ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.3953G>T (p.Gly1318Val) (rs199473220)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000505769 SCV000235461 likely pathogenic not provided 2021-03-28 criteria provided, single submitter clinical testing Reported in ClinVar (ClinVar Variant ID# 67838; Landrum et al., 2016); 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; This variant is associated with the following publications: (PMID: 23414114, 19843921, 12106943, 24400668, 24573164, 19889341, 20129283, 21273195, 19251209, 17854786, 24951569, 25179549, 22373669, 20646679, 30609406, 30662450, 29759671, 25904541, 30291343, 30847666, 31447099, 32377377, 33131149)
Invitae RCV000058616 SCV000291807 likely pathogenic Brugada syndrome 2020-06-10 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 1319 of the SCN5A protein (p.Gly1319Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is present in population databases (rs199473220, ExAC 0.002%). This variant has been observed in several individuals affected with Brugada syndrome (PMID: 17854786, 24951569, 25904541, Invitae) and in individuals with dilated cardiomyopathy and cardiac conduction disease (PMID: 25179549, 28790152). This variant is also known as G1318V in the literature. ClinVar contains an entry for this variant (Variation ID: 67838). Experimental studies have shown that this missense change enhances slow inactivation of the SCN5A channel (PMID: 17854786). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000252945 SCV000319730 likely pathogenic Cardiovascular phenotype 2020-10-01 criteria provided, single submitter clinical testing 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000058616 SCV000710928 likely pathogenic Brugada syndrome 2018-07-31 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000709762 SCV000840065 pathogenic Long QT syndrome 3 2017-04-04 criteria provided, single submitter clinical testing 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]
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001553760 SCV001774754 likely pathogenic Brugada syndrome (shorter-than-normal QT interval) 2021-07-29 criteria provided, single submitter clinical testing 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.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058616 SCV000090136 not provided Brugada syndrome no assertion provided literature only 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000505769 SCV001742170 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV000505769 SCV001918853 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000505769 SCV001958133 pathogenic not provided no assertion criteria provided clinical testing

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