rs199473116
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_001099404.2(SCN5A):c.1425A>C(p.Arg475Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,613,828 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R475T) has been classified as Uncertain significance.
Frequency
Consequence
NM_001099404.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.1425A>C | p.Arg475Ser | missense_variant | 11/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.1425A>C | p.Arg475Ser | missense_variant | 11/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.1425A>C | p.Arg475Ser | missense_variant | 11/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.1425A>C | p.Arg475Ser | missense_variant | 11/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.000125 AC: 19AN: 152166Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249098Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135126
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461662Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727102
GnomAD4 genome ? AF: 0.000125 AC: 19AN: 152166Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74336
ClinVar
Submissions by phenotype
Cardiac arrhythmia Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 05, 2023 | This missense variant replaces arginine with serine at codon 475 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 been reported in two healthy, African American individuals in the literature (PMID: 20129283, 15851227). This variant has been identified in 9/280488 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 | Color Diagnostics, LLC DBA Color Health | Nov 09, 2022 | This missense variant replaces arginine with serine at codon 475 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 been reported in two healthy, African American individuals in the literature (PMID: 20129283, 15851227). This variant has been identified in 9/280488 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 provided Uncertain:1Other: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 | Dec 12, 2023 | This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 475 of the SCN5A protein (p.Arg475Ser). This variant is present in population databases (rs199473116, gnomAD 0.04%). 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: 67662). 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 tolerated. 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. - |
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 | Sep 21, 2021 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 27, 2023 | The p.R475S variant (also known as c.1425A>C), located in coding exon 10 of the SCN5A gene, results from an A to C substitution at nucleotide position 1425. The arginine at codon 475 is replaced by serine, an amino acid with dissimilar properties. This variant has been detected in a cohort of individuals with pacemakers (Celestino-Soper PB et al. PLoS One. 2016 Jan;11(1):e0147455); however, detail was limited. This variant has also been detected in ostensibly healthy cohorts (Ackerman MJ et al. Heart Rhythm, 2004 Nov;1:600-7; Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46). This alteration has also been reported in a sudden death cohort and a pediatric dilated cardiomyopathy (DCM) cohort (Salfati EL et al. Genome Med, 2019 Dec;11:83; Khan RS et al. J Am Heart Assoc, 2022 Jan;11:e022854). This amino acid position is well 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