rs745435760

Variant names:

• chr3-38581092-G-A
• rs745435760
• NM_001099404.2:c.3067C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-38581092-G-A
• chr3-38581092-G-C
• chr3-38581092-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_001099404.2(SCN5A):​c.3067C>T​(p.Arg1023Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,613,736 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1023H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (1 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 3.53
• Publications: 5 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: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.3067C>T	p.Arg1023Cys	missense_variant	Exon 17 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.3067C>T	p.Arg1023Cys	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.3067C>T	p.Arg1023Cys	missense_variant	Exon 17 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.3067C>T	p.Arg1023Cys	missense_variant	Exon 17 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000202 AC: 5 AN: 247718 AF XY: 0.0000223

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000894

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461590 Hom.: 1 Cov.: 37 AF XY: 0.0000151 AC XY: 11 AN XY: 727062

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.000378 AC: 15 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111844

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74336

African (AFR) AF: 0.0000241 AC: 1 AN: 41418

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000203 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000248 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Jan 29, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in association with Brugada syndrome (Matsumura et al., 2017); Reported in an individual with recorded ventricular fibrillation as well as histology studies that showed myocardial abnormalities (Watanabe et al., 2013); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 574312; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29202755, 23168001, 22407026) -

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

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 1023 of the SCN5A protein (p.Arg1023Cys). This variant is present in population databases (rs745435760, gnomAD 0.006%). This missense change has been observed in individual(s) with SCN5A-related conditions (PMID: 23168001, 29202755, 29773157, 30059973, 31696929). ClinVar contains an entry for this variant (Variation ID: 574312). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiac arrhythmia Uncertain:2

Feb 22, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with cysteine at codon 1023 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with ventricular fibrillation and structural myocardial alteration (PMID: 23168001), Brugada syndrome (PMID: 29202755), alcohol-induced cardiomyopathy (ACM) (PMID: 29773157), and tetralogy of Fallot (PMID: 22407026, 29121719 ). This variant has also been reported in 6 individuals suspected of having epilepsy, and in 3 individuals affected with other diseases other than inherited arrhythmia (PMID: 31696929). This variant has been identified in 5/247718 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Aug 06, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with cysteine at codon 1023 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with ventricular fibrillation and structural myocardial alteration (PMID: 23168001), Brugada syndrome (PMID: 29202755), alcohol-induced cardiomyopathy (ACM) (PMID: 29773157), and tetralogy of Fallot (PMID: 22407026, 29121719 ). This variant has also been reported in 6 individuals suspected of having epilepsy, and in 3 individuals affected with other diseases other than inherited arrhythmia (PMID: 31696929). This variant has been identified in 5/247718 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified Uncertain:1

Sep 23, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SCN5A c.3067C>T (p.Arg1023Cys) results in a non-conservative amino acid change located in the Sodium ion transport-associated domain (IPR010526) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 247718 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3067C>T has been reported in the literature in individuals affected with Cardiomyopathy including Tetralogy of Fallot, Brugada syndrome, ventricular fibrillation (e.g. Chiu_2012, Chiu_2017, Hayano_2014, Matsumura_2017, Watanabe_2013). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Brugada syndrome 1 Uncertain:1

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. 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 long QT syndrome (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 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) 0112 - The condition associated with this gene has incomplete penetrance. Among individuals with a SCN5A pathogenic variant, aproximately 20%-30% have an ECG diagnostic of Brugada syndrome and approximately 80% manifest the characteristic ECG changes when challenged with a sodium channel blocker (PMID: 20301690). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (5 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 72 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated DII-DIII sodium ion transport-associated domain (NCBI; PMID: 29806494). (I) 0708 - Other missense variants comparable to the one identified in this case have conflicting previous evidence for pathogenicity. While the p.(Arg1023His) variant has been identified in one individual with Brugada syndrome and classified as likely pathogenic and pathogenic in LOVD, it has also been classified multiple times as a VUS, likely benign or benign variant. In addition, the p.(Arg1023Pro) variant has been classified as a VUS by a clinical diagnostic laboratory (LOVD, ClinVar, PMIDs: 16344400, 26746457, 30662450). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. While this variant has been reported in individuals with tetralogy of Fallot, ventricular fibrillation and Brugada syndome, it has also been classified as a VUS by clinical diagnostic laboratories (ClinVar; PMID: 22407026, 23168001, 29202755). (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 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

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS4_Supporting+PP3 -

Cardiovascular phenotype Uncertain:1

Apr 19, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1023C variant (also known as c.3067C>T), located in coding exon 16 of the SCN5A gene, results from a C to T substitution at nucleotide position 3067. The arginine at codon 1023 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the DII/DIII interdomain linker region. This variant has been detected in an individual with ventricular fibrillation, and early repolarization as well as cardiomyocyte disarray and fibrosis, and has also been detected in a Brugada syndrome cohort; however, clinical details were limited (Watanabe H et al. Int. J. Cardiol., 2013 May;165:e21-3; Matsumura H et al. J. Biomed. Sci., 2017 Dec;24:91). This alteration has also been reported in arrhythmia cohorts, in a cohort of subjects with tetralogy of Fallot and ventricular fibrillation, cardiomyopathy, epilepsy and control cohorts (Chiu SN et al. Int J Cardiol, 2017 Dec;249:156-160; Baruteau AE et al. Eur Heart J, 2018 Aug;39:2879-2887; Ware JS et al. J Am Coll Cardiol, 2018 May;71:2293-2302; Li X et al. Ann Hum Genet, 2020 Mar;84:161-168; Sarica AS et al. Am J Cardiol, 2021 Jul;151:51-56; (Kars ME et al. Proc Natl Acad Sci U S A, 2021 Sep;118:). This alteration was also reported along with an alteration in VCP in a one month old with amyotrophy, inclusion body myopathy with early onset Paget disease and frontotemporal dementia (Liu J et al. Hum Mutat, 2021 Nov;42:1443-1460). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
CardioboostArm	Benign	0.00062
CardioboostCm	Benign	0.0015
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.43	.;.;.;.;.;T;.;.;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.92	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.086	D
MutationAssessor	Benign	1.8	.;L;.;.;.;L;.;.;.
PhyloP100		3.5
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.31	N;N;N;N;N;N;N;N;N
REVEL	Pathogenic	0.81
Sift	Benign	0.17	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.065	T;T;T;T;T;T;T;T;T
Polyphen		0.0040	B;D;.;B;.;D;D;.;.
Vest4		0.77
MutPred		0.74		Loss of solvent accessibility (P = 0.1744);Loss of solvent accessibility (P = 0.1744);Loss of solvent accessibility (P = 0.1744);Loss of solvent accessibility (P = 0.1744);Loss of solvent accessibility (P = 0.1744);Loss of solvent accessibility (P = 0.1744);Loss of solvent accessibility (P = 0.1744);Loss of solvent accessibility (P = 0.1744);Loss of solvent accessibility (P = 0.1744);
MVP		0.57
MPC		0.24
ClinPred		0.46	T
GERP RS		5.3
Varity_R		0.060
gMVP		0.65
Mutation Taster		=0/100	disease causing

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: rs745435760; hg19: chr3-38622583; COSMIC: COSV61131641;