3-38597755-C-T

Variant names:

• chr3-38597755-C-T
• rs199473582
• NM_001099404.2:c.2236G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_000335.5(SCN5A):​c.2236G>A​(p.Glu746Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,608,482 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: SCN5A NM_000335.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8 O:1
• Conservation: PhyloP100: 1.39

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a helix (size 25) in uniprot entity SCN5A_HUMAN there are 4 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, 0.748

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.2236G>A	p.Glu746Lys	missense_variant	Exon 14 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.2236G>A	p.Glu746Lys	missense_variant	Exon 14 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.2236G>A	p.Glu746Lys	missense_variant	Exon 14 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.2236G>A	p.Glu746Lys	missense_variant	Exon 14 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152202 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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000201 AC: 5 AN: 248406 Hom.: 0 AF XY: 0.0000223 AC XY: 3 AN XY: 134666

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000581

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: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000117 AC: 17 AN: 1456162 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 723200

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000349

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000993

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.0000268 AC XY: 2 AN XY: 74490

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000307 Hom.: 0

Bravo AF: 0.0000113

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000219

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiac arrhythmia Uncertain:2

Mar 24, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glutamic acid with lysine at codon 746 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). Functional studies have shown that this variant causes a partial reduction in peak current density in cultured cells (PMID: 32533946, O'Neill et al. 2021, DOI: 10.1101/2021.09.22.461398). This variant has been reported in at least five unrelated individuals affected with Brugada syndrome (PMID: 20129283, 32268277, 32893267). This variant has also been reported in two individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 18304999) or inherited heart diseases (O'Neill et al. 2021, DOI:10.4081/cardiogenetics.2013.e5), and in an individual suspected of having inherited arrhythmia syndrome (PMID: 22956155). This variant has been identified in 6/279818 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. -

Mar 05, 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 glutamic acid with lysine at codon 746 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). Functional studies have shown that this variant causes a partial reduction in peak current density in cultured cells (PMID: 32533946, O'Neill et al. 2021, DOI: 10.1101/2021.09.22.461398). This variant has been reported in at least five unrelated individuals affected with Brugada syndrome (PMID: 20129283, 32268277, 32893267). This variant has also been reported in two individuals affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 18304999) or inherited heart diseases (O'Neill et al. 2021, DOI:10.4081/cardiogenetics.2013.e5), and in an individual suspected of having inherited arrhythmia syndrome (PMID: 22956155). This variant has been identified in 6/279818 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. -

Brugada syndrome Uncertain:1 Other:1

Oct 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 746 of the SCN5A protein (p.Glu746Lys). This variant is present in population databases (rs199473582, gnomAD 0.008%). This missense change has been observed in individuals with clinical features of SCN5A-related conditions (PMID: 18304999, 20129283, 30193851; Invitae). ClinVar contains an entry for this variant (Variation ID: 67721). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects SCN5A function (PMID: 32533946). 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 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:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

not specified Uncertain:1

Nov 20, 2023

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.2236G>A (p.Glu746Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 248406 control chromosomes (gnomAD). c.2236G>A has been reported in the literature in individuals affected with Brugada Syndrome or cardiomyopathy without strong evidence of causality (Peters_2008, Kapplinger_2010, Berthome_2019). These reports do not provide unequivocal conclusions about association of the variant with Brugada Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function, finding that it disrupts normal activity (Glazer_2020). The following publications have been ascertained in the context of this evaluation (PMID: 18304999, 20129283, 30193851, 32533946). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Brugada syndrome 1 Uncertain:1

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Nov 02, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Aug 13, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in association with Brugada syndrome and LQTS in published literature (PMID: 20129283, 30193851, 37547970); Identified in a patient with ARVC who also exhibited provocable coved-type ST-segment elevation in right precordial leads on ECG (PMID: 18304999); Published functional studies suggest a significantly reduced current density compared to wildtype (PMID: 32533946); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26332594, 22956155, 34426522, 30662450, 30193851, 20129283, 32533946, 18304999, 30203441, 37547970) -

Cardiovascular phenotype Uncertain:1

May 08, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E746K variant (also known as c.2236G>A), located in coding exon 13 of the SCN5A gene, results from a G to A substitution at nucleotide position 2236. The glutamic acid at codon 746 is replaced by lysine, an amino acid with similar properties. In one study, this variant was detected in an individual with features suggestive of arrhythmogenic right ventricular cardiomyopathy (ARVC) and Brugada syndrome (BrS) in whom ARVC gene analysis was limited (Peters S. Europace, 2008 Jul;10:816-20). This variant has also been detected in BrS cohorts; however, clinical details were limited and some case reports may overlap (Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46; Berthome P et al. Heart Rhythm, 2019 Feb;16:260-267; Campuzano O et al. EBioMedicine, 2020 Apr;54:102732; Glazer AM et al. Am J Hum Genet, 2020 Jul;107:111-123; Walsh R et al. Genet Med, 2021 Jan;23:47-58). One in vitro study indicated this variant may impact protein function; however, additional evidence is needed to confirm this finding (Glazer AM et al. Am J Hum Genet, 2020 Jul;107:111-123). 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	0.17
CardioboostCm	Benign	0.0065
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.30
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	.;.;.;.;.;D;.;.;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.90	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Benign	1.6	.;L;.;.;.;L;.;.;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.7	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.63
Sift	Benign	0.31	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.43	T;T;T;T;T;T;T;T;T
Polyphen		0.091	B;B;.;B;.;B;B;.;.
Vest4		0.84
MVP		0.95
MPC		0.43
ClinPred		0.25	T
GERP RS		3.8
Varity_R		0.18
gMVP		0.98

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

Publications

LitVar

Other links and lift over

dbSNP: rs199473582; hg19: chr3-38639246; COSMIC: COSV61120961;