Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000005067 | SCV000825974 | pathogenic | Hereditary sensory and autonomic neuropathy type 1 | 2020-02-07 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects the function of the SPTLC1 protein (PMID: 12417569, 19132419, 20097765, 26681808). This variant has been observed to segregate with hereditary sensory neuropathy in several families (PMID: 11242106, 11242114, 15546589). ClinVar contains an entry for this variant (Variation ID: 4800). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tyrosine at codon 133 of the SPTLC1 protein (p.Cys133Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. |
| Ambry Genetics | RCV002512792 | SCV003545159 | pathogenic | Inborn genetic diseases | 2021-08-19 | criteria provided, single submitter | clinical testing | The c.398G>A (p.C133Y) alteration is located in exon 5 (coding exon 5) of the SPTLC1 gene. This alteration results from a G to A substitution at nucleotide position 398, causing the cysteine (C) at amino acid position 133 to be replaced by a tyrosine (Y). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported to segregate with disease in multiple families with hereditary sensory neuropathy and is one of the most common mutations in SPTLC1 (Bejaoui 2001; Dawkins, 2001; Geraldes 2004; Fridman, 2015). This amino acid position is highly conserved in available vertebrate species. Experimental studies showed that this alteration results in significantly increased synthesis of 1-deoxy-sphingolipids and that accumulation of this neurotoxic metabolite is the pathological mechanism in HSAN1 (Bejaoui, 2001; Penno, 2010; Bode, 2016). In another study, in vitro overexpression of the C133Y mutant resulted in a 50% reduction in serine palmitoyltransferase (SPT) activity (Hornemann, 2009). Bejaoui, et al., 2002, showed that this mutation confers dominant negative effects on SPT activity in various cell types including cultured lymphocytes from HSN1 patients. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. |
| OMIM | RCV001249800 | SCV000025243 | pathogenic | Neuropathy, hereditary sensory and autonomic, type 1A | 2001-03-01 | no assertion criteria provided | literature only | |
| Gene |
RCV001249800 | SCV000058072 | not provided | Neuropathy, hereditary sensory and autonomic, type 1A | no assertion provided | literature only | ||
| Inherited Neuropathy Consortium | RCV001027483 | SCV001190056 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | provider interpretation |