chr3-38581092-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP2PP3_Moderate
The NM_001099404.2(SCN5A):c.3067C>T(p.Arg1023Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,613,736 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic 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. R1023H) has been classified as Likely benign.
Frequency
Consequence
NM_001099404.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.3067C>T | p.Arg1023Cys | missense_variant | 17/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.3067C>T | p.Arg1023Cys | missense_variant | 17/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.3067C>T | p.Arg1023Cys | missense_variant | 17/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.3067C>T | p.Arg1023Cys | missense_variant | 17/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152146Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000202 AC: 5AN: 247718Hom.: 0 AF XY: 0.0000223 AC XY: 3AN XY: 134572
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461590Hom.: 1 Cov.: 37 AF XY: 0.0000151 AC XY: 11AN XY: 727062
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152146Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74336
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 29, 2020 | Reported in association with Brugada syndrome (Matsumura et al., 2017); Reported in an individual with recorded ventricular fibrillation as well as histology studies that showed myocardial abnormalities (Watanabe et al., 2013); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 574312; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29202755, 23168001, 22407026) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 20, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1023 of the SCN5A protein (p.Arg1023Cys). This variant is present in population databases (rs745435760, gnomAD 0.006%). This missense change has been observed in individual(s) with SCN5A-related conditions (PMID: 23168001, 29202755, 29773157, 30059973). ClinVar contains an entry for this variant (Variation ID: 574312). 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. - |
Cardiac arrhythmia Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 22, 2023 | This missense variant replaces arginine with cysteine at codon 1023 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with ventricular fibrillation and structural myocardial alteration (PMID: 23168001), Brugada syndrome (PMID: 29202755), alcohol-induced cardiomyopathy (ACM) (PMID: 29773157), and tetralogy of Fallot (PMID: 22407026, 29121719 ). This variant has also been reported in 6 individuals suspected of having epilepsy, and in 3 individuals affected with other diseases other than inherited arrhythmia (PMID: 31696929). This variant has been identified in 5/247718 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 13, 2023 | This missense variant replaces arginine with cysteine at codon 1023 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with ventricular fibrillation and structural myocardial alteration (PMID: 23168001), Brugada syndrome (PMID: 29202755), alcohol-induced cardiomyopathy (ACM) (PMID: 29773157), and tetralogy of Fallot (PMID: 22407026, 29121719 ). This variant has also been reported in 6 individuals suspected of having epilepsy, and in 3 individuals affected with other diseases other than inherited arrhythmia (PMID: 31696929). This variant has been identified in 5/247718 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 | Sep 23, 2019 | Variant summary: SCN5A c.3067C>T (p.Arg1023Cys) 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 damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 247718 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3067C>T has been reported in the literature in individuals affected with Cardiomyopathy including Tetralogy of Fallot, Brugada syndrome, ventricular fibrillation (e.g. Chiu_2012, Chiu_2017, Hayano_2014, Matsumura_2017, Watanabe_2013). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 19, 2023 | The p.R1023C variant (also known as c.3067C>T), located in coding exon 16 of the SCN5A gene, results from a C to T substitution at nucleotide position 3067. The arginine at codon 1023 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the DII/DIII interdomain linker region. This variant has been detected in an individual with ventricular fibrillation, and early repolarization as well as cardiomyocyte disarray and fibrosis, and has also been detected in a Brugada syndrome cohort; however, clinical details were limited (Watanabe H et al. Int. J. Cardiol., 2013 May;165:e21-3; Matsumura H et al. J. Biomed. Sci., 2017 Dec;24:91). This alteration has also been reported in arrhythmia cohorts, in a cohort of subjects with tetralogy of Fallot and ventricular fibrillation, cardiomyopathy, epilepsy and control cohorts (Chiu SN et al. Int J Cardiol, 2017 Dec;249:156-160; Baruteau AE et al. Eur Heart J, 2018 Aug;39:2879-2887; Ware JS et al. J Am Coll Cardiol, 2018 May;71:2293-2302; Li X et al. Ann Hum Genet, 2020 Mar;84:161-168; Sarica AS et al. Am J Cardiol, 2021 Jul;151:51-56; (Kars ME et al. Proc Natl Acad Sci U S A, 2021 Sep;118:). This alteration was also reported along with an alteration in VCP in a one month old with amyotrophy, inclusion body myopathy with early onset Paget disease and frontotemporal dementia (Liu J et al. Hum Mutat, 2021 Nov;42:1443-1460). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at