chr3-38613799-G-A
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2BS1BS2
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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000335.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SCN5A | ENST00000423572.7 | c.647C>T | p.Ser216Leu | missense_variant | Exon 6 of 28 | 1 | NM_000335.5 | ENSP00000398266.2 | ||
| SCN5A | ENST00000413689.6 | c.703+176C>T | intron_variant | Intron 6 of 27 | 5 | NM_001099404.2 | ENSP00000410257.1 |
Frequencies
GnomAD3 genomes 0.000670 AC: 102AN: 152220Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000685 AC: 167AN: 243886Hom.: 1 AF XY: 0.000832 AC XY: 110AN XY: 132168
GnomAD4 exome AF: 0.00113 AC: 1641AN: 1458582Hom.: 3 Cov.: 30 AF XY: 0.00112 AC XY: 815AN XY: 725232
GnomAD4 genome 0.000670 AC: 102AN: 152338Hom.: 0 Cov.: 33 AF XY: 0.000658 AC XY: 49AN XY: 74496
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:7Other:1
- -
- -
This variant has been reported in the following publications (PMID:15851227;PMID:17210839;PMID:19412328;PMID:19841300;PMID:20129283;PMID:21705349). -
- -
- -
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. -
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. -
- -
- -
This 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) -
not specified Uncertain:1Benign:2
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. -
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. -
- -
Sick sinus syndrome 1 Uncertain:2
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. -
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. -
Long QT syndrome 3 Uncertain:2
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. -
PP3, BS1 -
Dilated cardiomyopathy 1E Uncertain:1Benign:1
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. -
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely benign. Following criteria are met: 0103 - Loss of function and gain of function are both known mechanisms of disease in this gene. Loss of function is usually associated with Brugada syndrome 1 (MIM#601144) and sick sinus syndrome 1 (SSS) (MIM#608567), whereas gain of function is usually associated with long QT syndrome-3 (LQTS) (MIM#603830). Dilated cardiomyopathy 1E (DCM) (MIM#601154) can be caused by variants with either a loss or gain of function mechanism (PMID: 29798782). However, some variants simultaneously result in both a loss and gain of function effect, and have been observed in patients with LQTS, Brugada or SSS, and patients with a blended phenotype. Additionally, different studies have shown conflicting mechanisms in association with familial atrial fibrillation 10 (MIM#614022) (PMIDs: 29806494, 19167345, 26798387, 29798782). (I) 0108 - This gene is associated with both recessive and dominant disease. Most conditions associated with this gene are dominantly inherited, however SSS is caused by biallelic variants (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to leucine. (I) 0251 - This variant is heterozygous. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of SCN5A-related disorders, gnomAD v2: 179 heterozygotes, 1 homozygote. (SB) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated S3 to S4 extracellular linker in ion transport domain I (Uniprot). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been previously reported in individuals with idiopathic dilated cardiomyopathy, LQTS, Brugada syndrome, sudden infant death syndrome (SIDS), and sudden unexplained death. However, the variant is generally classified as either likely benign or a VUS (PMIDs: 19412328, 27287068, 21705349, 17210839, 31043699, 22677073, ClinVar, VCGS). Additionally, this variant has been identified in healthy control individuals (PMID: 20129283). (I) 1010 - Functional evidence for this variant is conflicting. Patch clamp functional assays have reported that this variant causes a gain-of-function, however, the gain-of-function mechanism varies between functional studies (PMIDs: 17210841, 21705349, 27287068). Patch clamp assays have been shown to be unreliable, therefore results from these studies are used with caution during variant classification. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Cardiac arrhythmia Benign:2
- -
- -
Brugada syndrome 1 Uncertain:1
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. -
Ventricular fibrillation, paroxysmal familial, type 1 Uncertain:1
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. -
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
SCN5A 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
- -
Progressive familial heart block, type 1A Uncertain:1
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. -
Ventricular tachycardia Benign:1
- -
Cardiovascular phenotype Benign:1
This 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at