Submissions for variant NM_000335.5(SCN5A):c.4498C>G (p.Leu1500Val)

gnomAD frequency: 0.00002  dbSNP: rs199473266

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000756618	SCV000545032	pathogenic	not provided	2024-07-11	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1501 of the SCN5A protein (p.Leu1501Val). This variant is present in population databases (rs199473266, gnomAD 0.004%). This missense change has been observed in individuals with long QT syndrome (PMID: 10973849, 19841300, 24721456, 30193851). ClinVar contains an entry for this variant (Variation ID: 67904). 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: 24573164). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as 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 Diagnostics, LLC DBA Color Health	RCV001842366	SCV000913704	uncertain significance	Cardiac arrhythmia	2023-08-07	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 1501 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant may cause a reduction in sodium current density (PMID: 24573164). An RNA study has shown that this variant partially disrupts RNA splicing but due to the activation of a cryptic donor site but the mutant allele also produced the normal transcript (PMID: 30369311). This variant has been reported in four individuals with Brugada syndrome (PMID: 24721456, 30193851, 32533187, 33221895), two individuals with long QT syndrome (PMID: 10973849, 19841300), one individual with sudden cardiac death in his 70s (PMID: 34135346), as well as two asymptomatic individuals aged 70 years and older without a history of cardiovascular events (PMID: 34135346). This variant has been detected in a small family affected with Brugada syndrome, in which a variant in a different gene, but not this SCN5A variant, appeared to segregate with disease (PMID: 28494446). This variant has been identified in 5/251446 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to the conflicting clinical observations, the role of this variant in disease cannot be determined conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Ambry Genetics	RCV003162459	SCV003903627	uncertain significance	Cardiovascular phenotype	2022-12-07	criteria provided, single submitter	clinical testing	The c.4501C>G (p.L1501V) alteration is located in exon 26 (coding exon 25) of the SCN5A gene. This alteration results from a C to G substitution at nucleotide position 4501, causing the leucine (L) at amino acid position 1501 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004537262	SCV004118600	likely pathogenic	SCN5A-related disorder	2022-08-31	criteria provided, single submitter	clinical testing	The SCN5A c.4501C>G variant is predicted to result in the amino acid substitution p.Leu1501Val. This variant has frequently been reported in the literature individuals with various cardiovascular phenotypes (Long QT/Brugada syndromes) (Splawski et al 2000. PubMed ID: 10973849; Table S2, Berthome et al. 2019. PubMed ID: 30193851; Lacaze et al. 2021. PubMed ID: 34135346). This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-38597188-G-C). Taken together, this variant is interpreted as likely pathogenic.
GeneDx	RCV000756618	SCV005373370	uncertain significance	not provided	2024-04-02	criteria provided, single submitter	clinical testing	Reported in association with Brugada syndrome, fever-induced Brugada syndrome, long QT syndrome (LQTS), and sudden cardiac death (SCD) in published literature (PMID: 19716085, 20129283, 10973849, 19841300, 24721456, 30193851, 20102864, 23631430, 36516610); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis supports a deleterious effect on splicing; Did not segregate interdependently with Brugada syndrome in two families (PMID: 28494446, 29956481); Functional analysis has been unclear on this variant's impact on protein function (PMID: 24573164, 30369311, 29606593); This variant is associated with the following publications: (PMID: 24136861, 19716085, 10973849, 19841300, 24721456, 29956481, 31447099, 30059973, 28494446, 30193851, 33221895, 33131149, 34135346, 30203441, 34546463, 20129283, 20102864, 23631430, 36516610, 37942788, 32533187, 30369311, 29606593, 24573164, 22840528, 21185501)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786344	SCV005399935	likely pathogenic	Brugada syndrome 1	2022-03-31	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are both known mechanisms of disease in this gene. Loss of function is usually associated with Brugada syndrome 1 (MIM#601144) and sick sinus syndrome 1 (SSS) (MIM#608567), whereas gain of function is usually associated with long QT syndrome-3 (LQTS) (MIM#603830). Dilated cardiomyopathy 1E (DCM) (MIM#601154) can be caused by variants with either a loss or gain of function mechanism (PMID: 29798782). Dominant-negative has also been demonstrated as a possible mechanism associated with Brugada syndrome (PMIDs: 22739120, 24573164). (I) 0108 - This gene is associated with both recessive and dominant disease. Most conditions associated with this gene are dominantly inherited; however SSS is caused by biallelic variants (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to valine. (I) 0304 - Variant is present in gnomAD <0.01 (v2: 5 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a minor amino acid change. (SP) 0600 - Variant is located in the annotated DIII/DIV interdomain linker (PMID: 27566755). (I) 0710 - Another variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The p.(Leu1500Pro) has been classified once as a VUS (ClinVar). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in at least five individuals with either LQTS or Brugada syndrome (ClinVar, PMIDs: 10973849, 20129283, 27566755). (SP) 1010 - Functional evidence for this variant is inconclusive. While the mutant construct transfected into HEK293T cells did not demonstrate abnormal protein function, co-transfection of mutant and WT constructs resulted in a reduction of peak current density (PMID: 24573164). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV005031547	SCV005664484	likely pathogenic	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	2024-03-25	criteria provided, single submitter	clinical testing
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.