ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.1855C>T (p.Leu619Phe) (rs199473133)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413033 SCV000491131 uncertain significance not provided 2017-05-05 criteria provided, single submitter clinical testing The L619F variant of uncertain significance in the SCN5A gene has previously been reported in association with LQTS and Brugada syndrome (Wehrens et al., 2003; Lupoglazoff et al., 2004; Kapplinger et al., 2010). Wehrens et al. (2003) initially reported this variant in a female infant with a prolonged QTc interval of 538 ms. This variant was also identified in the proband's mother and maternal grandmother; however, as their QTc intervals were only borderline prolonged (450-460 ms) we cannot unequivocally confirm segregation with disease in this family (Wehrens et al., 2003). Nevertheless, this substitution occurs at a position within the cytoplasmic linker connecting domains I and II of the sodium channel that is conserved in mammals (Wehrens et al., 2003). Functional studies by Wehrens et al. (2003) demonstrated that L619F results in increased sustained sodium channel current compared to wild-type, causing prolonged depolarization and a speeding of recovery from inactivation. However, the L619F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In addition, this variant has been observed in 4/62,672 alleles from individuals of European (Non-Finnish) ancestry in the Exome Aggregation Consortium (ExAC) dataset (Lek et al., 2016). Furthermore, despite the fact that publications describe an association between the L619F variant and arrhythmia, segregation data was uninformative and some reported individuals harbor additional variants in other LQTS-associated genes.
Color RCV000777478 SCV000913340 uncertain significance Arrhythmia 2019-08-08 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000779409 SCV000916021 uncertain significance Long QT syndrome 3 2018-12-18 criteria provided, single submitter clinical testing The SCN5A c.1855C>T (p.Leu619Phe) variant is a missense variant that has been reported in three studies, in which it is found in a heterozygous state in two infants with long QT syndrome (LQTS) (Wehrens et al. 2003; Lupoglazoff et al. 2004). One neonate presented with fetal arrhythmia, collapse torsades de pointes, and ventricular tachycardia and also carried variants in two other genes, including KCNQ1 and HERG. In the other family, the infant's mother and maternal grandmother had borderline prolonged QTc and carried the variant. The variant was absent in the father or older sibling who normal QT intervals. The p.Leu619Phe variant was also found in a 40 year old individual with Brugada syndrome who was also heterozygous for a second truncating variant in SCN5A (Kapplinger et al. 2010). The p.Leu619Phe variant was absent from 150 control subjects but is reported at a frequency of 0.000077 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies demonstrated the p.Leu619Phe mutant Na+ channels caused increased sustained Na+ current and augmented Na+ channel window current. Based on the collective evidence, the p.Leu619Phe variant is classified as a variant of unknown significance but suspicious for long QT syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000058457 SCV000943321 uncertain significance Brugada syndrome 2019-11-27 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 619 of the SCN5A protein (p.Leu619Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs199473133, ExAC 0.006%). This variant has been observed in several individuals affected with long QT syndrome or Brugada syndrome; however, many of these individuals also carried variants in other LQTS-associated genes (PMID: 12673799, 20129283, 14998624). ClinVar contains an entry for this variant (Variation ID: 67693). Experimental studies have shown that this missense change impairs sodium channel activity and availability (PMID: 12673799). 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.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058457 SCV000089977 not provided Brugada syndrome no assertion provided literature only This variant has been reported as associated with Brugada syndrome in the following publications (PMID:12673799;PMID:14998624;PMID:20129283;PMID:22378279). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
CSER _CC_NCGL, University of Washington RCV000148861 SCV000190605 uncertain significance Long QT syndrome 2014-06-01 no assertion criteria provided research

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