rs199473175
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP2PP3_StrongPP5
The NM_001099404.2(SCN5A):c.2729C>T(p.Ser910Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,360 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S910S) has been classified as Likely benign.
Frequency
Consequence
NM_001099404.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.2729C>T | p.Ser910Leu | missense_variant | 16/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.2729C>T | p.Ser910Leu | missense_variant | 16/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.2729C>T | p.Ser910Leu | missense_variant | 16/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.2729C>T | p.Ser910Leu | missense_variant | 16/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250430Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135602
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461360Hom.: 0 Cov.: 36 AF XY: 0.00000275 AC XY: 2AN XY: 726958
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Brugada syndrome Pathogenic:1Uncertain:1Other:1
Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 18, 2023 | This missense variant replaces serine with leucine at codon 910 of the SCN5A protein. This variant is found within a highly conserved region of the transmembrane domain DII. Rare nontruncating variants in this region (a.a. 718 - 938) have been shown to be significantly overrepresented in individuals with Brugada syndrome (PMID: 32893267). A functional study has shown that this variant causes reduced cell surface expression of the SCN5A protein and decreased sodium current density compared to wild-type cells, indicating a trafficking deficit (PMID: 24768612). This variant has been reported in at least 6 unrelated individuals affected with or suspected of having Brugada syndrome (PMID: 11901046, 20129283, 24768612, 26173111, 28087566, 29574140, 32268277, 32893267), and several other individuals affected with sick sinus syndrome, atrial standstill, ventricular fibrillation, or dilated cardiomyopathy (PMID: 28104484, 31983221, 36147716, ClinVar SCV000741704.3). This variant has been identified in 1/250430 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
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 Brugada syndrome in the following publications (PMID:11901046;PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 04, 2024 | proposed classification - variant undergoing re-assessment, contact laboratory - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 02, 2023 | Reported in a child who experienced cardiac arrest with ventricular fibrillation and in her asymptomatic mother, both of whom had a positive ajmaline test (Pambrun et al., 2014); Reported in three individuals with features consistent with or suggestive of Brugada syndrome, in one individual with sick sinus syndrome and in one individual with DCM (Priori et al., 2002; Kapplinger et al., 2010; Selga et al., 2015; Ishikawa et al., 2017; Mazzarotto et al., 2020); Not observed at a significant frequency in large population cohorts (gnomAD); Published in vitro analysis showed that, in the heterozygous presence of S910L, SCN5A-encoded sodium channels are neither fully expressed on the cell surface nor produce normal levels of current compared to wild-type cells (Pambrun et al., 2014), though it is not clear how well these studies reproduce in vivo conditions; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30193851, 15655131, 14753626, 20129283, 12650874, 24768612, 14961552, 31983221, 25904541, 32268277, 30662450, 20100972, 25274057, 22999724, 22840528, 22766342, 19251209, 18378609, 17210839, 16684018, 16453024, 15840476, 14523039, 12736279, 10940383, 10471492, 32533946, 28104484, 26173111, 33131149, 29574140, 11901046, 33164571, 30203441, 34461752) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 23, 2022 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SCN5A function (PMID: 24768612). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 67753). This missense change has been observed in individuals with Brugada syndrome or sick sinus syndrome (PMID: 11901046, 24768612, 26173111, 28104484, 29574140; 20129283.). This variant is present in population databases (rs199473175, gnomAD 0.0009%). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 910 of the SCN5A protein (p.Ser910Leu). - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 30, 2023 | The p.S910L variant (also known as c.2729C>T), located in coding exon 15 of the SCN5A gene, results from a C to T substitution at nucleotide position 2729. The serine at codon 910 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in Brugada syndrome cohorts and individuals reported to have Brugada syndrome, cardiac arrest, ventricular arrhythmia or atrial standstill; however, in some cases clinical details were limited and some cohorts may overlap (Priori SG et al. Circulation, 2002;105:1342-7, Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46; Pambrun T et al. Heart Rhythm, 2014;11:1393-400; Selga E et al. PLoS ONE, 2015;10:e0132888; Ishikawa T et al. Heart Rhythm, 2017 May;14:717-724; Sonoda K et al. Heart Rhythm, 2018 Aug;15:1179-1188; Berthome P et al. Heart Rhythm, 2019 Feb;16:260-267; Kato Y et al. HeartRhythm Case Rep, 2022 Sep;8:636-638). This variant has also been detected in a dilated cardiomyopathy cohort; however, details were limited (Mazzarotto F et al. Circulation, 2020 Feb;141:387-398). A functional study found no visible-gated sodium current at any potential in p.S910L transfected cells as well as reduced cell surface expression of p.S910L channels compared to wild type. In addition, co-expression of p.S910L and wild-type resulted in a significant decrease in fast sodium current density by 49% compared to wild-type alone, suggesting this alteration has a dominant negative effect (Pambrun T et al. Heart Rhythm, 2014;11:1393-400). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved through mammals, but not in all available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at