ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.2729C>T (p.Ser910Leu) (rs199473175)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000617872 SCV000737644 likely pathogenic Cardiovascular phenotype 2017-02-08 criteria provided, single submitter clinical testing 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 was reported in unrelated individuals from distinct Brugada syndrome cohorts (Priori SG et al. Circulation, 2002;105:1342-7, Selga E et al. PLoS ONE, 2015;10:e0132888). 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 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.
Ambry Genetics RCV000624813 SCV000741704 likely pathogenic Inborn genetic diseases 2017-08-30 criteria provided, single submitter clinical testing
Invitae RCV000058522 SCV001236985 pathogenic Brugada syndrome 2020-08-09 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 910 of the SCN5A protein (p.Ser910Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with Brugada syndrome or sick sinus syndrome (PMID: 11901046, 29574140, 26173111, 24768612, 28104484, 20129283.). ClinVar contains an entry for this variant (Variation ID: 67753). This variant has been reported to affect SCN5A protein function (PMID: 24768612). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001588893 SCV001826926 uncertain significance not provided 2020-11-11 criteria provided, single submitter clinical testing 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 (Lek et al., 2016); 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: 33131149, 28104484, 32268277, 25904541, 32533946, 10471492, 10940383, 12736279, 14523039, 15840476, 16453024, 16684018, 17210839, 18378609, 19251209, 22766342, 22840528, 22999724, 25274057, 20100972, 30662450, 31983221, 14961552, 29574140, 26173111, 11901046, 24768612, 12650874, 20129283, 14753626, 30193851, 15655131)
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058522 SCV000090042 not provided Brugada syndrome no assertion provided literature only 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.

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