ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.5708C>T (p.Ser1903Leu) (rs150264233)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000041630 SCV000065326 uncertain significance not specified 2017-05-22 criteria provided, single submitter clinical testing The p.Ser1904Leu variant in SCN5A (ClinVar variation ID: 48310) has been reporte d in several individuals with a range of cardiac manifestations (1 with HCM, 1 w ith Brugada syndrome, 1 with SIDs, 1 with LQTS; Bankston 2007, Kapplinger 2010, Methner 2016, LMM data), and segregated in 2 symptomatic relatives (palpitations and syncope) from one family (Bankston 2007). Computational prediction tools an d conservation analyses predict an impact the protein and in vitro studies have shown that the p.Ser1904Leu variant impacts protein function (Bankston 2007, Gla aser 2012, Kapplinger 2010). However, this in vitro assay may not accurately rep resent biological function. This variant has been identified in 0.18% (43/24030) of African chromosomes by the genome Aggregation Database (gnomAD, http://gnoma; dbSNP rs150264233). This frequency is inconsistent with t he reported prevalence and mode of inheritance of SCN5A-associated disease. In summary, the available data are conflicting and therefore the clinical significa nce of the p.Ser1904Leu variant is uncertain.
GeneDx RCV000058802 SCV000235543 uncertain significance not provided 2018-07-11 criteria provided, single submitter clinical testing The S1904L variant of uncertain significance in the SCN5A gene has been reported previously in a 12 year-old male of Caribbean ancestry with mild QT prolongation, as well as in his mother with history of palpitations and maternal half-sister with history of syncope (Bankston et al., 2007). In addition, Kapplinger et al. (2010) reported S1904L in an individual with Brugada syndrome, and Methner et al. (2016) identified this variant in a 5 month-old African American female who died of SIDS. The S1904L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Functional studies report S1904L disrupts voltage-gated Na(+) channel inactivation (Bankston et al., 2007; Glaaser et al., 2012). Nevertheless, S1904L was observed in 43/24030 (0.2%) alleles from individuals of African ancestry in large population cohorts, indicating this may be a rare benign variant in this population (Lek et al., 2016). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae RCV001083009 SCV000637187 likely benign Brugada syndrome 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000620507 SCV000737262 likely benign Cardiovascular phenotype 2019-01-18 criteria provided, single submitter clinical testing Subpopulation frequency in support of benign classification;Other data supporting benign classification
Mendelics RCV000987195 SCV001136444 benign Brugada syndrome 1 2019-05-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000041630 SCV001338525 likely benign not specified 2020-04-13 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, 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 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). In addition, one 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). 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. Six ClinVar submitters (evaluation after 2014) cite the variant with conflicting interpretations: benign (n=1), likely benign (n=2), uncertain significance (n=2), and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Color RCV001192115 SCV001360092 likely benign Arrhythmia 2018-11-24 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

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