ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.4501C>G (p.Leu1501Val) (rs199473266)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000472311 SCV000545032 likely pathogenic Brugada syndrome 2018-04-12 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 1501 of the SCN5A protein (p.Leu1501Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs199473266, ExAC 0.004%). This variant has been reported in several individuals affected with long QT syndrome (PMID: 10973849, 19841300, Invitae) and one individual affected with Brugada syndrome (PMID: 24721456). ClinVar contains an entry for this variant (Variation ID: 67904). Experimental studies have shown that this missense change leads to a reduction of peak current densities when co-expressed with SCN5A (PMID: 24573164). In summary, this variant is a rare missense change that has been observed in several affected individuals and has an effect on protein function. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000709759 SCV000840060 likely pathogenic Long QT syndrome 3 2017-10-23 criteria provided, single submitter clinical testing The c.4501C>G (p.Leu1501Val) variant in the SCN5A has been observed in multiple individuals with Long QT syndrome (PMID: 10973849, 19841300) and one individual with Brugada syndrome (PMID: 24721456). In addition, experimental studies have shown that this missense change leads to altered SCN5A protein function (PMID: 24573164). Therefore, this variant in the SCN5A gene is classified as likely pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000756618 SCV000884486 uncertain significance not provided 2017-09-22 criteria provided, single submitter clinical testing The p.Leu1501Val variant (rs199473266) has been reported in several individuals with long QT syndrome, a single individual with Brugada syndrome, and was absent from controls (Kapa 2014, Kapplinger 2009, Kapplinger 2010, Savastano 2014, and Splawski 2000). The p.Leu1501Val variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.0045% in the Non-Finnish European population (identified in 5 out of 111,706 chromosomes), and is classified as likely pathogenic in ClinVar (Variant ID: 67904). Functional evidence demonstrates that the p.Leu1501Val variant reduces SCN5A sodium channel peak current density when co-expressed with wild type SCN5A; however, the clinical relevance of this observation is unclear. The leucine at codon 1501 is highly conserved considering 9 species up to zebrafish (Alamut software v2.10.0), and computational analyses suggest that this variant affects the structure/function of the SCN5A protein (SIFT: damaging, PolyPhen2: probably damaging, MutationTaster: disease causing). While the p.Leu1501Val variant is a strong candidate for a likely pathogenic classification, the clinical significance cannot be determined with certainty because the functional data does not have a well-established connection to disease.
Color RCV000777743 SCV000913704 uncertain significance Arrhythmia 2019-11-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001201272 SCV001372386 likely pathogenic Long QT syndrome 2020-06-24 criteria provided, single submitter clinical testing Variant summary: SCN5A c.4501C>G (p.Leu1501Val) results in a conservative amino acid change located in the Ion transport domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 255846 control chromosomes. c.4501C>G has been reported in the literature in multiple individuals affected with Long QT Syndrome (e.g. Splawski_2000, Kapplinger_2009, Kapa_2009), Brugada Synrome (Kapplinger_2010, Crotti_2012), or SCD (Adabag_2010, Goldenberg_2011). These data indicate that the variant is very likely to be associated with disease. Experimental studies have shown that this variant leads to a reduction of peak current densities when co-expressed with wild-type SCN5A (Hoshi_2014). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely pathogenic n=2, VUS n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058684 SCV000090204 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:10973849;PMID:19716085;PMID:19841300). 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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