rs879035421
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4
The NM_001099404.2(SCN5A):โc.1298G>Aโ(p.Arg433His) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,612,524 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 (โ โ ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R433C) 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 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.1298G>A | p.Arg433His | missense_variant | 10/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.1298G>A | p.Arg433His | missense_variant | 10/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.1298G>A | p.Arg433His | missense_variant | 10/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.1298G>A | p.Arg433His | missense_variant | 10/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152186Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000403 AC: 1AN: 248396Hom.: 0 AF XY: 0.00000742 AC XY: 1AN XY: 134754
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1460338Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 726302
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152186Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74350
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 15, 2023 | 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variantยฌโ is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 463296). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 31737537, 32145446, 32880476). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 433 of the SCN5A protein (p.Arg433His). - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 29, 2022 | Reported among individuals with arrhythmogenic disorders, sudden infant death syndrome, and dilated cardiomyopathy (Marschall C et al., 2019; Liebrechts-Akkerman G et al., 2020; Verdonschot JAJ et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32145446, 32880476, 31737537) - |
Cardiac arrhythmia Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 13, 2023 | This missense variant replaces arginine with histidine at codon 433 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 individuals affected with dilated cardiomyopathy, sudden infant death syndrome and suspected long QT syndrome (PMID: 31737537, 32145446, 32880476). This variant has been identified in 1/248396 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 | Aug 22, 2023 | This missense variant replaces arginine with histidine at codon 433 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 individuals affected with dilated cardiomyopathy, sudden infant death syndrome and suspected long QT syndrome (PMID: 31737537, 32145446, 32880476). This variant has been identified in 1/248396 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 16, 2022 | The p.R433H variant (also known as c.1298G>A), located in coding exon 9 of the SCN5A gene, results from a G to A substitution at nucleotide position 1298. The arginine at codon 433 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in different cohorts, including a long QT syndrome cohort, a dilated cardiomyopathy cohort, and a sudden infant death cohort; however, clinical details were limited in these cases (Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298; Verdonschot JAJ et al. Circ Genom Precis Med, 2020 10;13:476-487; Liebrechts-Akkerman G et al. Forensic Sci Int Genet, 2020 05;46:102266). This amino acid position is not 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. - |
Long QT syndrome 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues | Feb 14, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at