ClinVar Miner

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

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000505769 SCV000235461 likely pathogenic not provided 2018-10-30 criteria provided, single submitter clinical testing The G1319V variant that is likely pathogenic was identified in the SCN5A gene. This variant has previously been reported in association with Brugada syndrome and sudden cardiac death (Kapplinger et al., 2010; Meregalli et al., 2009; Casini et al., 2007; Amin et al., 2011; Conte et al., 2014). In addition, the G1319V variant (reported as G1318V due to the use of alternate nomenclature) has also been reported to segregate with DCM in two members of one family (Golbus et al., 2014). The G1319V variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a residue located in the DIIIS4–S5 linker that is conserved across species, which is the proposed docking site for the inactivation particle and is thus required for channel fast inactivation (Smits et al., 2005). Furthermore, functional studies by Casini et al. (2007) demonstrate that G1319V alters sodium channel gating properties and reduces the sodium current, which is consistent with a Brugada syndrome phenotype. However, although missense variants in nearby residues (L1316P, V1323G) have been reported in HGMD in association with SCN5A-related disorders (Stenson et al., 2014), the pathogenicity of these variants has not been definitively determined. Finally, the G1319V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties.
Invitae RCV000058616 SCV000291807 likely pathogenic Brugada syndrome 2019-12-23 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 an individual with dilated cardiomyopathy and cardiac conduction disease (PMID: 25179549). 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 2019-09-12 criteria provided, single submitter clinical testing In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
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 ( 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 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.

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