ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.4219G>A (p.Gly1407Arg) (rs137854612)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058649 SCV000090169 not provided Brugada syndrome no assertion provided literature only This variant has been reported as associated with Brugada syndrome in the following publications (PMID:11748104;PMID:14523039;PMID:19251209;PMID:20129283;PMID:20539757). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000058649 SCV000805034 likely pathogenic Brugada syndrome 2017-01-13 no assertion criteria provided clinical testing
GeneDx RCV000183190 SCV000235608 pathogenic not provided 2018-03-22 criteria provided, single submitter clinical testing The G1408R pathogenic variant in the SCN5A gene has been reported previously in a large French family in association with Brugada syndrome and isolated cardiac conduction defect (ICCD) (Kyndt et al., 2001). Kyndt et al. (2001) reported that the G1408R variant segregated with a cardiac disease phenotype in 12 individuals in a family: 4 individuals exhibited clinical Brugada syndrome and 8 members exhibited ICCD anomalies. Additionally, Benson et al. (2003) identified compound heterozygosity for G1408R and another SCN5A missense variant in 3 siblings with congenital sick sinus syndrome. Kapplinger et al. (2010) identified G1408R in 7 unrelated individuals with Brugada syndrome. Furthermore, the G1408R variant was not found in 100 control alleles (Kyndt et al., 2001), and was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Located between the DIII-S5 and DIIII-S6 domain, G1408R is a non-conservative amino acid substitution at a position that is conserved across species. Functional studies on SCN5A-related familial sick sinus syndrome reported that G1408R mutant channels failed to produce inward sodium currents despite normal surface localization, suggesting a gating defect (Gui et al., 2010). In summary, G1408R in the SCN5A gene is interpreted as a pathogenic variant.
Invitae RCV000058649 SCV000637149 pathogenic Brugada syndrome 2017-08-08 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 1408 of the SCN5A protein (p.Gly1408Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate in the heterozygous state with Brugada syndrome (BrS) and isolated cardiac conduction disease in a large multigenerational family (PMID: 11748104). It has also been reported to segregate in a family with first-degree heart block as a dominant trait and with sick sinus syndrome (SSS) as a recessive trait in the same family, being found in trans with Pro1298Leu in 3 siblings affected with SSS (PMID: 14523039). It has also been found in several individuals referred for BrS testing (PMID: 20129283). This variant is also known as G1406R in the literature. ClinVar contains an entry for this variant (Variation ID: 9395). This variant identified in the SCN5A gene is located in the transmembrane spanning DIII-S5/S6 region of the resulting protein (PMID: 25348405). For more information about the location of this variant, please visit www.invitae.com/SCN5A-topology. Experimental studies have shown that this missense change abrogates the Na+ inward current of the channel (PMID: 20539757). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000009995 SCV000030216 pathogenic Sick sinus syndrome 1, autosomal recessive 2003-10-01 no assertion criteria provided literature only
OMIM RCV000009996 SCV000030217 pathogenic Brugada syndrome 1 2003-10-01 no assertion criteria provided literature only
OMIM RCV000009997 SCV000030218 pathogenic Cardiac conduction defect, nonspecific 2003-10-01 no assertion criteria provided literature only

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