rs45553235
Positions:
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2PP2BP4_Strong
The NM_001099404.2(SCN5A):c.2074C>A(p.Gln692Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000236 in 1,613,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00024 ( 0 hom. )
Consequence
SCN5A
NM_001099404.2 missense
NM_001099404.2 missense
Scores
1
4
15
Clinical Significance
Conservation
PhyloP100: -0.0730
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 Likely_benign. Variant got -1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN5A. . Gene score misZ 2.7504 (greater than the threshold 3.09). Trascript score misZ 4.7729 (greater than threshold 3.09). GenCC has associacion of gene with progressive familial heart block, type 1A, Brugada syndrome, familial sick sinus syndrome, short QT syndrome, paroxysmal familial ventricular fibrillation, progressive familial heart block, long QT syndrome 3, familial atrial fibrillation, catecholaminergic polymorphic ventricular tachycardia, dilated cardiomyopathy, dilated cardiomyopathy 1E, arrhythmogenic right ventricular cardiomyopathy, Brugada syndrome 1, atrial standstill, familial isolated dilated cardiomyopathy, familial long QT syndrome, sick sinus syndrome 1.
BP4
Computational evidence support a benign effect (MetaRNN=0.042114347).
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SCN5A | NM_001099404.2 | c.2074C>A | p.Gln692Lys | missense_variant | 14/28 | ENST00000413689.6 | NP_001092874.1 | |
| SCN5A | NM_000335.5 | c.2074C>A | p.Gln692Lys | missense_variant | 14/28 | ENST00000423572.7 | NP_000326.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SCN5A | ENST00000413689.6 | c.2074C>A | p.Gln692Lys | missense_variant | 14/28 | 5 | NM_001099404.2 | ENSP00000410257 | P4 | |
| SCN5A | ENST00000423572.7 | c.2074C>A | p.Gln692Lys | missense_variant | 14/28 | 1 | NM_000335.5 | ENSP00000398266 | A1 |
Frequencies
GnomAD3 genomes 0.000230 AC: 35AN: 152242Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000333 AC: 83AN: 248922Hom.: 0 AF XY: 0.000363 AC XY: 49AN XY: 135012
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GnomAD4 exome AF: 0.000238 AC: 348AN: 1461576Hom.: 0 Cov.: 31 AF XY: 0.000249 AC XY: 181AN XY: 727058
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GnomAD4 genome 0.000217 AC: 33AN: 152360Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16AN XY: 74508
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:11Benign:14Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2Benign:3Other:1
| Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | SCN5A: PM2:Supporting - |
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 09, 2023 | The SCN5A c.2074C>A; p.Gln692Lys variant (rs45553235; ClinVar Variation ID: 67712) has been previously reported in multiple individuals evaluated for sudden cardiac death (SCD) with a diagnosis of long QT syndrome (Van Langen 2003, Tan 2005, Hofman 2007, Chung 2007), sudden infant death syndrome (SIDS; Millat 2009), and hypertrophic cardiomyopathy HCM (Lopes 2015 and Bottillo 2016). However, co-segregation of this variant with any of these phenotypes has not been demonstrated in affected family members, and in once case was shown to have been inherited from the proband’s unaffected father (Van Langen 2003). Moreover, multiple studies have noted the relatively high allele frequency of this variant in various healthy populations (Ackerman 2004, Kapa 2009, Kapplinger 2010) and the general population (Bottillo 2016, Refsgaard 2012, Andreasen 2013, Dorschner 2013, Amendola 2015, Ng 2013). For instance, this variant is found in the Genome Aggregation Database with an allele frequency in Ashkenazi Jewish individuals of 0.26% (27/10334 alleles). Additionally, at least one study has identified this variant in an adult Danish individual who had a QT interval within the normal range (Ghouse 2015). The glutamine at codon 692 is moderately conserved (Alamut software v2.11) and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Nonetheless, based on the available information, the clinical significance of this variant is uncertain. References: Ackerman et al. Spectrum and prevalence of cardiac sodium channel variants among black, white, Asian, and Hispanic individuals: implications for arrhythmogenic susceptibility and Brugada/long QT syndrome genetic testing. Heart Rhythm. 2004 Nov;1(5):600-7. Amendola LM et al. Actionable exomic incidental findings in 6503 participants: challenges of variant classification. Genome Res. 2015 Mar;25(3):305-15. Andreasen C et al. Mutations in genes encoding cardiac ion channels previously associated with sudden infant death syndrome (SIDS) are present with high frequency in new exome data. Can J Cardiol. 2013 Sep;29(9):1104-9. Bottillo et al. Molecular analysis of sarcomeric and non-sarcomeric genes in patients with hypertrophic cardiomyopathy. Gene. 2016 Feb 15;577(2):227-35. Chung SK et al. Long QT and Brugada syndrome gene mutations in New Zealand. Heart Rhythm. 2007 Oct;4(10):1306-14. Dorschner MO et al. Actionable, pathogenic incidental findings in 1,000 participants' exomes. Am J Hum Genet. 2013 Oct 3;93(4):631-40. 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. Hofman N et al. Contribution of inherited heart disease to sudden cardiac death in childhood. Pediatrics. 2007 Oct;120(4):e967-73. Kapa et al. Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. Circulation. 2009 Nov 3;120(18):1752-60. Kapplinger 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. Lopes LR et al. Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. Heart. 2015 Feb;101(4):294-301. Millat G et al. Contribution of long-QT syndrome genetic variants in sudden infant death syndrome. Pediatr Cardiol. 2009 May;30(4):502-9. Ng D et al. Interpreting secondary cardiac disease variants in an exome cohort. Circ Cardiovasc Genet. 2013 Aug;6(4):337-46. Refsgaard L et al. High prevalence of genetic variants previously associated with LQT syndrome in new exome data. Eur J Hum Genet. 2012 Aug;20(8):905-8. Tan HL et al. Sudden unexplained death: heritability and diagnostic yield of cardiological and genetic examination in surviving relatives. Circulation. 2005 Jul 12;112(2):207-13. Van Langen et al. The use of genotype-phenotype corre - |
| not provided, no classification provided | literature only | Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust | - | This variant has been reported in the following publications (PMID:12566525;PMID:15851227;PMID:17905336;PMID:19841300;PMID:20129283;PMID:22378279). - |
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Long QT syndrome 3 Uncertain:2Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 05, 2020 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | KardioGenetik, Herz- und Diabeteszentrum NRW | Oct 09, 2023 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Feb 21, 2019 | 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
not specified Uncertain:1Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 07, 2023 | Variant summary: SCN5A c.2074C>A (p.Gln692Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00033 in 248922 control chromosomes. The observed variant frequency is approximately 3.3 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 benign. Although reported in the literature, to our knowledge, no penetrant association of c.2074C>A in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a majority consensus as likely benign/benign. Based on the evidence outlined above, the variant was classified as likely benign. - |
| Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 22, 2017 | This variant is present in gnomAD: 0.29% (29/10130 AJ). This frequency is too hi gh for SCN5A-associated disorders. Glutamine (Gln) at position 692 is poorly c onserved in evolution and several species (including 1 mammal) carry the variant amino acid (Lys), suggesting that this change may be tolerated. Additional comp utational analyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) also suggest that this variant may not impact the protein. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 16, 2017 | The Q692K variant of uncertain significance in the SCN5A gene has been previously reported in association with multiple phenotypes (van Langren et al., 2003; Chung et al., 2007; Millat et al., 2009; Lopes et al., 2015). van Langren et al (2003) identified Q692K in a patient of Turkish ancestry who suffered sudden unexplained death during sleep at age 14, and who also harbored the R562M variant in the KCNQ1 gene; both variants were reported to be paternally inherited (van Langen et al., 2003). The Q692K variant has also been reported in a 10 year-old male with aborted sudden cardiac death and a prolonged QTc interval (Chung et al., 2007). Additionally, Millat et al. (2009) identified this variant in a patient who passed away from SIDS, but no segregation studies were performed. A patient with HCM was found to harbor Q692K, but no other clinical information was provided (Lopes et al., 2015). Nevertheless, Q692K has also been reported in apparently healthy individuals (Ackerman et al., 2004; Kapa et al., 2009; Ghouse et al., 2015; Kapplinger et al., 2015), and is classified in ClinVar as a variant of uncertain significance by two other clinical laboratories (SCV000200244.3, SCV000291789.1; Landrum et al., 2016). The Q692K variant was observed in approximately 0.02-0.10% of alleles from individuals of European ancestry in the NHLBI Exome Sequencing Project, the 1000 Genomes Project, and the Exome Aggregation Consortium (ExAC). This variant has also been identified independently and/or in conjunction with additional cardiogenetic variants in individuals referred for LQTS, Arrhythmia, or Cardiomyopathy genetic testing at GeneDx; however, thus far, segregation data is limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members. The Q692K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Additionally, this substitution occurs at a position that is not conserved. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
Long QT syndrome Uncertain:1Benign:2
| Uncertain significance, criteria provided, single submitter | research | Dept of Medical Biology, Uskudar University | Jan 08, 2024 | Criteria: PP2, BS1 - |
| Likely benign, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
| Likely benign, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Brugada syndrome 1 Uncertain:1Benign:1
| Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Feb 21, 2019 | 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
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Feb 21, 2019 | 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. - |
Dilated cardiomyopathy 1E Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Feb 21, 2019 | 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. - |
Progressive familial heart block, type 1A Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Feb 21, 2019 | 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. - |
Long QT syndrome 3;C4551804:Brugada syndrome 1 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Apr 12, 2015 | - - |
Cardiomyopathy Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jun 23, 2023 | - - |
Brugada syndrome Benign:1
| Likely benign, no assertion criteria provided | clinical testing | Blueprint Genetics | Oct 06, 2014 | - - |
Sick sinus syndrome 1 Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Feb 21, 2019 | 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. - |
Cardiovascular phenotype Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 15, 2021 | 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. - |
Cardiac arrhythmia Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 05, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
CardioboostCm
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
DEOGEN2
Uncertain
.;.;.;.;.;T;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
.;T;T;T;T;T;T;.;T
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
.;N;.;.;.;N;.;.;.
MutationTaster
Benign
N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N;N;N;N;N;N;N
REVEL
Uncertain
Sift
Benign
T;T;T;T;T;T;T;T;T
Sift4G
Benign
T;T;T;T;T;T;T;T;T
Polyphen
B;B;.;B;.;B;B;.;.
Vest4
MVP
MPC
0.44
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at