rs119482082
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_006415.4(SPTLC1):āc.399T>Gā(p.Cys133Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C133R) has been classified as Pathogenic.
Frequency
Consequence
NM_006415.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SPTLC1 | NM_006415.4 | c.399T>G | p.Cys133Trp | missense_variant | 5/15 | ENST00000262554.7 | NP_006406.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SPTLC1 | ENST00000262554.7 | c.399T>G | p.Cys133Trp | missense_variant | 5/15 | 1 | NM_006415.4 | ENSP00000262554.2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461788Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 727198
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Neuropathy, hereditary sensory and autonomic, type 1A Pathogenic:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 23, 2010 | - - |
Charcot-Marie-Tooth disease Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, London Health Sciences Centre | - | - - |
Sensorimotor neuropathy Pathogenic:1
Pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | - | - - |
Hereditary sensory and autonomic neuropathy type 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 22, 2023 | This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 133 of the SPTLC1 protein (p.Cys133Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary sensory and autonomic neuropathy type 1 (HSAN1) (PMID: 11242106, 11242114, 16364956, 18018475, 22302274, 26681808). ClinVar contains an entry for this variant (Variation ID: 4803). 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. Experimental studies have shown that this missense change affects SPTLC1 function (PMID: 14990347, 16210380, 19132419, 19923297). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Cys133 amino acid residue in SPTLC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11242106, 11242114, 15546589). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | SPTLC1: PS3, PM2, PM5, PS4:Moderate, PP3 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at