rs199473100

Variant names:

• chr3-38606683-G-A
• rs199473100
• NM_001099404.2:c.1126C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_001099404.2(SCN5A):​c.1126C>T​(p.Arg376Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R376H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1 O:1
• Conservation: PhyloP100: 2.87
• Publications: 9 publications found

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]

SCN5A Gene-Disease associations (from GenCC):

• Brugada syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Brugada syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1E

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• sick sinus syndrome 1

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• progressive familial heart block, type 1A

  Inheritance: SD, AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp
• atrial standstill

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial sick sinus syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• paroxysmal familial ventricular fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• progressive familial heart block

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• short QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_001099404.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-38606682-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 67639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949
• PP5: Variant 3-38606683-G-A is Pathogenic according to our data. Variant chr3-38606683-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 67638.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.1126C>T	p.Arg376Cys	missense_variant	Exon 9 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.1126C>T	p.Arg376Cys	missense_variant	Exon 9 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.1126C>T	p.Arg376Cys	missense_variant	Exon 9 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.1126C>T	p.Arg376Cys	missense_variant	Exon 9 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461024 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726738

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53110

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111716

Other (OTH) AF: 0.00 AC: 0 AN: 60358

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00233887), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Other:1

Dec 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 376 of the SCN5A protein (p.Arg376Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Brugada syndrome and/or SCN5A-related conditions (PMID: 24295898, 34461752; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67638). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SCN5A function (PMID: 24295898). This variant disrupts the p.Arg376 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15851228, 16344400, 28341781). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

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Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant has been reported in the following publications (PMID:19841300;PMID:20129283). -

Feb 20, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Arg376Cys variant was identified in three members of a family with sick sinus syndrome (Detta et al., 2014). Functional studies showed a significant reduction of the inward sodium current in heterologous cells that were expressing the Arg376Cys allele (Detta et al., 2014).The Arg376Cys variant results in a non-conservative amino acid substitution of a positively charged Arginine with an uncharged, polar Cysteine at a position that is conserved in mammals. This variant resides in the extracellular pore loop region between S5-S6 of DI. In silico analysis predicts Arg376Cys is damaging to the protein structure/function. While this allele has been observed in one out of 1300 control individuals (Kapa et al., 2009; Kapplinger et al., 2012), it was absent from individuals in both the NHLBI Exome Sequencing Project and the Exome Aggregation Consortium database, indicating it is not a common benign variant in these populations. Moreover, a missense pathogenic variant at the same residue (Arg376His) and in nearby residues (Met369Lys, Trp374Gly, Gly386Arg) have been reported in the Human Gene Mutation Database in association with Brugada syndrome (Stenson et al., 2014).Therefore, this variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded. -

not specified Pathogenic:1

Jul 05, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SCN5A c. 1126C>T; p. Arg376Cys variant (rs199473100) is reported in the literature in 1 family and 3 individuals, of which 2 were affected with sick sinus syndrome-1 (SSS1), and the third may not have yet manifested disease phenotypes (Detta 2014). Functional analyses in vitro demonstrate a significant reduction in sodium channel currents (Detta 2014), similar to analyses of other SCN5A variants associated with SSS1, and consistent with impaired excitability of cardiomyocytes leading to SSS1 (Gui 2010). This variant is reported as either likely pathogenic or of uncertain significance, each by 1 laboratory in ClinVar (Variation ID: 78534), and considered disease causing in HGMD. This variant is absent from most general population databases (1000 Genomes Project and Genome Aggregation Database), with a single individual in the Exome Variant Server, indicating it is not a common polymorphism. Additionally, other variants at this codon (c.1127G>A, p.Arg376His; c.1127G>T, p.Arg376Leu) have been reported in individuals with Brugada syndrome (Rossenbacker 2004) and sudden unexplained death (Christiansen 2016), respectively. The Arg376His variant is reported as pathogenic by 2 laboratories, and likely pathogenic by 1 laboratory in ClinVar (Variation ID: 78535). The Arg376Leu variant is not in ClinVar. The arginine at codon 376 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely pathogenic. -

Cardiovascular phenotype Pathogenic:1

Mar 21, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R376C variant (also known as c.1126C>T), located in coding exon 8 of the SCN5A gene, results from a C to T substitution at nucleotide position 1126. The arginine at codon 376 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was reported in individual(s) with features consistent with SCN5A-related arrhythmias including cases with Brugada syndrome, sick sinus syndrome, and other dysrhythmias (Detta N et al. Int. J. Cardiol., 2014 Jan;170:e63-5; Milman A. Circ Genom Precis Med. 2021 Oct;14(5):e003222; external communication; Ambry internal data), and segregated with disease in at least one family (Detta N et al. Int. J. Cardiol., 2014 Jan;170:e63-5). Other variant(s) at the same codon, p.R376H (c.1127G>A), have been identified in individual(s) with features consistent with Brugada syndrome (Rossenbacker T et al. Heart Rhythm. 2004;1(5):610-5). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Brugada syndrome 1 Uncertain:1

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
CardioboostArm	Pathogenic	0.92
CardioboostCm	Benign	0.097
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	.;.;.;.;.;D;.;.;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	.;M;.;.;.;M;.;.;.
PhyloP100		2.9
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.0	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;D;D;.;.
Vest4		0.89
MutPred		0.77		Loss of MoRF binding (P = 0.053);Loss of MoRF binding (P = 0.053);Loss of MoRF binding (P = 0.053);Loss of MoRF binding (P = 0.053);Loss of MoRF binding (P = 0.053);Loss of MoRF binding (P = 0.053);Loss of MoRF binding (P = 0.053);Loss of MoRF binding (P = 0.053);Loss of MoRF binding (P = 0.053);
MVP		0.92
MPC		1.3
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.64
gMVP		0.97
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs199473100; hg19: chr3-38648174; COSMIC: COSV105205316;