ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.647C>T (p.Ser216Leu) (rs41276525)

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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 RCV000248707 SCV000317413 uncertain significance Cardiovascular phenotype 2018-02-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058831 SCV000090351 not provided not provided no assertion provided literature only This variant has been reported in the following publications (PMID:15851227;PMID:17210839;PMID:19412328;PMID:19841300;PMID:20129283;PMID:21705349).
Color RCV000771200 SCV000903194 uncertain significance Arrhythmia 2018-06-18 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This is a missense variant located in the head domain of the SCN5A protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. Experimental functional studies have suggested that the variant affects the sodium ion channel function (PMID: 21705349, 27287068). However, clinical significance of these assays is not clear. This variant has been reported in individuals affected with Brugada syndrome, atrial fibrillation and long QT syndrome (PMID: 21705349, 22685113, 27287068). This variant is also fairly common in the general population and has been identified in 178/271904 chromosomes (123/124242 non-Finnish European chromosomes; 0.099%) by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that it is unlikely to be disease-causing. However, available evidence is insufficient to determine the pathogenicity of this variant conclusively.
GeneDx RCV000151805 SCV000235334 uncertain significance not specified 2017-10-09 criteria provided, single submitter clinical testing The S216L variant in the SCN5A gene has been published previously in association with various cardiac phenotypes, including DCM, atrial fibrillation, Brugada syndrome, and SIDS/SUD (Arnestad et al., 2007; Darbar et al., 2008; Hershberger et al., 2008; Marangoni et al., 2011; Crotti et al., 2012; Olesen et al., 2012; Tester et al., 2012; Sommariva et al., 2013; Riuró et al., 2014; Ortiz-Bonnin et al., 2016). Nevertheless, the S216L variant has also been reported in healthy control individuals (Ackerman et al., 2004; Kapplinger et al., 2010; Crotti et al., 2012), and was observed in 65/43,272 (0.15%) alleles from individuals of European (non-Finnish) ancestry, including one homozygous individual, in the Exome Aggregation Consortium (Lek et al., 2016). The S216L 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. Additionally, this substitution occurs at a position that is conserved across species in the fourth transmembrane spanning region of domain I, an area more prone to pathogenic variants associated with LQTS and Brugada syndrome (Hershberger et al., 2008). In vitro functional studies demonstrated increased persistent sodium currents and other abnormalities typical for variants associated with LQTS (Wang et al., 2007). Furthermore, Ortiz-Bonnin, et al. (2016) conducted electrophysiological studies of SCN5A variants and concluded that S216L exhibits gain-of-function effects and increases susceptibility to develop LQTS.
Integrated Genetics/Laboratory Corporation of America RCV000151805 SCV000053115 likely benign not specified 2017-11-13 criteria provided, single submitter clinical testing Variant summary: The c.647C>T (p.Ser216Leu) in SCN5A gene is a missense change that involves the alteration of a highly conserved nucleotide and 5/5 in silico tools predict a deleterious outcome. The variant is located in the extracellular S3-S4 loop of the first domain and was shown to result in a robust persistent Na+ current with remaining parameters being similar to WT (Wang_2007; Marangoni_2011; Ortiz-Bonnin_2016). Although the results of the in vitro functional studies may support in silico predictions, other data suggest the variant is benign. The variant was observed in the large and broad cohorts of the gnomAD project at an allele frequency of 0.00065 (178/271904 chrs tested, including 1 homozygote), predominantly in individuals of European (N-F) descent (0.001; 123/124242 chrs). Both the overall and subpopulation frequencies exceed the maximal expected allele frequency for a pathogenic variant in this gene (0.0001) by 7-10 times. In addition, the variant was identified in multiple healthy individuals with no history of arrhythmias or other cardiac diseases and normal ECG (Refsgaard_2012; Crotti_2012; Kapplinger_2010) and was shown to not segregate with disease (Marangoni_2011; Riuro_2015). The variant was identified in several arrhythmic individuals, with borderline QTs or with elevated QTs interval. However, at least one patient with a prolonged QTc interval (460ms) also carried a known pathogenic KCNQ1 variant (Illikova_2015), suggesting the variant is benign, since two pathogenic variants would likely cause a severely prolonged QTc interval. In addition, at least one reputable database/diagnostic center classified the variant of interest as Likely Benign. Taken together, the variant was classified as Likely Benign.
Invitae RCV000197633 SCV000255234 likely benign Brugada syndrome 2017-12-09 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000151805 SCV000200271 uncertain significance not specified 2014-08-07 criteria provided, single submitter clinical testing The p.Ser216Leu variant in SCN5A has been reported in 2 individuals with DCM, 2 individuals with atrial fibrillation, 1 individual with Brugada syndrome, and 1 infant with sudden infant death syndrome (Arnestad 2007, Hershberger 2008, Maran goni 2011, Olesen 2012). In addition, this variant has been identified in 0.3% ( 6/1888) of healthy Caucasian chromosomes (Ackerman 2004, Kapplinger 2010) and in 0.1% (11/8432) of European American chromosomes by the NHLBI Exome Sequencing P roject (; dbSNP rs41276525). Additionally, comp utational prediction tools and conservation analysis suggest that this variant m ay impact the protein, though this information is not predictive enough to deter mine pathogenicity. Finally, in vitro functional studies provide some evidence t hat the p.Ser216Leu variant may impact protein function (Wang 2007, Marangoni 20 11). However, these types of assays may not accurately represent biological func tion. In summary, there is conflicting evidence on the p.Ser216Leu variant and i ts clinical significance is uncertain.

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