele-specific antisense oligonucleotides (PMID: 41124364) have provided extensive experimental evidence to the gene curation. A randomized, placebo-controlled trial on oral L-serine supplementation in 16 HSAN1 patients with pathogenic variants in SPTLC1 (PMID: 30626650) has shown some clinically meaningful improvements (not significant in this pilot cohort), underscoring the treatment relevance of mechanistic disease understanding. In summary, strong clinical evidence, including a specific phenotype, variant recurrency, high LOD scores, and de-novo occurrence, is supported by experimental data on gene and variant level and has been replicated over time. We therefore classify the gene-disease relationship of SPTLC1 and autosomal dominant HSAN1 as definitive.
Clinical Genomic Database (CGD)
Manifestation: Neurologic
Intervention: Neurologic
Rationale: The condition involves sensory neuropathy with variable autonomic and motor involvement, and medical management (eg, with oral serine supplementation) has been reported as resulting in laboratory-based and clinical benefits
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SPTLC1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_006415.4. 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 | 2 | 85 | 87 | |||
| missense | 6 | 7 | 223 | 20 | 1 | 257 |
| nonsense | 14 | 14 | ||||
| start loss | 2 | 2 | ||||
| frameshift | 17 | 17 | ||||
| splice donor/acceptor (+/-2bp) | 22 | 1 | 23 | |||
| Total | 6 | 7 | 280 | 106 | 1 | 400 |
Highest pathogenic variant AF is 0.000013013684
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_006406.1 | 15 | MANE Select | |
| Ensembl | ENSP00000262554.2 | 15 | MANE Select | |
| RefSeq | NP_001268232.1 | 15 | Standard | |
| RefSeq | NP_001355201.1 | 11 | 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)
- Sphingolipid Metabolism
- Gaucher Disease
- Globoid Cell Leukodystrophy
Biological Process
- sphingolipid metabolic process
- sphingomyelin biosynthetic process
- sphingolipid biosynthetic process
- sphinganine biosynthetic process
- sphingosine biosynthetic process
Molecular Function
- serine C-palmitoyltransferase activity
- protein binding
- pyridoxal phosphate binding
Cellular Component
- endoplasmic reticulum
- endoplasmic reticulum membrane
- integral component of membrane
- serine C-palmitoyltransferase complex
- SPOTS complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000262554
- Coding exons
- 15
- Length
- 83386
- Individuals with no LoFs
- 125697
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 51
- Defined
- 125748
- p
- 0.000203
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.13 | 208 | 259 | 0.803 | 0.0000141 | 3065 |
| Missense (PolyPhen) | 68 | 98.358 | 0.69135 | 1128 | ||
| Synonymous | -0.300 | 97 | 93.3 | 1.04 | 0.00000509 | 914 |
| Loss of Function | 1.65 | 21 | 30.9 | 0.679 | 0.00000167 | 364 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00038 | 0.00037 | rare |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0.00010 | 0.000099 | rare |
| East Asian | 0.00038 | 0.00038 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00023 | 0.00023 | rare |
| South Asian | 0.00023 | 0.00023 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Serine palmitoyltransferase (SPT). The heterodimer formed with SPTLC2 or SPTLC3 constitutes the catalytic core. The composition of the serine palmitoyltransferase (SPT) complex determines the substrate preference. The SPTLC1-SPTLC2-SPTSSA complex shows a strong preference for C16-CoA substrate, while the SPTLC1-SPTLC3-SPTSSA isozyme uses both C14-CoA and C16-CoA as substrates, with a slight preference for C14-CoA. The SPTLC1- SPTLC2-SPTSSB complex shows a strong preference for C18-CoA substrate, while the SPTLC1-SPTLC3-SPTSSB isozyme displays an ability to use a broader range of acyl-CoAs, without apparent preference. {ECO:0000269|PubMed:19416851}.;
- Disease
- DISEASE: Neuropathy, hereditary sensory and autonomic, 1A (HSAN1A) [MIM:162400]: A form of hereditary sensory and autonomic neuropathy, a genetically and clinically heterogeneous group of disorders characterized by degeneration of dorsal root and autonomic ganglion cells, and by prominent sensory abnormalities with a variable degree of motor and autonomic dysfunction. The neurological phenotype is often complicated by severe infections, osteomyelitis, and amputations. HSAN1A is an autosomal dominant axonal form with onset in the second or third decades. Initial symptoms are loss of pain, touch, heat, and cold sensation over the feet, followed by distal muscle wasting and weakness. Loss of pain sensation leads to chronic skin ulcers and distal amputations. {ECO:0000269|PubMed:11242114, ECO:0000269|PubMed:19132419, ECO:0000269|PubMed:19651702, ECO:0000269|PubMed:20504773, ECO:0000269|PubMed:21618344, ECO:0000269|PubMed:22302274, ECO:0000269|PubMed:24247255}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=SPTLC1 mutations at Ser-331 are responsible for severe hereditary motor and sensory neuropathy (HMSN) forms, whose core features are severe, diffuse muscle wasting and hypotonia, motor and sensory disturbances, foot ulcers, amputations and/or burns, joint hypermobility, cataracts and considerable growth retardation. {ECO:0000269|PubMed:23454272}.;
Recessive Scores
- pRec
- 0.225
Intolerance Scores
- LoFtool
- 0.286
- RVIS EVS
- -0.25
- RVIS percentile EVS
- 35.99
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- N
- Essential (gene trap)
- K
- Indispensability pred.
- E
- Indispensability score
- 0.965
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |