Submission Details

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).