SPTLC2

Inheritance Pattern: AD

Disease ID:MONDO:0004976

Submitter: ClinGen

*SPTLC2* encodes serine palmitoyltransferase, long-chain base subunit 2, which is a key enzyme in sphingolipid biosynthesis. Sphingolipids have important roles in signal transduction and cell recognition. *SPTLC2* was first reported in relation to hereditary sensory and autonomic neuropathy type 1C in a pedigree analysis of multiple families (HSAN1C; OMIM: 613640) in 2010 (Rotthier et al., PMID: 20920666), following a screening of the gene based on the previous association of *SPTLC1* with hereditary sensory and autonomic neuropathy type 1A. Similarly, following reports of an association between *SPTLC1* and amyotrophic lateral sclerosis (ALS), Li et al. (PMID: 36966328) performed a rare variant association study to determine if *SPTLC2* was associated with ALS in 2023. Although the gene did not display a significant gene burden-based association with ALS, there were 16 individuals with ALS found to carry rare variants in *SPTLC2*. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found that the associations between the molecular mechanism and phenotypic variability of *SPTLC2*’s associations with HSAN1C and ALS, and the disease entities were split. No case-control analyses or familial segregation evidence were scorable for the curation of *SPTLC2*. However, 24 variants, all of which being missense variants, reported in 11 probands from four publications (PMIDs: 36966328, 38041679, 38316966, 38041684) were scored in this curation. Importantly, 10 of the variants had functional evidence supporting their pathogenicity, nine of the variants were maternally and paternally confirmed to be *de novo*, and eight of the variants were carried by individuals with juvenile-onset ALS. Based on the curation, a genetic evidence score of 10.9 was reached. The gene-disease association is not supported by additional experimental evidence, resulting in an experimental evidence score of zero. Although the total score of 10.9 would typically result in *SPTLC2* being assigned a moderate classification, upon review of the evidence supporting the gene-disease classification, the ALS GCEP chose to upgrade the classification to strong. In particular, the experts believe that the repeated reports of confirmed *de novo* variants in individuals with juvenile onset of ALS needed to be taken into consideration. It is anticipated that with time more evidence will emerge regarding the molecular mechanism of pathogenic variants in the form of experimental evidence. Further, as the first association between *SPTLC2* and ALS is relatively recent, replication over the coming years may afford the classification to upgrade to definitive. This classification was approved by the ClinGen ALS GCEP on May 14, 2024 (SOP Version 10).

Inheritance Pattern: AD

Disease ID:MONDO:0013337

Submitter: ClinGen

SPTLC2 was first reported in relation to autosomal dominant hereditary sensory and autonomic neuropathy type 1 (HSAN1) in 2010 (Rotthier A, et al., 2010, PMID: 20920666). HSAN1 is an axonal peripheral neuropathy associated with progressive distal sensory loss and severe ulcerations with variable age of onset from first to sixth decade of life. SPTLC2 encodes a subunit of the enzyme serine palmitoyltransferase (SPT) which catalyzes the first and rate-limiting step in the de novo sphingolipid synthesis pathway. The mechanism of pathogenicity is known to be partial or complete loss of function which leads to the accumulation of the atypical and neurotoxic sphingoid metabolite 1-deoxy-sphinganine. This gene-disease association is also supported by experimental evidence, including animal models, expression studies, and functional assays (PMIDs: 26573920; 20920666; 29761896; 16216550; 25567748). At least 7 missense variants in 9 families have been reported in humans and are included in this curation (PMIDs: 20920666; 23658386; 26573920; 30955194). Evidence supporting this gene-disease relationship includes case level data. In summary, SPTLC2 is definitively associated with autosomal dominant hereditary sensory and autonomic neuropathy type 1 (HSAN1). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Inheritance Pattern: AD

Disease ID:MONDO:0013337

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0013337

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0013337

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0018213

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0013337

Submitter: Labcorp Genetics (formerly Invitae)