Submissions for variant NM_000335.5(SCN5A):c.1855C>T (p.Leu619Phe)

gnomAD frequency: 0.00006  dbSNP: rs199473133

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413033	SCV000491131	uncertain significance	not provided	2023-10-26	criteria provided, single submitter	clinical testing	Reported in the literature in patients with LQTS or Brugada syndrome; however, segregation data are uninformative, and some individuals harbor additional variants in other genes (PMID: 12673799, 14998624, 20129283, 30193851); Published functional studies demonstrate a damaging effect; variant expressed in HEK cells results in increased sustained sodium channel current compared to wild-type, causing prolonged depolarization and a speeding of recovery from inactivation (PMID: 12673799); however, this in vitro assay may not accurately represent biological function; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Variant occurs at a position within the cytoplasmic linker connecting domains I and II of the sodium channel that is conserved in mammals (PMID: 12673799); This variant is associated with the following publications: (PMID: 19027780, 29728395, 23414114, 22378279, 25637381, 14998624, 17504259, 12673799, 31589614, 26582918, 30193851, 30203441, 20129283)
Color Diagnostics, LLC DBA Color Health	RCV001842300	SCV000913340	uncertain significance	Cardiac arrhythmia	2023-03-20	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 619 of the SCN5A protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An experimental functional study has shown that this variant may impact the cardiac sodium channel function of the SCN5A protein (PMID: 12673799). This variant has been reported in two infants affected with long QT syndrome (PMID: 12673799, 14998624) as well as in two unaffected family members of one infant (PMID: 12673799). It has also been reported in individuals affected with Brugada syndrome (PMID: 20129283, 30193851). One of these individuals also carried a pathogenic variant in the same gene (PMID: 20129283). Additionally, this variant has been reported in two individuals in a healthy control population (PMID: 23414114). This variant has been identified in 9/223308 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Illumina Laboratory Services, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000413033	SCV000943321	uncertain significance	not provided	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 619 of the SCN5A protein (p.Leu619Phe). This variant is present in population databases (rs199473133, gnomAD 0.008%). This missense change has been observed in individuals with SCN5A-related conditions (PMID: 12673799, 30193851). ClinVar contains an entry for this variant (Variation ID: 67693). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SCN5A function (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.
Fulgent Genetics, Fulgent Genetics	RCV002477195	SCV002789652	uncertain significance	Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1; Progressive familial heart block, type 1A; Ventricular fibrillation, paroxysmal familial, type 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10	2021-07-12	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537259	SCV004118930	uncertain significance	SCN5A-related disorder	2022-11-21	criteria provided, single submitter	clinical testing	The SCN5A c.1855C>T variant is predicted to result in the amino acid substitution p.Leu619Phe. This variant has been reported in multiple individuals with Long QT or Brugada syndrome (Wehrens et al. 2003. PubMed ID: 12673799; Lupoglazoff et al. 2004. PubMed ID: 14998624; Kapplinger et al. 2009. PubMed ID: 20129283; Table S2 - Berthome et al. 2018. PubMed ID: 30193851). Functional studies found this variant increased sustained sodium channel current resulting in a prolonged depolarization (Wehrens et al. 2003. PubMed ID: 12673799). This variant is reported in 0.0085% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-38645238-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV001842300	SCV004818078	uncertain significance	Cardiac arrhythmia	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 619 of the SCN5A protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An experimental functional study has shown that this variant may impact the cardiac sodium channel function of the SCN5A protein (PMID: 12673799). This variant has been reported in two infants affected with long QT syndrome (PMID: 12673799, 14998624) as well as in two unaffected family members of one infant (PMID: 12673799). It has also been reported in individuals affected with Brugada syndrome (PMID: 20129283, 30193851). One of these individuals also carried a pathogenic variant in the same gene (PMID: 20129283). Additionally, this variant has been reported in two individuals in a healthy control population (PMID: 23414114). This variant has been identified in 9/223308 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV004019039	SCV004943820	uncertain significance	Cardiovascular phenotype	2022-01-05	criteria provided, single submitter	clinical testing	The c.1855C>T (p.L619F) alteration is located in exon 12 (coding exon 11) of the SCN5A gene. This alteration results from a C to T substitution at nucleotide position 1855, causing the leucine (L) at amino acid position 619 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
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