ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.1700T>A (p.Leu567Gln) (rs199473124)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000619630 SCV000738223 uncertain significance Cardiovascular phenotype 2020-08-12 criteria provided, single submitter clinical testing The p.L567Q variant (also known as c.1700T>A), located in coding exon 11 of the SCN5A gene, results from a T to A substitution at nucleotide position 1700. The leucine at codon 567 is replaced by glutamine, an amino acid with dissimilar properties, and is located in the DI/DII interdomain linker region. This alteration has been described in an individual with sudden cardiac arrest, as well as in her three asymptomatic family members. The family history was significant for sudden death at a young age, and the individual's ECG showed signs of Brugada syndrome (Priori SG et al. Lancet, 2000 Mar;355:808-9). This alteration has been reported in a pregnant female who had a family history of sudden cardiac death, but did not display any prenatal or postnatal cardiac symptoms (Giambanco L et al. Case Rep Obstet Gynecol, 2014 May;2014:531648). In addition, this alteration has been reported in a pediatric sudden unexplained death cohort (Rochtus AM et al. Mol Genet Genomic Med, 2020 May;:e1309). In vitro studies suggested that this alteration could accelerate inactivation (Wan X et al. Am. J. Physiol. Heart Circ. Physiol., 2001 Jan;280:H354-60), or reduce channel current under the tested condition (Hoshi M et al. Circ Cardiovasc Genet, 2014 Apr;7:123-31). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000058442 SCV000813706 uncertain significance Brugada syndrome 2020-05-20 criteria provided, single submitter clinical testing This sequence change replaces leucine with glutamine at codon 567 of the SCN5A protein (p.Leu567Gln). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and glutamine. This variant is present in population databases (rs199473124, ExAC 0.002%). This variant has been reported to segregate with disease in a family affected with Brugada syndrome (PMID: 10711933). Additionally, it has been reported in an individual affected with Brugada syndrome (PMID: 11076825) and an individual who suffered a sudden unexplained death (PMID: 29915097). ClinVar contains an entry for this variant (Variation ID: 67678). Experimental studies have shown that this missense change causes a decrease in current density and a negative shift in the voltage dependence of inactivation in vitro and in rat and human cardiomyocytes (PMID: 24573164, 11123251). 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. 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 RCV000776285 SCV000911572 uncertain significance Arrhythmia 2019-10-16 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000845516 SCV000987619 likely pathogenic Long QT syndrome criteria provided, single submitter clinical testing
Baylor Genetics RCV001329631 SCV001521123 uncertain significance Atrial fibrillation, familial, 10 2020-02-04 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058442 SCV000089962 not provided Brugada syndrome no assertion provided literature only This variant has been reported as associated with Brugada syndrome in the following publications (PMID:10711933;PMID:11901046;PMID:11076825;PMID:11123251). 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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