ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.4222G>A (p.Gly1408Arg) (rs137854612)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183190 SCV000235608 pathogenic not provided 2021-03-26 criteria provided, single submitter clinical testing Segregated with a cardiac disease phenotype in 12 individuals in a family: 4 individuals exhibited clinical Brugada syndrome and 8 members exhibited ICCD anomalies (Kyndt et al., 2001); Published functional studies indicated mutant channels failed to produce inward sodium currents despite normal surface localization, suggesting a gating defect (Gui et al., 2010); Reported in ClinVar as pathogenic (ClinVar Variant ID# 9395; Landrum et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27766308, 27381756, 28150151, 30193851, 11748104, 20129283, 20031634, 19251209, 17368591, 26154754, 28018021, 28341781, 30662450, 32569262, 30147658, 31993492, 14523039, 20539757, 33131149)
Invitae RCV000058649 SCV000637149 pathogenic Brugada syndrome 2020-04-13 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 observed to segregate 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 (PMID: 14523039). It has also been observed in 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). 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
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

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