ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.5708C>T (p.Ser1903Leu) (rs150264233)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000620507 SCV000737262 uncertain significance Cardiovascular phenotype 2017-04-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
CSER_CC_NCGL; University of Washington Medical Center RCV000148839 SCV000190580 likely benign Long QT syndrome 2014-06-01 no assertion criteria provided research
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).
Forensic Genetics Laboratory,Harris County Institute of Forensic Sciences RCV000234983 SCV000263116 pathogenic Death in infancy 2015-03-27 no assertion criteria provided clinical testing
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 RCV000540204 SCV000637187 likely benign Brugada syndrome 2017-08-22 criteria provided, single submitter clinical testing
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 d.broadinstitute.org/; 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.

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