Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000414705 | SCV000491282 | pathogenic | not provided | 2016-11-04 | criteria provided, single submitter | clinical testing | The S331Y pathogenic variant in the SPTLC1 gene has been reported previously as a heterozygous de novo variant in an individual with a diagnosis of HSN1A who presented with normal early development followed by failure to thrive in childhood, abnormal gait, frequent falls, and moderate hand tremor. Later in childhood, general muscle hypotrophy and hypotonia with pronounced limb weakness, growth retardation, fasciculations, joint hypermobility, juvenile cataracts, foot burns and scars and prominent sensory disturbances were noted (Auer-Grumbach et al., 2013). The S331Y variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S331Y variant is a semi-conservative amino acid substitution, which occurs at a position that is conserved across species. Functional studies show a significant reduction in the canonical SPT activity and a significant increase of 1-deoxy-sphinganin formation in HEK293 cells compared to wild type cells (Auer-Grumbach et al., 2013; Bode et al., 2016). A missense variant at the same residue (S331F) has also been reported in multiple individuals with severe and early onset HSN1A (Rotthier et al., 2011; Rotthier et al., 2009). Therefore, we interpret S331Y as a pathogenic variant. |
| Invitae | RCV000795948 | SCV000935430 | pathogenic | Hereditary sensory and autonomic neuropathy type 1 | 2022-11-17 | criteria provided, single submitter | clinical testing | This missense change has been observed in individual(s) with SPTCL1-related disease (PMID: 23454272). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 331 of the SPTLC1 protein (p.Ser331Tyr). ClinVar contains an entry for this variant (Variation ID: 372788). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser331 amino acid residue in SPTLC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19651702, 21618344, 24247255). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects SPTLC1 function (PMID: 26681808). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. |
| Inherited Neuropathy Consortium | RCV000790228 | SCV000929620 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only | ||
| OMIM | RCV001249813 | SCV000996521 | pathogenic | Neuropathy, hereditary sensory and autonomic, type IA, severe | 2023-03-14 | no assertion criteria provided | literature only | |
| OMIM | RCV003152600 | SCV003841238 | pathogenic | Amyotrophic lateral sclerosis 27, juvenile | 2023-03-14 | no assertion criteria provided | literature only |