chr3-38585749-G-A

Variant names:

• chr3-38585749-G-A
• rs199473175
• NM_001099404.2:c.2729C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001099404.2(SCN5A):​c.2729C>T​(p.Ser910Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,360 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S910S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 U:1 O:1
• Conservation: PhyloP100: 8.04
• 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: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• PP5: Variant 3-38585749-G-A is Pathogenic according to our data. Variant chr3-38585749-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 67753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001099404.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN5A	NM_001099404.2	MANE Plus Clinical	c.2729C>T	p.Ser910Leu	missense	Exon 16 of 28	NP_001092874.1
	SCN5A	NM_000335.5	MANE Select	c.2729C>T	p.Ser910Leu	missense	Exon 16 of 28	NP_000326.2
	SCN5A	NM_198056.3		c.2729C>T	p.Ser910Leu	missense	Exon 16 of 28	NP_932173.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN5A	ENST00000413689.6	TSL:5 MANE Plus Clinical	c.2729C>T	p.Ser910Leu	missense	Exon 16 of 28	ENSP00000410257.1
	SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.2729C>T	p.Ser910Leu	missense	Exon 16 of 28	ENSP00000398266.2
	SCN5A	ENST00000333535.9	TSL:1	c.2729C>T	p.Ser910Leu	missense	Exon 16 of 28	ENSP00000328968.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250430 AF XY: 0.00

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: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461360 Hom.: 0 Cov.: 36 AF XY: 0.00000275 AC XY: 2 AN XY: 726958

African (AFR) AF: 0.0000299 AC: 1 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111654

Other (OTH) AF: 0.00 AC: 0 AN: 60350

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000620 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brugada syndrome Pathogenic:1 Uncertain:1 Other:1

Sep 18, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces serine with leucine at codon 910 of the SCN5A protein. This variant is found within a highly conserved region of the transmembrane domain DII. Rare nontruncating variants in this region (a.a. 718 - 938) have been shown to be significantly overrepresented in individuals with Brugada syndrome (PMID: 32893267). A functional study has shown that this variant causes reduced cell surface expression of the SCN5A protein and decreased sodium current density compared to wild-type cells, indicating a trafficking deficit (PMID: 24768612). This variant has been reported in at least 6 unrelated individuals affected with or suspected of having Brugada syndrome (PMID: 11901046, 20129283, 24768612, 26173111, 28087566, 29574140, 32268277, 32893267), and several other individuals affected with sick sinus syndrome, atrial standstill, ventricular fibrillation, or dilated cardiomyopathy (PMID: 28104484, 31983221, 36147716, ClinVar SCV000741704.3). This variant has been identified in 1/250430 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

Jan 04, 2024

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory

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 Brugada syndrome in the following publications (PMID:11901046;PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

not provided Pathogenic:2

Apr 10, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in individuals with features consistent with or suggestive of Brugada syndrome and in individuals with sick sinus syndrome and DCM (PMID: 20129283, 11901046, 26173111, 28104484, 31983221); Identified in a child who experienced cardiac arrest with ventricular fibrillation and in her asymptomatic mother, both of whom had a positive ajmaline test (PMID: 24768612); Not observed at significant frequency in large population cohorts (gnomAD); Published in vitro analysis showed that S910L destroys channel peak current and has a dominant negative effect on current density (PMID: 24768612, 35305865); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30193851, 15655131, 14753626, 12650874, 24768612, 14961552, 31983221, 25904541, 32268277, 30662450, 20100972, 25274057, 22999724, 22840528, 22766342, 19251209, 18378609, 17210839, 16684018, 16453024, 15840476, 14523039, 12736279, 10940383, 10471492, 32533946, 28104484, 26173111, 33131149, 29574140, 11901046, 33164571, 34461752, 36147716, 30203441, 35130036, 20129283, 37652022, 35305865, 22581653, 28087566, 38777137, 32893267)

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 910 of the SCN5A protein (p.Ser910Leu). This variant is present in population databases (rs199473175, gnomAD 0.0009%). This missense change has been observed in individuals with Brugada syndrome or sick sinus syndrome (PMID: 11901046, 24768612, 26173111, 28104484, 29574140; 20129283.). ClinVar contains an entry for this variant (Variation ID: 67753). 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: 24768612). For these reasons, this variant has been classified as Pathogenic.

Brugada syndrome 1 Pathogenic:1

Apr 01, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.01 (v4: 4 heterozygote(s), 0 homozygote(s)) ; This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in the literature in multiple individuals with Brugada syndrome or symptoms consistent with Brugada syndrome (PMIDs: 24768612, 28087566, 37061847, 28104484, 36147716, 20129283, 32268277; personal communication), and has been classified as pathogenic and likely pathogenic by clinical laboratories (ClinVar); Missense variant predicted to be damaging by in silico tool(s) or highly conserved with a major amino acid change. Additional information: Variant is predicted to result in a missense amino acid change from serine to leucine; This variant is heterozygous; This gene is associated with both recessive and dominant disease. Most conditions associated with this gene have autosomal dominant inheritance. SSS is usually caused by biallelic variants; however, heterozygotes may show symptoms (OMIM, PMID: 30364184); Variant is located in the annotated ion transport domain (DECIPHER); 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) (MONDO:0024562), 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); The condition associated with this gene has incomplete penetrance. Among individuals with an SCN5A pathogenic variant, approximately 20%-30% have an ECG diagnostic of Brugada syndrome and approximately 80% manifest the characteristic ECG changes when challenged with a sodium channel blocker (e.g. ajmaline) (PMID: 20301690); Inheritance information for this variant is not currently available in this individual.

Cardiovascular phenotype Pathogenic:1

Mar 01, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S910L variant (also known as c.2729C>T), located in coding exon 15 of the SCN5A gene, results from a C to T substitution at nucleotide position 2729. The serine at codon 910 is replaced by leucine, an amino acid with dissimilar properties. This variant was reported in individual(s) with features consistent with SCN5A-related arrhythmias and/or cardiomyopathy including Brugada syndrome, cardiac arrest, ventricular arrhythmia, conduction system disease and dilated cardiomyopathy (Priori SG et al. Circulation, 2002;105:1342-7, Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46; Pambrun T et al. Heart Rhythm, 2014;11:1393-400; Selga E et al. PLoS ONE, 2015;10:e0132888; Ishikawa T et al. Heart Rhythm, 2017 May;14:717-724; Sonoda K et al. Heart Rhythm, 2018 Aug;15:1179-1188; Berthome P et al. Heart Rhythm, 2019 Feb;16:260-267; Mazzarotto F et al. Circulation, 2020 Feb;141:387-398; Kato Y et al. HeartRhythm Case Rep, 2022 Sep;8:636-638; Pannone L et al. Europace. 2023 May;25(5)). In multiple assays testing SCN5A function, this variant showed functionally abnormal results (Pambrun T et al. Heart Rhythm, 2014;11:1393-400; O'Neill MJ et al. Genet Med. 2022 Jun;24(6):1238-1248). This amino acid position is highly conserved through mammals, but not in all 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.

Dilated cardiomyopathy 1E;C1859062:Long QT syndrome 3;C1879286:Progressive familial heart block, type 1A;C3151464:Atrial fibrillation, familial, 10;C4551804:Brugada syndrome 1 Pathogenic:1

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
CardioboostArm	Pathogenic	0.97
CardioboostCm	Uncertain	0.18
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		8.0
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.85		Gain of helix (P = 0.0078)
MVP		0.95
MPC		0.93
ClinPred		0.97	D
GERP RS		4.2
Varity_R		0.41
gMVP		0.94
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: rs199473175; hg19: chr3-38627240; COSMIC: COSV100347038;