Total submissions: 8
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV003152613 | SCV006059867 | pathogenic | Amyotrophic lateral sclerosis 27, juvenile | 2023-11-16 | criteria provided, single submitter | clinical testing | The SPTLC1 c.115_117del p.(Leu39del) variant results in an in-frame deletion and has been identified in individuals with a juvenile-onset ALS phenotype, including two individuals in whom the variant occurred in a de novo state (PMID: 34059824; 34459874; 37497262). The c.115_117del variant was also shown to segregate with disease in one family that included four affected children with juvenile-onset ALS and father with mild sensorimotor axonal neuropathy (PMID: 34059824). This variant is reported in the Genome Aggregation Database in one allele at a frequency of 0.000009 in the European (non-Finnish) population (version 2.1.1). The c.115_117del variant is located in exon 2, which encodes the transmembrane domain and is a hotspot for SPTLC1-ALS variants (PMID: 34059824; 35900868). Functional studies in cell lines demonstrated that the p.Leu39del variant impairs binding of the negative regulator ORMDLs to the holoenzyme complex, resulting in increased canonical sphingolipid synthesis and a distinct lipid signature that is also observed in patient plasma sphingolipid analysis (PMID: 35900868). The p.Leu39del variant was identified in a de novo state in the proband. Based on the available evidence, the c.115_117del p.(Leu39del) variant is classified as pathogenic for SPTLC1-related disorders. |
| Revvity Omics, |
RCV001560232 | SCV003819743 | pathogenic | not provided | 2021-11-15 | criteria provided, single submitter | clinical testing | |
| Institute of Human Genetics Munich, |
RCV002468610 | SCV002764914 | likely pathogenic | Proximal muscle weakness; Falls; Muscle spasm; EMG abnormality; Proximal lower limb amyotrophy | 2022-03-01 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001858688 | SCV002213359 | pathogenic | Hereditary sensory and autonomic neuropathy type 1 | 2021-09-24 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects SPTLC1 function (PMID: 34059824). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. This variant has been observed in individual(s) with juvenile ALS (PMID: 34059824; Invitae). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This variant, c.115_117del, results in the deletion of 1 amino acid(s) of the SPTLC1 protein (p.Leu39del), but otherwise preserves the integrity of the reading frame. |
| Gene |
RCV001560232 | SCV001782597 | likely pathogenic | not provided | 2019-08-14 | criteria provided, single submitter | clinical testing | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In-frame deletion of 1 amino acid in a non-repeat region; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 34059824) |
| Mendelics | RCV000988188 | SCV001137822 | likely pathogenic | Neuropathy, hereditary sensory and autonomic, type 1A | 2019-05-28 | criteria provided, single submitter | clinical testing | |
| Solve- |
RCV000988188 | SCV005200025 | likely pathogenic | Neuropathy, hereditary sensory and autonomic, type 1A | 2022-06-01 | no assertion criteria provided | provider interpretation | Variant confirmed as disease-causing by referring clinical team |
| OMIM | RCV003152613 | SCV003841241 | pathogenic | Amyotrophic lateral sclerosis 27, juvenile | 2023-03-16 | no assertion criteria provided | literature only |