Submissions for variant NM_000335.5(SCN5A):c.5708C>T (p.Ser1903Leu)

gnomAD frequency: 0.00040  dbSNP: rs150264233

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041630	SCV000065326	likely benign	not specified	2020-08-05	criteria provided, single submitter	clinical testing	The p.Ser1904Leu variant in SCN5A has been reported in several individuals with a range of cardiac manifestations (Bankston 2007 PMID: 18708744, Kapplinger 2010 PMID: 20129283, Methner 2016 PMID: 27435932, LMM data). However, this variant has also been identified in 0.17% (42/24204) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is inconsistent with the reported prevalence of SCN5A-associated disease. This variant has also been reported in ClinVar (Variation ID: 48310). Computational prediction tools and conservation analyses predict an impact to the protein and in vitro studies suggest that the p.Ser1904Leu variant may impact protein function (Bankston 2007 PMID: 18708744, Glaaser 2012 PMID: 22426227, Kapplinger 2010 PMID: 20129283). However, this in vitro assay may not accurately represent biological function. In summary, because of the frequency, this variant is classified as likely benign. ACMG/AMP Criteria applied: PP3, PS4_Supporting, BS1.
GeneDx	RCV000058802	SCV000235543	uncertain significance	not provided	2023-10-13	criteria provided, single submitter	clinical testing	LQTS is caused by gain of function variants in the SCN5A channel (NaV1.5), while Brugada syndrome is caused by loss of function variants; as this variant has been identified in individuals with diseases that have different mechanisms of pathogenicity, its clinical significance is uncertain; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22378279, 20129283, 25904541, 28988457, 30847666, 25637381, 22426227, 26159999, 26332594, 24892747, 27435932, 29728395, 26746457, 34021086, 30153324, 21167176, 18708744, 30203441, Tomaselli2023[Functional], 35662881, 24055113)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000058802	SCV000637187	likely benign	not provided	2024-01-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000620507	SCV000737262	likely benign	Cardiovascular phenotype	2019-01-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Mendelics	RCV000987195	SCV001136444	benign	Brugada syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000041630	SCV001338525	likely benign	not specified	2022-05-23	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.5711C>T (p.Ser1904Leu) results in a non-conservative amino acid change in 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 0.00017 in 283812 control chromosomes (gnomAD, Bankston_2007, Kapplinger_2010, Kapplinger_2015), predominantly at a frequency of 0.0017 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 68 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.5711C>T has been reported in at least one individual with LQTS and segregated with symptoms of disease in two family members, however only a subset of LQTS-associated genes were sequenced in these individuals (Bankston_2007). In addition, the variant has been reported in at least one individual affected with SIDS (Methner_2017). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Several publications report experimental evidence evaluating an impact on protein function. These studies report that the variant disrupts sodium channel gate inactivation and promotes late Na+ channel currents by increasing the propensity of the channel to reopen during prolonged depolarization (Bankston_2007, Glaaser_2012). Another study reports that the variant may have a more severe electrophysiological impact in certain tissue types, as the effect in Purkinje fiber cells was more significant than that observed in a ventricular myocyte model (Iyer_2014). A recent study showed that the variant had had reduced affinity for Calmodulin binding compared to wildtype (Kang_2021). These in-vitro studies do not allow convincing conclusions about the variant effect, however, as the variant does not appear to alter the overall function of the sodium channels and it is unclear how these findings would translate in-vivo. Eight ClinVar submitters have assessed the variant since 2014: two classified the variant as of uncertain significance, four as likely benign, one as benign and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV001841613	SCV001360092	likely benign	Cardiac arrhythmia	2018-11-24	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000058802	SCV001713278	uncertain significance	not provided	2019-06-23	criteria provided, single submitter	clinical testing
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058802	SCV000090322	not provided	not provided		no assertion provided	literature only	This variant has been reported in the following publications (PMID:18708744;PMID:20129283;PMID:22378279;PMID:22426227).
CSER _CC_NCGL, University of Washington	RCV000148839	SCV000190580	likely benign	Long QT syndrome	2014-06-01	no assertion criteria provided	research
Forensic Genetics Laboratory, Harris County Institute of Forensic Sciences	RCV000234983	SCV000263116	pathogenic	Death in infancy	2015-03-27	no assertion criteria provided	clinical testing