ClinVar Genomic variation as it relates to human health

ACMG codes: PS3, PP3, PP5

The SPTLC1 c.431T>A; p.Val144Asp variant (rs119482083) is reported in the literature in several individuals affected with hereditary sensory neuropathy (Dawkins 2001, Ho 2018). This variant is found on only two chromosomes in the Genome Aggregation Database (2/250360 alleles), indicating it is not a common polymorphism. The valine at codon 144 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.921). Consistent with predictions, functional studies suggest the variant protein has reduced enzymatic activity and is associated with mitochondrial alterations (Hornemann 2009, Myers 2014, Stimpson 2014). Based on available information, this variant is considered to be likely pathogenic. References: Dawkins et al., Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I. Nat Genet. 2001 Mar;27(3):309-12. PMID 11242114. Ho and Jerath. V144D Mutation of SPTLC1 Can Present with Both Painful and Painless Phenotypes in Hereditary Sensory and Autonomic Neuropathies Type I. Case Rep Genet. 2018 Oct 18;2018:1898151. PMID: 30420926. Hornemann et al., A systematic comparison of all mutations in hereditary sensory neuropathy type I (HSAN I) reveals that the G387A mutation is not disease associated. Neurogenetics. 2009 Apr;10(2):135-43. PMID 19132419. Myers et al., Mutations in the SPTLC1 protein cause mitochondrial structural abnormalities and endoplasmic reticulum stress in lymphoblasts. DNA Cell Biol. 2014 Jul;33(7):399-407. PMID 24673574. Stimpson et al., Mitochondrial protein alterations in a familial peripheral neuropathy caused by the V144D amino acid mutation in the sphingolipid protein, SPTLC1. J Chem Biol. 2014 Nov 14;8(1):25-35. PMID 25584079.

Reported in multiple individuals with hereditary neuropathy previously tested at at GeneDx and in the published literature (Dawkins et al., 2001; Vogt et al., 2020); Protein expression studies show that p.(V144D) is associated with changes to the mitochondrial proteins (Stimpson et al., 2015); additionally, p.(V144D) is associated with structural changes to the mitochondria including electron dense and enlarged cristae (Myers et al., 2014).; Published functional studies demonstrate a damaging effect on SPT activity and calcium regulation (Antony et al., 2022; Hornemann et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30420926, 26681808, 25584079, 33497257, 34986032, 30778062, 34337561, 32730653, 15546589, 26395456, 24175284, 23454272, 30762923, 20920666, 24673574, 19132419, 32195206, 32399692, 20301564, 18348718, 25947379, 35895683, 35181405, 35904184, 35899376, 11242114)

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals, and segregates with disease in at least one family with HSAN. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 11781309, 19132419)

This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 144 of the SPTLC1 protein (p.Val144Asp). This variant is present in population databases (rs119482083, gnomAD 0.002%). This missense change has been observed in individuals with hereditary sensory neuropathy (PMID: 11242114; Invitae). ClinVar contains an entry for this variant (Variation ID: 4801). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SPTLC1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SPTLC1 function (PMID: 11242114, 19132419, 24673574, 25584079, 26681808). For these reasons, this variant has been classified as Pathogenic.

The p.V144D variant (also known as c.431T>A), located in coding exon 6 of the SPTLC1 gene, results from a T to A substitution at nucleotide position 431. The valine at codon 144 is replaced by aspartic acid, an amino acid with highly dissimilar properties. The p.V144D alteration has been reported to co-segregate with disease in several families with sensory neuropathy (Nicholson GA et al. Nat. Genet., 1996 May;13:101-4; Dawkins JL et al. Nat. Genet., 2001 Mar;27:309-12; Ho KWD et al. Case Rep Genet, 2018 Oct;2018:1898151; Vogt B et al. J Neurol, 2020 Sep;267:2648-2654). The functional studies of V144D show an impact on mitochondrial structure and protein expression; however, a direct link to the mechanism of pathology is not clear and enzymatic activity studies are conflicting (Hornemann T et al. Neurogenetics, 2009 Apr;10:135-43; Myers SJ et al. DNA Cell Biol., 2014 Jul;33:399-407; Stimpson SE et al. J Chem Biol, 2015 Jan;8:25-35; Bode H et al. Hum. Mol. Genet., 2016 Mar;25:853-65). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

The SPTLC1 c.431T>A variant is predicted to result in the amino acid substitution p.Val144Asp. This variant has been reported in multiple individuals with hereditary sensory neuropathy (Table 2, Dawkins et al. 2001. PubMed ID: 11242114; Ho and Jerath. 2018. PubMed ID: 30420926; Table 1, Vogt et al. 2020. PubMed ID: 32399692). This variant is reported in 0.0018% of alleles in individuals of European (non-Finnish) descent in gnomAD. In vitro experimental studies suggest this variant decreases enzymatic activity of the protein and negatively regulates the BiP pathway (Hornemann et al. 2009. PubMed ID: 19132419; Myers et al. 2014. PubMed ID: 24673574). This variant is interpreted as pathogenic or likely pathogenic by multiple submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/4801/). In summary, this variant is interpreted as likely pathogenic.