ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.4478A>G (p.Lys1493Arg) (rs199473260)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171569 SCV000055299 likely pathogenic Atrial fibrillation 2013-06-24 criteria provided, single submitter research
Ambry Genetics RCV000619395 SCV000737722 uncertain significance Cardiovascular phenotype 2019-11-19 criteria provided, single submitter clinical testing The p.K1493R variant (also known as c.4478A>G), located in coding exon 25 of the SCN5A gene, results from an A to G substitution at nucleotide position 4478. The lysine at codon 1493 is replaced by arginine, an amino acid with highly similar properties, and is located in the interdomain linker DIII/DIV. This alteration has been reported in a mother and son pair with atrial fibrillation; the same authors suggested this alteration had an effect on voltage dependent inactivation (Li Q et al. Biochem. Biophys. Res. Commun., 2009 Feb;380:132-7). In a study of long QT syndrome clinical genetic testing, this alteration was reported in two patients; however, clinical details were limited (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303). This alteration has also been reported as a secondary cardiac variant in an exome cohort (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000638673 SCV000760212 uncertain significance Brugada syndrome 2020-09-17 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 1493 of the SCN5A protein (p.Lys1493Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs199473260, ExAC 0.004%). This variant has been reported in two relatives with atrial fibrillation, individuals referred for testing for LQTS, and in one individual with a history of supraventricular ectopy (PMID: 19167345, 19716085, 23861362). ClinVar contains an entry for this variant (Variation ID: 67898). Experimental studies have shown that this missense change leads to a positive shift in voltage-dependence of sodium channel inactivation and enhanced cardiomyocyte excitability consistent with a gain-of-function effect (PMID: 19167345). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Health, Inc RCV001187865 SCV001354767 uncertain significance Arrhythmia 2019-09-23 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV001508490 SCV001714687 uncertain significance not provided 2019-11-18 criteria provided, single submitter clinical testing
Genomics England Pilot Project,Genomics England RCV001542741 SCV001760121 likely pathogenic Long QT syndrome 3 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058678 SCV000090198 not provided Congenital long QT syndrome no assertion provided literature only This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19167345;PMID:19716085). 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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