ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.647C>T (p.Ser216Leu) (rs41276525)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000151805 SCV000053115 benign not specified 2019-04-08 criteria provided, single submitter clinical testing Variant summary: SCN5A c.647C>T (p.Ser216Leu) results in a non-conservative amino acid change located in the Voltage-dependent channel domain superfamily (IPR027359) 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 0.00068 in 280270 control chromosomes, predominantly at a frequency of 0.00099 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 10 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Arrhythmia phenotype (0.0001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.647C>T has been reported in the literature in multiple testing cohorts among individuals with borderline or with elevated QT intervals. Several of these studies predate as well as postdate the emergence of large scale control datasets such as ExAC and gnomad. Furthermore, several of these studies reported a classification of this variant as a VUS (example Seidelmann_2017, Riuro_2015, Ortiz-Bonnin_2016). Therefore, no firm conclusions can be drawn from these data. 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). Co-occurrences with other pathogenic variant(s) have been reported in the literature (KCNQ1) as well as our internal testing (SCN5A) experience (KCNQ1 c.686G>A, p.Gly229Asp; SCN5A c.535C>T, p.R179*), providing supporting evidence for a benign role. Several publications report experimental evidence evaluating an impact on protein function, at-least one of which concluded that the variant should remain as a variant of unknown significance due to inconclusive findings (example Ortiz-Bonnin_SCN5A_EJP_2016). Other publications reporting a functional impact present findings that are not firmly correlated to in-vivo mechanisms of disease (ex Wang_2007 and Marangoni_2011). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and one of these reported a classification of likely benign. Based on the evidence outlined above, the variant was classified as benign.
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 (http://evs.gs.washington.edu/EVS/; 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.
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.
Invitae RCV001081940 SCV000255234 likely benign Brugada syndrome 2020-12-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000248707 SCV000317413 uncertain significance Cardiovascular phenotype 2020-05-07 criteria provided, single submitter clinical testing The p.S216L variant (also known as c.647C>T), located in coding exon 5 of the SCN5A gene, results from a C to T substitution at nucleotide position 647. The serine at codon 216 is replaced by leucine, an amino acid with dissimilar properties. This variant has been described in patient cohorts with mixed phenotypes including Brugada syndrome, atrial fibrillation, QT prolongation, cardiomyopathy and sudden infant death syndrome (Arnestad et al. Circulation. 2007;115:361-367; Hershberger RE et al. Clin Transl Sci. 2008;1(1):21-6; Marangoni et al. Cardiovasc Res. 2011;91(4):606-616; Olesen MS et al. Circ Cardiovasc Genet. 2012;5(4):450-9; Illikova V et al. J Electrocardiol. 2015;48(2):150-6; Adler A et al. Circ Arrhythm Electrophysiol. 2016;9(1):e003440; Ortiz-Bonnin B et al. Pflugers Arch. 2016;468(8):1375-87). However, this alteration also has been observed in healthy individuals and control subjects (Ackerman MJ et al. Heart Rhythm. 2004;1(5):600-7; Kapa S et al. Circulation. 2009;120(18):1752-60). In functional in vitro analyses, this variant has adversely affected the voltage-gated sodium ion channel, resulting in increased persistent sodium current density in two studies (Wang DW et al. Circulation. 2007;115(3):368-76; Ortiz-Bonnin B et al. Pflugers Arch. 2016;468(8):1375-87) but reduced sodium current density and membrane localization in another (Marangoni S et al. Cardiovasc Res. 2011;91(4):606-16). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Color Health, Inc RCV000771200 SCV000903194 likely benign Arrhythmia 2019-06-18 criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852966 SCV000995715 likely benign Ventricular tachycardia 2019-03-04 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001149157 SCV001310095 uncertain significance Dilated cardiomyopathy 1E 2018-05-01 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001149158 SCV001310096 uncertain significance Long QT syndrome 3 2018-05-01 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001149159 SCV001310097 uncertain significance Paroxysmal familial ventricular fibrillation 1 2018-05-01 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001149160 SCV001310098 uncertain significance Progressive familial heart block, type 1A 2018-05-01 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001149161 SCV001310099 uncertain significance Brugada syndrome 1 2018-05-01 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001149162 SCV001310100 uncertain significance Sick sinus syndrome 1, autosomal recessive 2018-05-01 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001149162 SCV001368347 uncertain significance Sick sinus syndrome 1, autosomal recessive 2019-10-10 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,BS2.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285753 SCV001472233 uncertain significance none provided 2019-09-25 criteria provided, single submitter clinical testing The SCN5A c.647C>T; p.Ser216Leu variant (rs41276525) is reported in the literature in individuals and families affected with dilated cardiomyopathy, Brugada syndrome, long QT syndrome, or arrhythmias (Hershberger 2008, Marangoni 2011, Olesen 2012, Ortiz-Bonnin 2016). However, this variant has also been observed in healthy control individuals (Kapplinger 2010), and one study observed no significant difference in QT interval of individuals with and without the variant (Ghouse 2015). This variant is found in the non-Finnish European population with an overall allele frequency of 0.10% (126/126006 alleles) in the Genome Aggregation Database. The serine at codon 216 is highly conserved, computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious, and functional analyses indicate an increased current density relative to wildtype protein (Marangoni 2011, Ortiz-Bonnin 2016). However, due to conflicting information, the clinical significance of the p.Ser216Leu variant is uncertain at this time. References: Ghouse J et al. Rare genetic variants previously associated with congenital forms of long QT syndrome have little or no effect on the QT interval. Eur Heart J. 2015 Oct 1;36(37):2523-9. Hershberger RE et al. Coding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP from 313 patients with familial or idiopathic dilated cardiomyopathy. Clin Transl Sci. 2008 May;1(1):21-6. Kapplinger JD et al. An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing. Heart Rhythm. 2010 Jan;7(1):33-46. Marangoni S et al. A Brugada syndrome mutation (p.S216L) and its modulation by p.H558R polymorphism: standard and dynamic characterization. Cardiovasc Res. 2011 Sep 1;91(4):606-16. Olesen MS et al. High prevalence of long QT syndrome-associated SCN5A variants in patients with early-onset lone atrial fibrillation. Circ Cardiovasc Genet. 2012 Aug 1;5(4):450-9. Ortiz-Bonnin B et al. Electrophysiological characterization of a large set of novel variants in the SCN5A-gene: identification of novel LQTS3 and BrS mutations. Pflugers Arch. 2016 Aug;468(8):1375-87.
Molecular Genetics Laboratory,BC Children's and BC Women's Hospitals RCV001081940 SCV001571580 uncertain significance Brugada syndrome 2021-01-18 criteria provided, single submitter clinical testing
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).
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000058831 SCV001553234 uncertain significance not provided no assertion criteria provided clinical testing The SCN5A p.Ser216Leu variant was identified in 12 of 6956 proband chromosomes (freq: 0.00173) from individuals or families with familial cardiovascular disease, sudden cardiac death, Brugada syndrome and Long QT syndrome and 8 of 5200 control chromosomes (freq: 0.002) (Seidelmann_2017_PMID: 28087566, Methner_2016_PMID: 27435932, Ortiz-Bonnin_2016_PMID: 27287068, Adler_2016_PMID: 26743238, Riuro_2015_PMID: 24667783, Olesen_2012_PMID: 22685113, Crotti_2012_PMID: 22840528, Kapplinger_2010_PMID: 20129283). The variant was also identified in dbSNP (ID: rs41276525), ClinVar (conflicting interpretations of pathogenicity; classified likely benign by Invitae and Integrated genetics, and VUS by Laboratory for Molecular Medicine, GeneDx and Ambry Genetics; associated conditions are Brugada syndrome, arrhythmia, and cardiovascular phenotype), and LOVD 3.0. The variant was not identified in Cosmic. The variant was found in control databases in 181 of 275296 chromosomes (1 homozygous in the South Asian population) at a frequency of 0.000657 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 126 of 126006 chromosomes (freq: 0.001), Ashkenazi Jewish in 10 of 10216 chromosomes (freq: 0.000979), Latino in 22 of 34780 chromosomes (freq: 0.000633), South Asian in 17 of 29594 chromosomes (freq: 0.000574), Other in 4 of 7056 chromosomes (freq: 0.000567), African in 1 of 23612 chromosomes (freq: 0.000042) and European (Finnish) in 1 of 24754 chromosomes (freq: 0.00004), while the variant was not observed in the East Asian population. In vitro electrophysiological studies performed using the two-electrode voltage-clamp technique (TEVC) in Xenopus laevis oocytes showed that the S216L variant has the potential to cause 60% reduction in maximum Na(+) current (I(Na)) density and a QT interval prolongation (Ortiz-Bonnin_2016_PMID: 27287068; Marangoni_2011_PMID: 21705349). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Ser216 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, BLOSUM, MutationTaster) suggest that the S variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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