rs199473182

Variant names:

• chr3-38581215-A-G
• rs199473182
• NM_001099404.2:c.2944T>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 5P and 7B. PM1 PM2 PP2 BP4_Moderate BP6 BS1

The NM_000335.5(SCN5A):​c.2944T>C​(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: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: SCN5A NM_000335.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:17 B:6 O:1
• 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]

ACMG classification

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 AF: 0.000316 AC: 48 AN: 152014 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000747 AC: 18 AN: 241118 Hom.: 0 AF XY: 0.0000685 AC XY: 9 AN XY: 131352

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.0000889

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000332

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000462

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000171 AC: 249 AN: 1459292 Hom.: 0 Cov.: 36 AF XY: 0.000152 AC XY: 110 AN XY: 725740

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.0000904

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000169

Gnomad4 OTH exome AF: 0.000216

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152132 Hom.: 0 Cov.: 32 AF XY: 0.000256 AC XY: 19 AN XY: 74356

Gnomad4 AFR AF: 0.000988

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000170 Hom.: 0

Bravo AF: 0.000359

ESP6500AA AF: 0.000772 AC: 3

ESP6500EA AF: 0.000242 AC: 2

ExAC AF: 0.0000827 AC: 10

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:17 Benign:6 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:7 Benign:1

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, 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, 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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 01, 2014	- -

not specified Uncertain:1 Benign:1

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. -
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. -

Long QT syndrome 3 Uncertain:1 Benign: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. -
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 -

Sudden cardiac death Uncertain:1 Other: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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
CardioboostCm	Benign	0.0033
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	.;.;.;.;.;D;.;.;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.66	.;T;T;T;T;T;T;.;T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.079	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.47	.;N;.;.;.;N;.;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.54	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.45
Sift	Benign	0.35	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.36	T;T;T;T;T;T;T;T;T
Polyphen		0.0010	B;B;.;B;.;B;B;.;.
Vest4		0.77
MVP		0.77
MPC		0.041
ClinPred		0.017	T
GERP RS		2.6
Varity_R		0.27
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs199473182; hg19: chr3-38622706; COSMIC: COSV61128386;