3-38551334-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP2PP3

The NM_000335.5(SCN5A):c.5035G>A(p.Ala1679Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000682 in 1,613,912 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 0.000086 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

SCN5A
NM_000335.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1O:1

Conservation

PhyloP100: 3.36

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 Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a repeat IV (size 297) in uniprot entity SCN5A_HUMAN there are 68 pathogenic changes around while only 2 benign (97%) 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, 0.802

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2 link	c.5038G>A	p.Ala1680Thr	missense_variant	Exon 28 of 28	ENST00000413689.6	NP_001092874.1	Q14524H9KVD2
SCN5A	NM_000335.5 link	c.5035G>A	p.Ala1679Thr	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.5038G>A	p.Ala1680Thr	missense_variant	Exon 28 of 28	5	NM_001099404.2	ENSP00000410257.1		H9KVD2
SCN5A	ENST00000423572.7 link	c.5035G>A	p.Ala1679Thr	missense_variant	Exon 28 of 28	1	NM_000335.5	ENSP00000398266.2		Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152018

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251494

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000527

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000664

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.0000729

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000927

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.0000665

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.0000855

AC:

AN:

152018

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74212

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000114

Hom.:

Bravo

AF:

0.0000869

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

May 09, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in individuals with sudden adult death syndrome and in several individuals with definite or probable Brugada syndrome (Hofman-Bang et al., 2006; Kapplinger et al., 2010; Stefek et al., 2018; Bennett et al., 2019; Miles et al., 2021); Also reported in family members of individuals with sudden cardiac death (Behr et al., 2008; Lambiase et al., 2009; Papadakis et al., 2013); however, p.(A1680T) did not segregate with the disease phenotype in one publication, suggesting it could be a polymorphism (Behr et al., 2008); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional patch clamp studies found no damaging effect (Glazer et al., 2020; Pearman et al., 2020); This variant is associated with the following publications: (PMID: 23631430, 19564561, 20129283, 18508782, 31535183, 30254039, 33131149, 23671135, 34620408, 16712702, 32746448, 32533946) -

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SCN5A: PM2 -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1680 of the SCN5A protein (p.Ala1680Thr). This variant is present in population databases (rs199473294, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 16712702, 18508782, 19564561, 20129283, 23631430, 23671135, 30254039, 32533946). ClinVar contains an entry for this variant (Variation ID: 67952). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 32533946) did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN5A function. 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. -

Brugada syndrome

Uncertain:2Other:1

Aug 16, 2019

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ala1680Thr variant in SCN5A has been identified in 1 individual with sudden adult death syndrome (SADS) and 5 individuals with suspected or established Brugada syndrome (Hofman-Bang 2006, Behr 2008, Lambiase 2009, Kapplinger 2010, Lieve 2013) and by our laboratory in 1 individual with a complex presentation (biventricular cardiomyopathy, VT, Brugada/ARVC pattern EKG) who carried a second, likely pathogenic variant in the DSP gene. Both variants were present in a sib with reduced ejection fraction but also in the unaffected mother. This variant is also present in a relative with Afib palpations and syncope. The p.Ala1680Thr variant reportedly did not segregate with disease in one family though no data was provided (Behr 2008). Non-segregation with disease raises some concern on whether the variant can cause disease. It has been identified in 9/126710 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs199473294). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Ala1680Thr variant is uncertain. -

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:16712702;PMID:18508782;PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Cardiovascular phenotype

Uncertain:1

Oct 13, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5038G>A (p.A1680T) alteration is located in coding exon 27 of the SCN5A gene results from a G to A substitution at nucleotide position 5038, causing the Alanine (A) at amino acid position 1680 to be replaced by a Threonine (T). This alteration has been described in several patients; however, the available clinical information in the literate is often limited. This alteration has been reported in heterozygous state in a patient with Sudden Adult Death Syndrome (SADS) (Hofman-Bang, 2006) as well as in two other unrelated patients with Brugada syndrome (Kapplinger, 2010) and in a patient with Long QT syndrome (Lieve, 2013). This variant is reported in the SNP Database as rs199473294. Based on data from ExAC, the c.5038G>A allele has an overall frequency of approximately 0.002% (3/121408). Based on data from the NHLBI Exome Sequencing Project (ESP), the SCN5A c.5038G>A alteration was not observed among 6503 individuals tested (0.0%). Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project. The p.A1680T amino acid is very well conserved in the available vertebrate species. In addition, this alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Based on the majority of available evidence to date, the c.5038G>A (p.A1680T) variant is likely to be pathogenic._x000D_ _x000D_ Hofman-Bang J, et al. (2006) Clin Genet 69: 504–511_x000D_ _x000D_ Kapplinger J, et al. (2010) Heart Rhythm7(1):33-46_x000D_ _x000D_ Lieve KV, et al. (2013) Genet Test Mol Biomarkers. 17(7):553-61 Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Cardiac arrhythmia

Uncertain:1

Nov 20, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces alanine with threonine at codon 1680 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in three individuals affected with Brugada syndrome (PMID: 19564561, 30254039, 34620408) and in two individuals affected with sudden death (PMID: 16712702, 18508782). In one of these families, it was stated that this variant did not segregate with the disease phenotype (PMID: 18508782). This variant has been reported in individuals suspected to be affected with Brugada syndrome (PMID: 20129283, 23631430, 23671135). This variant has been identified in 13/282862 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Sudden cardiac death

Benign:1

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

CardioboostCm

Uncertain

0.10

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.52

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

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

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

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

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.80

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

.;.;.;.;.;H;.;.;.

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.4

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

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.033

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

Polyphen

1.0

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

Vest4

0.46

MVP

0.96

MPC

0.79

ClinPred

0.98

GERP RS

4.1

Varity_R

0.80

gMVP

0.98

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