rs199473220
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_001099404.2(SCN5A):c.3956G>T(p.Gly1319Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000385 in 1,608,316 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 Likely pathogenic (★★).
Frequency
Consequence
NM_001099404.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.3956G>T | p.Gly1319Val | missense_variant | 22/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.3953G>T | p.Gly1318Val | missense_variant | 22/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.3956G>T | p.Gly1319Val | missense_variant | 22/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.3953G>T | p.Gly1318Val | missense_variant | 22/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152206Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000420 AC: 10AN: 238270Hom.: 0 AF XY: 0.0000465 AC XY: 6AN XY: 129124
GnomAD4 exome AF: 0.0000385 AC: 56AN: 1456110Hom.: 0 Cov.: 31 AF XY: 0.0000415 AC XY: 30AN XY: 723674
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152206Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74350
ClinVar
Submissions by phenotype
not provided Pathogenic:8
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Nov 18, 2021 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 19, 2023 | Published functional studies demonstrate this variant alters sodium channel gating properties and reduces the sodium current, which is consistent with a Brugada syndrome phenotype (Casini et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(G1318V); This variant is associated with the following publications: (PMID: 23414114, 19843921, 12106943, 24400668, 34461752, 34697415, 24573164, 19889341, 20129283, 21273195, 19251209, 24951569, 22373669, 30609406, 30662450, 29759671, 25904541, 30291343, 30847666, 31447099, 32377377, 17854786, 33131149, 22581653, 28790152, 30203441, 20646679, 33087929, 29709244, 33164571, 34135346, 25179549) - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 22, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1319 of the SCN5A protein (p.Gly1319Val). This variant is present in population databases (rs199473220, gnomAD 0.009%). This missense change has been observed in individuals with autosomal dominant SCN5A-related conditions (PMID: 17854786, 24951569, 25179549, 25904541, 28790152; Invitae). This variant is also known as G1318V. ClinVar contains an entry for this variant (Variation ID: 67838). 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: 17854786). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 15, 2022 | - - |
Brugada syndrome Pathogenic:2Other: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 Brugada syndrome in the following publications (PMID:12106943;PMID:17854786;PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 28, 2023 | This missense variant replaces glycine with valine at codon 1319 of the SCN5A protein. This variant is also known as p.Gly1318Val in the literature based on a different NM_000335 transcript. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved region of the transmembrane domain III. Rare nontruncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). Functional studies have shown that this variant causes a significant reduction in sodium current (PMID: 17854786, 19251209). This variant has been reported in over ten unrelated individuals affected with Brugada syndrome (PMID: 12106943, 17854786, 19251209, 21273195, 24951569, 29759671, 30847666, 32893267, 36516610, ClinVar SCV000291807.6), in an individual affected with long QT syndrome (PMID: 32893267), and in two individuals affected with progressive cardiac conduction disorders (PMID: 30059973). This variant has been shown to segregates with disease in four first-degree relatives from two families affected with cardiac conduction disease and cardiomypoathy (PMID: 25179549, 28790152). This variant has been identified in 11/269654 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 31, 2018 | proposed classification - variant undergoing re-assessment, contact laboratory - |
Brugada syndrome (shorter-than-normal QT interval) Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 29, 2021 | Variant summary: SCN5A c.3956G>T (p.Gly1319Val) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-05 in 238270 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in SCN5A causing Brugada Syndrome (4.2e-05 vs 0.00017), allowing no conclusion about variant significance. c.3956G>T has been reported in the literature in individuals affected with or suspected of Brugada Syndrome (example: Amin_2011, Casini_2007, Kapplinger_2010, Adler_2016) as well as in other in individuals of various cardiac phenotypes (example: Tadros_2017, Meregalli_2009). The variant was also reported in a proband and his son with dilated cardiomyopathy (Golbus_2014) as well as in a mother with reduced left ventricular ejection fraction and frequent ventricular ectopic beats and in her son with possible Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC). The son also carried another LMNA variant (Hoorntje_2017). These data indicate that the variant is likely to be associated with disease. In an in vitro functional study, the variant was shown to enhance slow inactivation of SCN5A channel (Casini_2007). However, another in vitro study, co-expressing the wild-type channel and the variant report no reduction in channel current densities (Hoshi_2014). Five ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
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 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 10, 2021 | - - |
Long QT syndrome 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Apr 04, 2017 | The c.3956G>T (p.Gly1319Val) variant has been reported in several patients with Brugada syndrome [PMID 12106943, 19251209, 21273195]. Functional assays showed that this variant contributes to a reduction in sodium currents [PMID 17854786]. This variant was observed in only one individual at the heterozygous state in the ExAC population database (http://exac.broadinstitute.org/variant/3-38603913-C-A).This variant is conserved in mammals and while not clinically validated, computer-based algorithms (SIFT and Polyphen-2) predict this p.Gly1319Val change to be deleterious. This variant is thus classified as pathogenic. Pathogenic variants in SCN5A are also considered medically actionable [ACMG 59, PMID 27854360] - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 22, 2024 | The p.G1319V variant (also known as c.3956G>T), located in coding exon 21 of the SCN5A gene, results from a G to T substitution at nucleotide position 3956. The glycine at codon 1319 is replaced by valine, an amino acid with dissimilar properties. This variant has been previously reported in multiple affected individuals with confirmed or suspected Brugada syndrome or other arrhythmia phenotypes (Casini S et al. Cardiovasc Res. 2007;76(3):418-29; Meregalli PG et al. Heart Rhythm. 2009;6(3):341-8; Kapplinger JD et al. Heart Rhythm. 2010;7(1):33-46; van der Werf C et al. Heart Rhythm. 2010;7(10):1383-9; Amin AS et al. Europace. 2011;13(7):968-75), and was also reported in an adult male with dilated cardiomyopathy (DCM) and arrhythmia, and in his son who had signs of DCM (Golbus JR et al. Circ Cardiovasc Genet. 2014;7(6):751-9 (reported as p.G1318V)). One study reported that this alteration resulted in abnormal ion channel function (Casini S et al. Cardiovasc Res. 2007;76(3):418-29), while a second study found no impact on sodium current density when co-expressed with wild-type channels (Hoshi M et al. Circ Cardiovasc Genet. 2014;7(2):123-31). This amino acid position is highly conserved in 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. - |
Cardiac arrhythmia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 24, 2023 | This missense variant replaces glycine with valine at codon 1319 of the SCN5A protein. This variant is also known as p.Gly1318Val in the literature based on a different NM_000335 transcript. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved region of the transmembrane domain III. Rare nontruncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome and long QT syndrome (PMID: 32893267). Functional studies have shown that this variant causes a significant reduction in sodium current (PMID: 17854786, 19251209). This variant has been reported in over ten unrelated individuals affected with Brugada syndrome (PMID: 12106943, 17854786, 19251209, 21273195, 24951569, 29759671, 30847666, 32893267, 36516610, 37061847, ClinVar SCV000291807.6), in an individual affected with long QT syndrome (PMID: 32893267), and in two individuals affected with progressive cardiac conduction disorders (PMID: 30059973). This variant has been shown to segregates with disease in four first-degree relatives from two families affected with cardiac conduction disease and cardiomypoathy (PMID: 25179549, 28790152). This variant has been identified in 11/269654 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at