rs199473260

Variant names:

• chr3-38555720-T-C
• rs199473260
• NM_001099404.2:c.4478A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PP3_Moderate

The NM_001099404.2(SCN5A):​c.4478A>G​(p.Lys1493Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000626 in 1,613,916 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).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:10 O:1
• Conservation: PhyloP100: 7.97
• Publications: 18 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 4 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_001099404.2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.9

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.4478A>G	p.Lys1493Arg	missense_variant	Exon 26 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.4475A>G	p.Lys1492Arg	missense_variant	Exon 26 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.4478A>G	p.Lys1493Arg	missense_variant	Exon 26 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.4475A>G	p.Lys1492Arg	missense_variant	Exon 26 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152100 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251474 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000657 AC: 96 AN: 1461816 Hom.: 0 Cov.: 31 AF XY: 0.0000674 AC XY: 49 AN XY: 727218

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

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

European-Non Finnish (NFE) AF: 0.0000782 AC: 87 AN: 1111966

Other (OTH) AF: 0.000149 AC: 9 AN: 60392

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152100 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74292

African (AFR) AF: 0.00 AC: 0 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000260 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:10 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:2

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SCN5A: PS4:Moderate, PP3, PS3:Supporting -

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 1493 of the SCN5A protein (p.Lys1493Arg). This variant is present in population databases (rs199473260, gnomAD 0.002%). This missense change has been observed in individuals with autosomal dominant long QT syndrome, atrial fibrillation, and/or supraventricular ectopy (PMID: 19167345, 19716085, 23861362; internal data). ClinVar contains an entry for this variant (Variation ID: 67898). 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 tolerated. Experimental studies have shown that this missense change affects SCN5A function (PMID: 19167345). For these reasons, this variant has been classified as Pathogenic. -

Nov 18, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome 3 Pathogenic:1 Uncertain:2

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant p.K1492R in SCN5A (NM_000335.5) has been previously reported in individuals with atrial fibrillation, long QT syndrome and supraventricular ectopy. It has been reported as a secondary variant in an exome study performed for cardiac diseases (Li Q et al,.Kapplinger JD et al, Ng D et al)The p.K1492R variant is observed in 4/1,13,768 (0.0035%) alleles from individuals of European (NonFinnish) background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. It has been submitted to ClinVar with conflicting interpretations of Uncertain Significance/Likely Pathogenic. Experimental studies have shown that this missense change leads to a positive shift in voltage-dependence of sodium channel inactivation and enhanced cardiomyocyte excitability consistent with a gain-of-function effect ( Li Q et al). The p.K1492R missense variant is predicted to be damaging by both SIFT and PolyPhen2. The lysine residue at codon 1492 of SCN5A is conserved in all mammalian species. The nucleotide c.4475 in SCN5A is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance -

Oct 29, 2024

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

This variant in SCN5A, p.(Lys1492Arg), is rare in gnomAD (v2.1, 0.000039 maf in NFE) and has been reported in individuals with atrial fibrillation (PMID: 19167345), and long QT syndrome (PMID: 19716085, PMID: 32893267). The REVEL score for this variant is 0.911 which supports pathogenicity. Functional studies show some impact on protein function with limited controls. Based on this information we classify this variant as a variant of uncertain significance. PS4_Supporting, PP3_Moderate. -

-

Genomics England Pilot Project, Genomics England

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: clinical testing

- -

Cardiac arrhythmia Uncertain:2

Jun 07, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces lysine with arginine at codon 1493 of the SCN5A protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373).Functional studies have shown that this variant impacts voltage-dependence of sodium channel inactivation and cardiomyocyte excitability consistent with a gain-of-function effect (PMID: 19167345, 33712541). This variant has been reported in two related individuals affected with atrial fibrillation (PMID: 19167345), in two individuals affected with and another two individuals suspected to be affected with long QT syndrome (PMID: 19716085, 32893267). This variant has also been found in one individual affected with dilated cardiomyopathy, one individual with hypertrophic cardiomyopathy (PMID: 38489124), and another with a history of supraventricular ectopy (PMID: 23861362). This variant has been identified in 5/282810 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 lysine with arginine at codon 1493 of the SCN5A protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373).Functional studies have shown that this variant impacts voltage-dependence of sodium channel inactivation and cardiomyocyte excitability consistent with a gain-of-function effect (PMID: 19167345, 33712541). This variant has been reported in two related individuals affected with atrial fibrillation (PMID: 19167345), in two individuals affected with and another two individuals suspected to be affected with long QT syndrome (PMID: 19716085, 32893267). This variant has also been found in one individual affected with dilated cardiomyopathy, one individual with hypertrophic cardiomyopathy (PMID: 38489124), and another with a history of supraventricular ectopy (PMID: 23861362). This variant has been identified in 5/282810 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. -

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 Pathogenic:1

May 03, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Apr 11, 2025

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.4478A>G (p.Lys1493Arg) results in a conservative amino acid change located in the Voltage-gated sodium channel alpha subunit, inactivation gate (IPR044564) 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 1.6e-05 in 251474 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance.c.4478A>G has been observed in settings of multi-gene panel testing or whole exome sequencing in individuals affected with Long QT Syndrome, atrial fibrilation, coronary artery disease risk and/or and/or supraventricular ectopy (e.g. Mullally_2013, Kapplinger_2009, Lieve_2013, Li_2009, Ng_2013, Murphy_2024, Labcorp (formerly Invitae)), with some patients carrying unknown variants in causative genes (e.g. Mullally_2013) or without definitive evidence of causation. These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function in vitro, suggesting altered cellular hyperexcitability in the cardiac sodium channel (e.g. Li_2009). The following publications have been ascertained in the context of this evaluation (PMID: 19716085, 19167345, 23631430, 23174487, 23861362, 38489124). ClinVar contains an entry for this variant (Variation ID: 67898). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Brugada syndrome 1 Uncertain:1

Oct 19, 2020

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_v1.3.3, this variant is classified as 3A-VUS. 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, whereas gain of function is usually associated with LQTS, however some variants simultaneously result in both a loss and gain of function, and have been observed in patients with LQTS, Brugada syndrome, and patients with a blended phenotype. Additionally, different studies have shown conflicting mechanisms in association with atrial fibrillation (PMID: 29806494, PMID: 19167345). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from lysine to arginine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (5 heterozygotes, 0 homozygotes). (SP) 0309 - A single amino acid inframe deletion at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions, but very high conservation. (I) 0600 - Variant is located at an acetylated residue in the annotated DIII-DIV intracellular linker region which mediates sodium channel inactivation (NCBI, PDB, Phosphosite, PMID: 23840796). (I) 0704 - Another variant comparable to the one identified in this case has limited previous evidence for pathogenicity. An inframe deletion of the same residue has previously been reported to segregate in a large family with cardiac conduction disease. The affected individuals did not exhibit signs of either Brugada syndrome or LQTS however, functional studies of the variant demonstrated both a gain and loss of function (PMID: 23840796). (SP) 0808 - Previous reports of pathogenicity for this variant are conflicting. The variant has previously been reported in patients with LQTS and lone atrial fibrillation, and was not present in an unaffected family member however, it has also been classified as both likely pathogenic and a VUS in relation to atrial fibrillation and Brugada syndrome, respectively (ClinVar, HGMD, LOVD, PMID: 19167345, PMID: 25904541). It has also previously been observed at VCGS in a patient with probable LQTS and classified as a 3A-VUS. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies demonstrated a significant positive shift in voltage-dependence of inactivation and a large ramp current near resting membrane potential, indicating a gain of function (PMID: 19167345). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

SCN5A-related disorder Uncertain:1

Oct 03, 2022

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SCN5A c.4478A>G variant is predicted to result in the amino acid substitution p.Lys1493Arg. This variant has been reported in two patients with atrial fibrillation from a single family (Li et al. 2009. PubMed ID: 19167345) and in two patients with long QT syndrome (Table S3, Kapplinger et al. 2009. PubMed ID: 19716085). Functional experiments demonstrated this variant led to a gain of function effect (Li et al. 2009. PubMed ID: 19167345). This variant is reported in 0.0039% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-38597211-T-C). This variant is reported in ClinVar with conflicting interpretations of uncertain and likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/67898/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cardiovascular phenotype Uncertain:1

Sep 22, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4478A>G (p.K1493R) alteration is located in exon 26 (coding exon 25) of the SCN5A gene. This alteration results from a A to G substitution at nucleotide position 4478, causing the lysine (K) at amino acid position 1493 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Congenital long QT syndrome Other:1

-

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 as associated with Long QT syndrome in the following publications (PMID:19167345;PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
CardioboostArm	Pathogenic	1.0
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	.;.;.;.;.;D;.;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	.;.;.;.;.;M;.;.;.
PhyloP100		8.0
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.8	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.013	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.040	D;D;D;D;D;D;D;D;D
Polyphen		0.52	P;B;.;P;.;B;P;.;.
Vest4		0.95
MVP		0.99
MPC		1.0
ClinPred		0.96	D
GERP RS		4.5
Varity_R		0.74
gMVP		0.81
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: rs199473260; hg19: chr3-38597211;