3-38605956-G-C

Variant names:

• chr3-38605956-G-C
• rs199473112
• NM_001099404.2:c.1333C>G

Variant summary

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

The NM_001099404.2(SCN5A):​c.1333C>G​(p.His445Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000128 in 1,604,710 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. H445Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:9 O:1
• Conservation: PhyloP100: 6.68
• Publications: 13 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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.1333C>G	p.His445Asp	missense_variant	Exon 10 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.1333C>G	p.His445Asp	missense_variant	Exon 10 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.1333C>G	p.His445Asp	missense_variant	Exon 10 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.1333C>G	p.His445Asp	missense_variant	Exon 10 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000533 AC: 13 AN: 243840 AF XY: 0.0000378

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000294

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000472

Gnomad NFE exome AF: 0.0000904

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.000129 AC: 188 AN: 1452388 Hom.: 0 Cov.: 31 AF XY: 0.000112 AC XY: 81 AN XY: 721306

African (AFR) AF: 0.0000603 AC: 2 AN: 33186

American (AMR) AF: 0.0000679 AC: 3 AN: 44152

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25624

East Asian (EAS) AF: 0.00 AC: 0 AN: 39580

South Asian (SAS) AF: 0.00 AC: 0 AN: 84920

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53146

Middle Eastern (MID) AF: 0.000350 AC: 2 AN: 5722

European-Non Finnish (NFE) AF: 0.000153 AC: 169 AN: 1106054

Other (OTH) AF: 0.000183 AC: 11 AN: 60004

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74482

African (AFR) AF: 0.0000962 AC: 4 AN: 41578

American (AMR) AF: 0.000261 AC: 4 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.000132

ExAC AF: 0.0000496 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brugada syndrome 1 Uncertain:2

Feb 02, 2022

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 1 (SSS) (MIM#608567), whereas gain of function is usually associated with long QT syndrome-3 (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). (I) 0108 - This gene is associated with both recessive and dominant disease. Most conditions associated with this gene are dominantly inherited; however SSS is caused by biallelic variants (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from histidine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (17 heterozygotes, 0 homozygotes). (SP) 0309 - Alternative amino acid changes at the same position has been observed in gnomAD (v2) (3 heterozygotes, 0 homozygote). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated DI to DII intracellular linker domain (UniProt). (I) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. The p.(His445Gln) and p.(His445Tyr) variants have each been reported once as a VUS in ClinVar. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has previously been reported in individuals with Brugada syndrome, atrial fibrillation, and sudden infant death syndrome (SIDS), and has been classified as both a VUS and potentially disease causing (PMID: 30193851, PMID: 25650408, PMID: 18378609, PMID: 30086531, ClinVar). (I) 0903 - This variant has limited evidence for segregation with disease. This variant has been shown to segregate with atrial fibrillation in a proband and two affected family members. Additionally, the variant was absent from an unaffected family member (PMID: 18378609). (SP) 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 -

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:2

Feb 26, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in patients with LQTS, atrial fibrillation, Brugada syndrome, or sudden infant death either tested at GeneDx or in the published literature (Darbar et al., 2008; Le Scouarnec et al., 2015; Campuzano et al., 2018); however, some individuals harbor additional variants that could explain their phenotype; Observed to segregate with atrial fibrillation in one proband's affected father and brother (Darbar et al., 2008); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 30046; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 19808477, 22581653, 25650408, 18378609, 28150151, 30086531, 28086167, 30193851) -

Nov 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 445 of the SCN5A protein (p.His445Asp). This variant is present in population databases (rs199473112, gnomAD 0.008%). This missense change has been observed in individual(s) with Brugada syndrome, dilated cardiomyopathy, or atrial fibrillation (PMID: 18378609, 19808477, 25650408, 30193851, 37652022). ClinVar contains an entry for this variant (Variation ID: 30046). 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. This variant disrupts the p.His445 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been observed in individuals with SCN5A-related conditions (internal data), which suggests that this may be a clinically significant amino acid residue. 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. -

Cardiovascular phenotype Uncertain:2

Aug 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.H445D variant (also known as c.1333C>G), located in coding exon 9 of the SCN5A gene, results from a C to G substitution at nucleotide position 1333. The histidine at codon 445 is replaced by aspartic acid, an amino acid with similar properties. This variant has been detected in individuals from various cohorts including sudden infant death, sudden death, arrhythmia, and Brugada syndrome; however, clinical details were limited, some reports may overlap, and additional variants in were also detected in some cases (Le Scouarnec S et al. Hum Mol Genet, 2015 May;24:2757-63; Campuzano O et al. Forensic Sci Int, 2017 Feb;271:120-125; Amin AS et al. Int J Cardiol, 2018 Sep;266:128-132; Campuzano O et al. Forensic Sci Int Genet, 2018 11;37:54-63; Berthome P et al. Heart Rhythm, 2019 02;16:260-267). This variant has also been reported in association with atrial fibrillation and, in one family, was detected in three affected individuals (Darbar D et al. Circulation, 2008 Apr;117:1927-35; Watanabe H et al. Circ Arrhythm Electrophysiol, 2009 Jun;2:268-75). 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Atrial fibrillation, familial, 10 Pathogenic:1

Apr 15, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not specified Uncertain:1

Jun 27, 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.1333C>G (p.His445Asp) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 5.3e-05 in 243840 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in SCN5A causing Brugada Syndrome (5.3e-05 vs 0.00017), allowing no conclusion about variant significance. c.1333C>G has been observed in individuals affected with Atrial Fibrillation, Brugada Syndrome or Dilated Cardiomyopathy (Darbar_2008, Watanabe_2009, Le Scouarnec_2015. Berthome_2019, McGurk_2023). These reports do not provide unequivocal conclusions about association of the variant with Brugada Syndrome. 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: 30193851, 18378609, 25650408, 37652022, 19808477). ClinVar contains an entry for this variant (Variation ID: 30046). Based on the evidence outlined above, the variant was classified as 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 Uncertain:1

Feb 14, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiac arrhythmia Uncertain:1

Jun 05, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces histidine with aspartic acid at codon 445 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant alters voltage-dependence of activation, recovery and inactivation of the sodium channel (Gillani et al., 2010). This variant has been reported in individuals affected with atrial fibrillation (PMID: 18378609, 19808477), Brugada syndrome (PMID: 25650408, 30193851, 32893267), dilated cardiomyopathy (PMID: 32826072), and sudden death in infancy (PMID: 30086531). This variant has also been identified in 14/275240 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. -

Atrial fibrillation 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 Atrial fibrillation in the following publications (PMID:18378609). 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	Uncertain	0.37
CardioboostArm	Benign	0.00011
CardioboostCm	Benign	0.0020
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	.;.;.;.;.;T;.;.;.
Eigen	Benign	0.067
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;D;D;D;D;D;D;.;D
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.55	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	0.20	.;N;.;.;.;N;.;.;.
PhyloP100		6.7
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.4	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.63
Sift	Uncertain	0.013	D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.079	T;T;T;T;T;T;T;T;T
Polyphen		0.011	B;B;.;B;.;B;B;.;.
Vest4		0.57
MutPred		0.75		Loss of MoRF binding (P = 0.0487);Loss of MoRF binding (P = 0.0487);Loss of MoRF binding (P = 0.0487);Loss of MoRF binding (P = 0.0487);Loss of MoRF binding (P = 0.0487);Loss of MoRF binding (P = 0.0487);Loss of MoRF binding (P = 0.0487);Loss of MoRF binding (P = 0.0487);Loss of MoRF binding (P = 0.0487);
MVP		0.88
MPC		0.61
ClinPred		0.13	T
GERP RS		5.5
Varity_R		0.21
gMVP		0.72
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199473112; hg19: chr3-38647447;