ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.1858C>T (p.Arg620Cys) (rs199473577)

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Total submissions: 3
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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 RCV000058458 SCV000089978 not provided Brugada syndrome no assertion provided literature only This variant has been reported as associated with Brugada syndrome in the following publications (PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Color RCV000772088 SCV000905121 uncertain significance Arrhythmia 2018-08-05 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the linker region between transmembrane domains DI and DII of the SCN5A protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. Experimental functional assays have shown that this variant does not reduce peak current densities when co-expressed with a wild type protein (PMID: 24573164). This variant has been reported in an individual suspected of having Brugada syndrome (PMID: 20129283). This variant has also been observed in three individuals in a family affected with Long QT syndrome (PMID: 24667783). However, all of these individuals carried a pathogenic variant in KCNQ1, suggesting that this SCN5A variant was likely not the primary cause of disease. This variant has been identified in 6/219910 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although available evidence suggests that this variant is unlikely to be disease-causing, additional study is necessary to rule out the pathogenicity of this variant conclusively.
Invitae RCV000058458 SCV000637091 uncertain significance Brugada syndrome 2017-06-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 620 of the SCN5A protein (p.Arg620Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs199473577, ExAC 0.02%). This variant has been reported in an individual affected with suspected Brugada syndrome (PMID: 20129283). This variant has also been observed in three individuals in a family affected with Long QT syndrome (PMID: 24667783). However, in  these individuals, a pathogenic allele was also identified in KCNQ1, which suggests that this c.1858C>T variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 67694). This variant identified in the SCN5A gene is located in the interdomain linker DI/DII 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 causes an increased recovery time from inactivation that can be partially rescued by co-expressing the wild type protein in vitro but does not change the reduced steady state inactivation voltage. Co-expression with protein with the p.Gln1077del variant caused a significant change in steady state inactivation voltage (PMID: 24573164, 25904541). However, the clinical significance of these observations is uncertain. In summary, this variant has uncertain impact on SCN5A function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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