rs199473182
Variant names:
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 5P and 7B. PM1PM2PP2BP4_ModerateBP6BS1
The NM_000335.5(SCN5A):āc.2944T>Cā(p.Cys982Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000185 in 1,611,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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: š 0.00032 ( 0 hom., cov: 32)
Exomes š: 0.00017 ( 0 hom. )
Consequence
SCN5A
NM_000335.5 missense
NM_000335.5 missense
Scores
5
15
Clinical Significance
Conservation
PhyloP100: 2.64
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 -2 ACMG points.
PM1
In a topological_domain Cytoplasmic (size 267) in uniprot entity SCN5A_HUMAN there are 26 pathogenic changes around while only 11 benign (70%) in NM_000335.5
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the SCN5A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 99 curated pathogenic missense variants (we use a threshold of 10). The gene has 60 curated benign missense variants. Gene score misZ: 2.7504 (below the threshold of 3.09). Trascript score misZ: 4.8279 (above the threshold of 3.09). GenCC associations: The gene is linked to 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=0.079470575).
BP6
Variant 3-38581215-A-G is Benign according to our data. Variant chr3-38581215-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67769.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=12, Benign=1, Likely_benign=5, not_provided=1}.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000322 (49/152132) while in subpopulation AFR AF= 0.000988 (41/41516). AF 95% confidence interval is 0.000748. There are 0 homozygotes in gnomad4. There are 19 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SCN5A | NM_001099404.2 | c.2944T>C | p.Cys982Arg | missense_variant | Exon 17 of 28 | ENST00000413689.6 | NP_001092874.1 | |
| SCN5A | NM_000335.5 | c.2944T>C | p.Cys982Arg | missense_variant | Exon 17 of 28 | ENST00000423572.7 | NP_000326.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SCN5A | ENST00000413689.6 | c.2944T>C | p.Cys982Arg | missense_variant | Exon 17 of 28 | 5 | NM_001099404.2 | ENSP00000410257.1 | ||
| SCN5A | ENST00000423572.7 | c.2944T>C | p.Cys982Arg | missense_variant | Exon 17 of 28 | 1 | NM_000335.5 | ENSP00000398266.2 |
Frequencies
GnomAD3 genomes 0.000316 AC: 48AN: 152014Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000747 AC: 18AN: 241118Hom.: 0 AF XY: 0.0000685 AC XY: 9AN XY: 131352
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GnomAD4 exome AF: 0.000171 AC: 249AN: 1459292Hom.: 0 Cov.: 36 AF XY: 0.000152 AC XY: 110AN XY: 725740
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GnomAD4 genome 0.000322 AC: 49AN: 152132Hom.: 0 Cov.: 32 AF XY: 0.000256 AC XY: 19AN XY: 74356
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:17Benign:6Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:7Benign:1
| Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 30, 2025 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jul 21, 2020 | The SCN5A c.2944T>C, p.Cys982Arg variant (rs199473182), has been reported in multiple individuals selected for cardiac arrhythmia (Hofman-Bang 2006), sudden cardiac death (Cann 2017), or actionable variants in genomic medicine studies (Amendola 2015 and Dorschner 2013). This variant has been submitted to the ClinVar database (Variation ID: 67769). It is found in the African population with an allele frequency of 0.08% (18/23,286 alleles) in the Genome Aggregation Database. The cysteine at codon 982 is highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Cys982Arg variant is uncertain at this time. References: Amendola et al. Actionable Exomic Incidental Findings in 6503 Participants: Challenges of Variant Classification. Genome Res. 2015 Mar. Cann et al. Phenotype-driven Molecular Autopsy for Sudden Cardiac Death. Clin Genet. 2017 Jan. Dorschner et al. Actionable, Pathogenic Incidental Findings in 1,000 Participants' Exomes. Am J Hum Genet. 2013 Oct 3. Hofman-Bang et al. High-efficiency Multiplex Capillary Electrophoresis Single Strand Conformation Polymorphism (multi-CE-SSCP) Mutation Screening of SCN5A: A Rapid Genetic Approach to Cardiac Arrhythmia. Clin Genet. 2006 Jun. Gene statement: Pathogenic germline variants in the SCN5A gene are inherited in an autosomal dominant manner and are associated with dilated cardiomyopathy 1E (MIM: 601154), familial atrial fibrillation 10 (MIM: 614022), Brugada syndrome 1 (MIM: 601144), nonprogressive heart block and progressive heart block 1A (MIM: 113900), Long QT syndrome-3 (MIM: 603830), familial ventricular fibrillation (MIM: 603829), and, more rarely, autosomal recessive sick sinus syndrome-1 (MIM: 608567). - |
| Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 16, 2024 | In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20102864, 19841300, 24055113, 25637381, 25351510, 27000522, 22581653, 26746457, 32880476, 19862833, 25904541, 16712702, 33906374) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 01, 2014 | - - |
not specified Uncertain:1Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 07, 2019 | Variant classified as Uncertain Significance - Favor Benign. The p.Cys982Arg variant in SCN5A has been previously reported in 1 individual with sudden death (Hofman-Bang, 2006) and in 0.077% of African chromosomes in gnomAD (dbSNP rs199473182). This variant is located in a domain that is believed to be enriched in variants that are present in controls although this does not rule out a pathogenic role (Kapa 2009). Uncertain significance in ClinVar. In summary, the clinical significance of the p.Cys982Arg variant is uncertain. - |
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 28, 2023 | Variant summary: SCN5A c.2944T>C (p.Cys982Arg) results in a non-conservative amino acid change located in the Sodium ion transport-associated domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 7.7 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 African or African-American origin. c.2944T>C has been reported in the literature in individuals affected with DCM, Sudden Adult Death Syndrome and other familial or idiopathic cardiomyopathy, without strong evidence for causality (Verdonschot_2020, Hofman-Bang_2006, Ware_2021). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. Co-occurrences with other pathogenic variant(s) have been reported (TTR c.424G>A, p.Val142Ile, internal data), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32880476, 16712702, 33906374). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments including four likely benign/benign and five VUS. Based on the evidence outlined above, the variant was classified as likely benign. - |
Long QT syndrome 3 Uncertain:1Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 06, 2021 | 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 (SSS) (MIM#608567), whereas gain of function is usually associated with LQTS (MIM#603830). 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 syndrome or SSS, and patients with a blended phenotype. Additionally, different studies have shown conflicting mechanisms in association with atrial fibrillation (MIM#614022) (PMID: 29806494, PMID: 19167345, PMID: 26798387). (I) 0108 - This gene is associated with both recessive and dominant disease. Most conditions associated with this gene are dominantly inherited, however SSS can be caused by recessive variants (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to arginine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (48 heterozygotes, 0 homozygotes). (SP) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0600 - Variant is located in the annotated sodium ion transport-associated domain (NCBI). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. This alternative missense variant (p.Cys982Tyr) has been reported as a VUS (ClinVar). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been observed in multiple individuals with cardiac phenotypes including sudden death syndrome, bundle branch block, long QT syndrome (LQTS), coronary heart disease and dilated cardiomyopathy (DCM) (PMID: 16712702, PMID: 26746457, PMID: 20102864). However, this variant has been reported as either a VUS, likely benign or benign (LOVD, ClinVar, Verdonschot, JAJ. (2021), PMID: 24055113). Additionally, this variant has been observed in control cohorts, and has been described as non-pathogenic and as a polymorphism (PMID: 25904541, PMID: 27000522). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 20, 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. - |
Sudden cardiac death Uncertain:1Other:1
| not provided, no classification provided | literature only | Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust | - | This variant has been reported as associated with Sudden adult death syndrome in the following publications (PMID:16712702). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. - |
| Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Brugada syndrome 1 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 20, 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. - |
Ventricular fibrillation, paroxysmal familial, type 1 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 20, 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. - |
SCN5A-related disorder Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 14, 2022 | The SCN5A c.2944T>C variant is predicted to result in the amino acid substitution p.Cys982Arg. This variant was reported in individuals with sudden cardiac death (Hofman-Bang et al. 2006. PubMed ID: 16712702; Adabag et al. 2010. PubMed ID: 20102864), dilated cardiomyopathy (Table S4, Verdonschot et al. 2020. PubMed ID: 32880476), or hypertrophic cardiomyopathy (Table S1, Lopes et al. 2015. PubMed ID: 25351510). This variant was also detected in three unaffected family members of a sudden cardiac death proband, and this variant was considered non-pathogenic in a more recent study (Cann et al. 2017. PubMed ID: 27000522). This variant is reported in 0.077% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-38622706-A-G) and has conflicting interpretations of pathogenicity in ClinVar ranging from benign to uncertain (http://www.ncbi.nlm.nih.gov/clinvar/variation/67769). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Sudden cardiac arrest Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego | Mar 15, 2019 | - - |
Dilated cardiomyopathy 1E Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 20, 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. - |
Primary familial dilated cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | - | - - |
Progressive familial heart block, type 1A Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 20, 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. - |
Sick sinus syndrome 1 Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 20, 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 | Sep 14, 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 | Oct 28, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
CardioboostCm
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
.;.;.;.;.;D;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
.;T;T;T;T;T;T;.;T
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;N;.;.;.;N;.;.;.
PrimateAI
Uncertain
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
0.041
ClinPred
T
GERP RS
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gMVP
Splicing
Name
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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