rs199473287
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5
The NM_001099404.2(SCN5A):c.4930C>T(p.Arg1644Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1644H) has been classified as Pathogenic.
Frequency
Consequence
NM_001099404.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.4930C>T | p.Arg1644Cys | missense_variant | 28/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.4927C>T | p.Arg1643Cys | missense_variant | 28/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.4930C>T | p.Arg1644Cys | missense_variant | 28/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.4927C>T | p.Arg1643Cys | missense_variant | 28/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251472Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135908
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461882Hom.: 0 Cov.: 34 AF XY: 0.00000413 AC XY: 3AN XY: 727238
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 19, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1644 of the SCN5A protein (p.Arg1644Cys). This variant is present in population databases (rs199473287, gnomAD 0.003%). This missense change has been observed in individuals with clinical features of long QT syndrome or Brugada syndrome (PMID: 16344400, 16414944, 19716085, 24721456; Invitae). ClinVar contains an entry for this variant (Variation ID: 67941). 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. Experimental studies have shown that this missense change affects SCN5A function (PMID: 16344400). This variant disrupts the p.Arg1644 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8541846, 8620612, 10973849, 19026623, 19841300). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Brugada syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Mar 17, 2023 | Well-established functional studies suggest that this variant results in a deleterious effect to the protein that is sufficient to be disease-causing (PMID: 8541846, 8620612, 16344400, 8917568). This variant has been reported in multiple individuals with Brugada syndrome and long QT syndrome (PMID: 16344400, 19411664, 19716085, 25904541, 16414944, 24721456, 28341781, 29691127, 32893267, 33390472, 35956023, 29728395). This variant is located in a well-established functional domain of the protein where other pathogenic or likely pathogenic variants have been described. (PMID: 32893267). This variant is present in 1/251472 total alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is predicted to be deleterious by in silico analysis. This prediction has not been confirmed by functional studies. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 22, 2019 | The p.R1644C variant (also known as c.4930C>T), located in coding exon 27 of the SCN5A gene, results from a C to T substitution at nucleotide position 4930. The arginine at codon 1644 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the DIV/S4 region. This alteration has been reported in association with Brugada syndrome and long QT syndrome (LQTS); however, in several instances, clinical details were limited (Frustaci A et al. Circulation, 2005 Dec;112:3680-7; Napolitano C et al. JAMA, 2005 Dec;294:2975-80; Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303). One in vitro study indicated this variant may have some impact on channel function (Frustaci A et al. Circulation, 2005 Dec;112:3680-7). Another alteration affecting the same amino acid, p.R1644H (c.4931G>A), has been reported in association with LQTS (Wang Q et al. Hum Mol Genet. 1995;4(9):1603-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Congenital long QT syndrome Other:1
not provided, no classification provided | literature only | Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust | - | This variant has been reported as associated with Long QT syndrome in the following publications (PMID:16344400;PMID:16414944;PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at