chr3-38551243-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_000335.5(SCN5A):c.5126C>T(p.Ser1709Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,964 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 (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

SCN5A
NM_000335.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14O:1

Conservation

PhyloP100: 8.12

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1

In a intramembrane_region Pore-forming (size 22) in uniprot entity SCN5A_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000335.5

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the SCN5A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 99 curated pathogenic missense variants (we use a threshold of 10). The gene has 60 curated benign missense variants. Gene score misZ: 2.7504 (below the threshold of 3.09). Trascript score misZ: 4.8279 (above the threshold of 3.09). GenCC associations: The gene is linked to progressive familial heart block, type 1A, Brugada syndrome, familial sick sinus syndrome, short QT syndrome, paroxysmal familial ventricular fibrillation, progressive familial heart block, long QT syndrome 3, familial atrial fibrillation, catecholaminergic polymorphic ventricular tachycardia, dilated cardiomyopathy, dilated cardiomyopathy 1E, arrhythmogenic right ventricular cardiomyopathy, Brugada syndrome 1, atrial standstill, familial isolated dilated cardiomyopathy, familial long QT syndrome, sick sinus syndrome 1.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant 3-38551243-G-A is Pathogenic according to our data. Variant chr3-38551243-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38551243-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2 link	c.5129C>T	p.Ser1710Leu	missense_variant	Exon 28 of 28	ENST00000413689.6	NP_001092874.1	Q14524H9KVD2
SCN5A	NM_000335.5 link	c.5126C>T	p.Ser1709Leu	missense_variant	Exon 28 of 28	ENST00000423572.7	NP_000326.2	Q14524-2Q86V90

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6 link	c.5129C>T	p.Ser1710Leu	missense_variant	Exon 28 of 28	5	NM_001099404.2	ENSP00000410257.1		H9KVD2
SCN5A	ENST00000423572.7 link	c.5126C>T	p.Ser1709Leu	missense_variant	Exon 28 of 28	1	NM_000335.5	ENSP00000398266.2		Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251446

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152076

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Jan 14, 2014

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Ser1710Leu (S1710L; c.5129 C>T) in the SCN5A gene This variant has been previously observed in five unrelated cases of Brugada syndrome (including one case of idiopathic VF without a strict Brugada diagnosis). No published segregation data is available, but good in-vitro functional data is available. With our 2 cases (both have Mexican ancestry), this makes 7 families. Akai et al. (2000) first reported the variant in a Japanese patient with idiopathic ventricular fibrillation, a history of recurrent syncope, and sudden death in a paternal uncle and paternal grandfather, but no type 1 Brugada pattern on EKG. Shin et al. (2007) reported the variant in a male Korean patient with a type 1 Brugada syndrome pattern on EKG that was unmasked by flecainide and a family history of sudden cardiac death. The testing laboratory reports that Ser1710Leu has also been seen in three additional unrelated individuals tested for Brugada syndrome at their lab (as of January 2014). Functional data is available. The SCN5A gene produces the cardiac sodium channel alpha subunit, and Ser1710 is located in the highly conserved pore-forming linker between segments 5 and 6 in transmembrane domain 4 (Akai et al. 2000; Shin et al. 2007). Functional studies show that Ser1710Leu mutant channels have altered biophysical properties, which may result in diminished sodium current into the myocyte. Akai et al. (2000) and Shirai et al. (2002) showed that mutant channels expressed in human embryonic kidney cells show faster inactivation and current decay, a large hyperpolarizing shift in the voltage-dependent threshold for steady-state inactivation, a positive shift in the voltage-dependent threshold for channel activation, and delayed recovery from inactivation. Variants at nearby residues (within 10 amino acids to either side) have been associated with Brugada syndrome, suggesting the functional importance of this region of the protein. These include Thr1709Arg, Thr1709Met, Thr1709del, Gly1712Ser, Asp1714Gly (inherited arrhythmias database: Molecular Cardiology Laboratories of IRCCS Fondazione Salvatore Maugeri; GeneDx report of HGMD variants). Ser1710Leu is a nonconservative amino acid change from a polar Serine to a nonpolar Leucine. The Serine at codon 1710 is completely conserved across 39 vertebrate species examined. Surrounding residues are also very highly conserved. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be "probably damaging" (with a maximum score of 1). In total the variant has not been seen in ~6850 individuals from published reports and publicly available population datasets. There is no variation at residue 1710 listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. There is also no variation at this residue listed in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP) or 1000 genomes (http://browser.1000genomes.org/index.htm) as of June 27, 2012. The variant was not observed in published controls: Akai et al. (2000) did not find Ser1710Leu in 150 (Japanese?) controls. Shin et al. (2007) did not detect it in 200 Korean controls. GeneDx did not report controls. -

Oct 11, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM1, PS3_moderate, PS4_moderate -

Jan 12, 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 1710 of the SCN5A protein (p.Ser1710Leu). This variant is present in population databases (rs137854604, gnomAD 0.009%). This missense change has been observed in individuals with Brugada syndrome, idiopathic ventricular fibrillation, progressive familial heart block type I, sick sinus syndrome and paroxysmal familial ventricular fibrillation (PMID: 10940383, 14961552, 19026623, 22247482, 23139254, 25326637, 26798387). ClinVar contains an entry for this variant (Variation ID: 9383). 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: 10940383). For these reasons, this variant has been classified as Pathogenic. -

Aug 27, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect by causing a negative shift in the voltage-dependence of fast inactivation and slower recovery from fast inactivation compared to wildtype (PMID: 10940383); Not observed at significant frequency in large population cohorts (gnomAD); 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: 14961552, 17141278, 10940383, 22247482, 26798387, 25326637, 23139254, 30975432, 11827685, 17698727, 28150151, 19026623, 32091595, 30609406, 29625023, 28152038, 32553838, 34649698, 33221895, 36516610, 35052356) -

Brugada syndrome 1

Pathogenic:3

Jul 07, 2023

Clinical Genomics Laboratory, Stanford Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser1710Leu variant in the SCN5A gene has been previously reported in at least 4 unrelated individuals with Brugada syndrome (Shin et al., 2007; Millat et al., 2009; Lee et al., 2014; Ciconte et al., 2021), and in at least 3 unrelated individuals with various arrhythmias including sick sinus syndrome, progressive familial heart block, and ventricular fibrillation (Akai et al., 2000; Makita et al., 2012; Lee et al., 2016). This variant has been observed to segregate in at least 7 affected relatives of this individual (Stanford Medicine Clinical Genomics Lab, internal data). This variant has been identified in 3/34,592 Latino/Admixed American chromosomes (4/251,446 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is present in ClinVar (Variation ID: 9383). Functional studies of the p.Ser1710Leu variant have demonstrated that this variant results in altered sodium channel activity (Akai et al., 2000; Shirai et al., 2002). The serine at position 1710 is evolutionarily conserved. Computational tools predict that the p.Ser1710Leu variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Ser1710Leu variant as pathogenic for autosomal dominant Brugada syndrome based on the information above. [ACMG evidence codes used: PP1_Strong; PS4_Moderate; PM2; PS3_Supporting; PP3] -

Sep 10, 2013

UCLA Clinical Genomics Center, UCLA

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 17, 2017

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported in a patient with clinically diagnosed Brugada Syndrome (PMID: 10940383). Multiple clinical labs have also classified the variant as pathogenic or likely pathogenic. Functional studies demonstrate that p.Ser1710Leu channels have abnormal biophysical properties, which may result in fast inactivation dysfunction of the sodium channel (PMID: 10940383, 11827685). Ser1710Leu is located in the highly conserved pore-forming linker between segments 5 and 6 in transmembrane domain 4. Ser1710Leu results in a non-conservative amino acid substitution of a polar serine with a non-polar leucine at a position that is highly conserved across species. There are four reports of this variant in gnomAD, thus it is presumed to be rare. Based on the available evidence, the variant is classified as pathogenic. -

Brugada syndrome

Pathogenic:2

Aug 31, 2024

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 1710 in the transmembrane domain DIV 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). A functional study has shown that this variant causes alterations in channel activation and inactivation properties (PMID: 10940383). This variant has been reported in three individuals affected with Brugada syndrome (PMID: 14961552, 17141278, 19026623) and in an individual suspected of having Brugada syndrome (PMID: 25326637) in the literature. External laboratories have reported multiple carriers of this variant affected with Brugada syndrome (Clinvar SCV000235512.11, SCV000280476.1). This variant has also been observed in individuals affected with idiopathic ventricular fibrillation (PMID: 10940383), progressive familial heart block type I and idiopathic ventricular fibrillation (PMID: 22247482), paroxysmal familial ventricular fibrillation (PMID:23139254) and sick sinus syndrome (PMID: 26798387). This variant has been identified in 4/246266 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic. -

Dec 03, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser1710Leu variant in SCN5A (also referred to as p.Ser1709Leu) has been reported in at least 6 individuals with features of SCN5A-associated disorders (Akai 2000, Shin 2007, Millat 2009, Makita 2012, Lee 2014, Lee 2016). This variant has also been reported in ClinVar (Variation ID 9383) and was identified in 1/113744 European and 3/34592 Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies support an impact on protein function (Akai 2000, Shirai 2002, Millat 2009). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant SCN5A-associated disorders. ACMG/AMP Criteria applied: PM2, PS4_Moderate, PP3, PS3_Supporting. -

Ventricular fibrillation, paroxysmal familial, type 1

Pathogenic:1

Aug 11, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Jun 18, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Pathogenic:1

Jan 12, 2022

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S1710L variant (also known as c.5129C>T) is located in coding exon 27 of the SCN5A gene. This alteration results from a C to T substitution at nucleotide position 5129. The serine at codon 1710 is replaced by leucine, an amino acid with dissimilar properties. This variant has been reported in individuals with Brugada syndrome (Shin DJ et al. Life Sci, 2007 Jan;80:716-24; Millat G et al. Clin Biochem, 2009 Apr;42:491-9; Lee H et al. JAMA, 2014 Nov;312:1880-7; Ciconte G et al. Eur Heart J, 2021 03;42:1082-1090). This variant has also been detected in individuals with other SCN5A-related arrhythmias, including idiopathic ventricular fibrillation (IVF), progressive family heart block, and sick sinus syndrome (Akai J et al. FEBS Lett, 2000 Aug;479:29-34; Makita N et al. Circ Arrhythm Electrophysiol, 2012 Feb;5:163-72; Lee YS et al. Korean Circ J, 2016 Jan;46:63-71). Limited functional studies in human kidney cells have demonstrated that the alteration affected the duration of activation and inactivation of the protein (Akai J et al FEBS Lett. 2000;479(1-2):29-34 and Sharai N et al. Cardiovasc Res. 2002;53(2):348-354). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Cardiac arrhythmia

Pathogenic:1

Dec 17, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Long QT syndrome 3;C4551804:Brugada syndrome 1

Pathogenic:1

Sep 15, 2022

New York Genome Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5126C>T (aka c.5129C>T) variant in SCN5A has previously been reported in individuals with Brugada syndrome, idiopathic ventricular fibrillation, progressive familial heart block type I and sick sinus syndrome [PMID: 10940383, 19026623, 17141278 , 22247482, 26798387, 33221895] and it has been deposited in ClinVar [ClinVar ID: 9383] as Pathogenic/Likely Pathogenic. The c.5126C>T variant is observed in 8 alleles (0.0011% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), suggesting it is not a common benign variant in the populations represented in those databases. The c.5126C>T variant in SCN5A is located in exon 28 of this 28-exon gene and predicted to replace an evolutionarily conserved serine amino acid with leucine at position 1709 in the transmembrane DIV-S5/S6 region of the protein [PMID: 10940383, 30364184]. In vitro functional studies demonstrated a damaging effect by causing a negative shift in the voltage-dependence of fast inactivation and slower recovery in cells carrying c.5126C>T variant compared to wildtype [PMID:10940383, 11827685]. In silico predictions are in favor of damaging effect for p.(Ser1709Leu) (aka Ser1710Leu) variant [(CADD v1.6 = 38, REVEL = 0.958)]. Based on available evidence, this inherited c.5126C>T p.(Ser1709Leu) variant identified in SCN5A is classified as Likely Pathogenic. -

Ventricular 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 Ventricular Fibrillation, idiopathic in the following publications (PMID:10940383;PMID:11827685;PMID:17141278;PMID:22247482). 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

Pathogenic

0.91

CardioboostCm

Uncertain

0.84

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

.;.;.;.;.;D;.;.;.

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

.;D;D;D;D;D;D;.;D

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

2.0

.;.;.;.;.;M;.;.;.

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-5.5

D;D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D;D;D;D;D;D

Polyphen

1.0

D;D;.;D;.;D;D;.;.

Vest4

0.97

MutPred

0.96

.;.;Gain of helix (P = 0.062);.;.;Gain of helix (P = 0.062);.;.;.;

MVP

0.99

MPC

1.3

ClinPred

0.98

GERP RS

4.7

Varity_R

0.89

gMVP

0.99

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over