rs199473196
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate
The NM_001099404.2(SCN5A):c.3346C>T(p.Arg1116Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000028 in 1,605,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1116Q) has been classified as Likely benign.
Frequency
Consequence
NM_001099404.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.3346C>T | p.Arg1116Trp | missense_variant | 18/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.3343C>T | p.Arg1115Trp | missense_variant | 18/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.3346C>T | p.Arg1116Trp | missense_variant | 18/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.3343C>T | p.Arg1115Trp | missense_variant | 18/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152108Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000211 AC: 5AN: 236978Hom.: 0 AF XY: 0.00000775 AC XY: 1AN XY: 129100
GnomAD4 exome AF: 0.0000255 AC: 37AN: 1453016Hom.: 0 Cov.: 31 AF XY: 0.0000277 AC XY: 20AN XY: 721662
GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152108Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74288
ClinVar
Submissions by phenotype
not provided Uncertain:3Other:1
not provided, no classification provided | literature only | Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust | - | This variant has been reported in the following publications (PMID:19841300;PMID:20129283). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 17, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1116 of the SCN5A protein (p.Arg1116Trp). This variant is present in population databases (rs199473196, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. ClinVar contains an entry for this variant (Variation ID: 67793). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 09, 2022 | Reported in at least two individuals from a control cohort (Kapa et al., 2009); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20129283, 19841300, 22581653, 26746457) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 20, 2018 | - - |
Cardiac arrhythmia Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 07, 2023 | This missense variant replaces arginine with tryptophan at codon 1116 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been reported in two ostensibly healthy individuals (PMID: 20129283). This variant has also been identified in 6/268350 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 01, 2023 | This missense variant replaces arginine with tryptophan at codon 1116 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been reported in two ostensibly healthy individuals (PMID: 20129283). This variant has also been identified in 6/268350 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 02, 2024 | Variant summary: SCN5A c.3346C>T (p.Arg1116Trp) results in a non-conservative amino acid change located in the Sodium ion transport-associated domain (IPR010526) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.1e-05 in 236978 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3346C>T in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 67793). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
SUDDEN INFANT DEATH SYNDROME;C1832680:Dilated cardiomyopathy 1E;C1837845:Sick sinus syndrome 1;C1859062:Long QT syndrome 3;C1879286:Progressive familial heart block, type 1A;C2751898:Ventricular fibrillation, paroxysmal familial, type 1;C3151464:Atrial fibrillation, familial, 10;C4551804:Brugada syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 25, 2021 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 08, 2022 | The c.3346C>T (p.R1116W) alteration is located in exon 18 (coding exon 17) of the SCN5A gene. This alteration results from a C to T substitution at nucleotide position 3346, causing the arginine (R) at amino acid position 1116 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at