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rs41276525

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PP2

The NM_000335.5(SCN5A):c.647C>T(p.Ser216Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,610,920 control chromosomes in the GnomAD database, including 3 homozygotes. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00067 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0011 ( 3 hom. )

Consequence

SCN5A
NM_000335.5 missense

Scores

13
3
3

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12B:12O:1

Conservation

PhyloP100: 10.0
Variant links:
Genes affected
SCN5A (HGNC:10593): (sodium voltage-gated channel alpha subunit 5) The protein encoded by this gene is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. This protein is found primarily in cardiac muscle and is responsible for the initial upstroke of the action potential in an electrocardiogram. Defects in this gene have been associated with long QT syndrome type 3 (LQT3), atrial fibrillation, cardiomyopathy, and Brugada syndrome 1, all autosomal dominant cardiac diseases. Alternative splicing results in several transcript variants encoding different isoforms. [provided by RefSeq, May 2022]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000335.5
PP2
Missense variant where missense usually causes diseases, SCN5A

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SCN5ANM_000335.5 linkuse as main transcriptc.647C>T p.Ser216Leu missense_variant 6/28 ENST00000423572.7
SCN5ANM_001099404.2 linkuse as main transcriptc.703+176C>T intron_variant ENST00000413689.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SCN5AENST00000423572.7 linkuse as main transcriptc.647C>T p.Ser216Leu missense_variant 6/281 NM_000335.5 A1Q14524-2
SCN5AENST00000413689.6 linkuse as main transcriptc.703+176C>T intron_variant 5 NM_001099404.2 P4

Frequencies

GnomAD3 genomes
AF:
0.000670
AC:
102
AN:
152220
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00157
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00104
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000970
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000685
AC:
167
AN:
243886
Hom.:
1
AF XY:
0.000832
AC XY:
110
AN XY:
132168
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000648
Gnomad ASJ exome
AF:
0.00101
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000574
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00103
Gnomad OTH exome
AF:
0.000670
GnomAD4 exome
AF:
0.00113
AC:
1641
AN:
1458582
Hom.:
3
Cov.:
30
AF XY:
0.00112
AC XY:
815
AN XY:
725232
show subpopulations
Gnomad4 AFR exome
AF:
0.000120
Gnomad4 AMR exome
AF:
0.000948
Gnomad4 ASJ exome
AF:
0.000576
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000749
Gnomad4 FIN exome
AF:
0.0000188
Gnomad4 NFE exome
AF:
0.00130
Gnomad4 OTH exome
AF:
0.00101
GnomAD4 genome
AF:
0.000670
AC:
102
AN:
152338
Hom.:
0
Cov.:
33
AF XY:
0.000658
AC XY:
49
AN XY:
74496
show subpopulations
Gnomad4 AFR
AF:
0.0000962
Gnomad4 AMR
AF:
0.00157
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00104
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.000970
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.00118
Hom.:
0
Bravo
AF:
0.000756
TwinsUK
AF:
0.00135
AC:
5
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.000244
AC:
1
ESP6500EA
AF:
0.00130
AC:
11
ExAC
AF:
0.000686
AC:
83

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:12Benign:12Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2Benign:7Other:1
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Likely benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
not provided, no classification providedliterature onlyCardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust-This variant has been reported in the following publications (PMID:15851227;PMID:17210839;PMID:19412328;PMID:19841300;PMID:20129283;PMID:21705349). -
Uncertain significance, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-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. -
Likely benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Likely benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Uncertain significance, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesSep 25, 2019The 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. -
Likely benign, criteria provided, single submitterclinical testingGeneDxJan 21, 2021This variant is associated with the following publications: (PMID: 30356750, 30677491, 19412328, 15851227, 21705349, 17210841, 23414114, 22378279, 23158531, 22685113, 20129283, 23465283, 23299917, 18378609, 23272275, 22677073, 17210839, 24136861, 23321620, 24667783, 26406308, 22337857, 26159999, 25904541, 27287068, 25554238, 28316956, 26916278, 28341588, 29672598, 31043699, 30847666, 33131149, 32880476) -
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
not specified Uncertain:1Benign:2
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpApr 08, 2019Variant 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. -
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineAug 07, 2014The 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. -
Sick sinus syndrome 1 Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMay 01, 2018This 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. -
Uncertain significance, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaOct 10, 2019This 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. -
Brugada syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMay 01, 2018This 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. -
Ventricular fibrillation, paroxysmal familial, type 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMay 01, 2018This 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. -
SUDDEN INFANT DEATH SYNDROME;C1832680:Dilated cardiomyopathy 1E;C1837845:Sick sinus syndrome 1;C1859062:Long QT syndrome 3;C1879286:Progressive familial heart block, type 1A;C2751898:Ventricular fibrillation, paroxysmal familial, type 1;C3151464:Atrial fibrillation, familial, 10;C4551804:Brugada syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomics, Ann and Robert H. Lurie Children's Hospital of ChicagoMar 30, 2021SCN5A NM_198056.2 exon 6 p.Ser216Leu (c.647C>T): This variant has been reported in the literature in several individuals with various cardiac phenotypes (DCM, BrS, LQTS, Afib) (Hershberger 2008 PMID:19412328, Marangoni 2011 PMID:21705349, Crotti 2012 PMID:23158531, Olesen 2012 PMID:22685113, Riuro 2015 PMID:24667783). This variant has also been reported in a SIDS case and in a SUD case of an individual with a history of epilepsy (Wang 2007 PMID:17210841, Marcondes 2018 PMID:29672598). However, this variant is also present in 0.1% (126/126006) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/3-38655290-G-A) and is present in ClinVar (Variation ID:36767). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, functional studies have shown a deleterious effect of this variant (Wang 2007 PMID:17210841, Marangoni 2011 PMID:21705349). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Brugada syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingMolecular Genetics Laboratory, BC Children's and BC Women's HospitalsJan 18, 2021- -
Dilated cardiomyopathy 1E Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMay 01, 2018This 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. -
Progressive familial heart block, type 1A Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMay 01, 2018This 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. -
Long QT syndrome 3 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMay 01, 2018This 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. -
Ventricular tachycardia Benign:1
Likely benign, criteria provided, single submitterclinical testingCenter for Advanced Laboratory Medicine, UC San Diego Health, University of California San DiegoMar 04, 2019- -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJul 07, 2021This 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. -
Cardiac arrhythmia Benign:1
Likely benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthJun 18, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.89
CardioboostArm
Pathogenic
0.96
CardioboostCm
Benign
0.0082
BayesDel_addAF
Pathogenic
0.26
D
BayesDel_noAF
Pathogenic
0.55
Cadd
Pathogenic
30
Dann
Pathogenic
1.0
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.76
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
D;D;D
M_CAP
Pathogenic
0.91
D
MetaRNN
Uncertain
0.53
D;D;D
MetaSVM
Pathogenic
0.92
D
MutationAssessor
Uncertain
2.7
M;M;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D
PROVEAN
Pathogenic
-5.8
D;D;D
REVEL
Pathogenic
0.96
Sift
Pathogenic
0.0
D;D;D
Sift4G
Benign
0.066
T;T;T
Polyphen
1.0
D;P;.
Vest4
0.96
MVP
0.99
ClinPred
0.23
T
GERP RS
4.3
Varity_R
0.92

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.090
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs41276525; hg19: chr3-38655290; API