rs759924541
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4
The NM_001099404.2(SCN5A):c.3285G>T(p.Trp1095Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,460,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.
Frequency
Consequence
NM_001099404.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.3285G>T | p.Trp1095Cys | missense_variant | 18/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.3282G>T | p.Trp1094Cys | missense_variant | 18/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.3285G>T | p.Trp1095Cys | missense_variant | 18/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.3282G>T | p.Trp1094Cys | missense_variant | 18/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000811 AC: 2AN: 246604Hom.: 0 AF XY: 0.00000744 AC XY: 1AN XY: 134458
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1460348Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 726438
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 03, 2022 | Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SCN5A function (PMID: 29574140). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 432236). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 26669661, 29574140). This variant is present in population databases (rs759924541, gnomAD 0.01%). This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 1095 of the SCN5A protein (p.Trp1095Cys). - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 19, 2017 | A variant of uncertain significance has been identified in the SCN5A gene. The W1095C variant has been published in one family with LQTS (Itoh et al., 2015); however, specific clinical details were not provided. Additionally, this substitution occurs at a position that is not conserved across species and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Nevertheless, this variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The W1095C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 11, 2020 | The p.W1095C variant (also known as c.3285G>T), located in coding exon 17 of the SCN5A gene, results from a G to T substitution at nucleotide position 3285. The tryptophan at codon 1095 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was detected in two individuals from one family with long QT syndrome (LQTS) family; however, specific phenotypic information was not provided (Itoh H et al. Eur. J. Hum. Genet., 2016 08;24:1160-6). In addition, this alteration was detected once in a cohort of individuals with brugada syndrome who were symptomatic or had a family history of brugada syndrome, sudden death, syncope, or arrhythmic diseases (Sonoda K et al. Heart Rhythm, 2018 08;15:1179-1188). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at