3-38551334-C-T

Position:

• chr3-38551334-C-T

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.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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1 O:1
• Conservation: PhyloP100: 3.36

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 (HGNC:):

ACMG classification

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 gene, where missense usually causes diseases (based on misZ statistic), SCN5A. . Gene score misZ 2.7504 (greater than the threshold 3.09). Trascript score misZ 4.8279 (greater than threshold 3.09). GenCC has associacion of gene with 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/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.5038G>A	p.Ala1680Thr	missense_variant	28/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.5035G>A	p.Ala1679Thr	missense_variant	28/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.5038G>A	p.Ala1680Thr	missense_variant	28/28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.5035G>A	p.Ala1679Thr	missense_variant	28/28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152018 Hom.: 0 Cov.: 31

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: 10 AN: 251494 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135920

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: 97 AN: 1461894 Hom.: 0 Cov.: 35 AF XY: 0.0000729 AC XY: 53 AN XY: 727248

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: 13 AN: 152018 Hom.: 0 Cov.: 31 AF XY: 0.0000808 AC XY: 6 AN XY: 74212

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.: 0

Bravo AF: 0.0000869

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Brugada syndrome Uncertain:3 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 31, 2022	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). 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 disruptive. 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. -
not provided, no classification provided	literature only	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	-	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2019	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Aug 16, 2019	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	SCN5A: PM2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2022	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) -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2022

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

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 20, 2023

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

Likely benign, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
CardioboostCm	Uncertain	0.10
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.52
CADD	Benign	20
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	.;.;.;.;.;D;.;.;.
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	.;.;.;.;.;H;.;.;.
PrimateAI	Uncertain	0.68	T
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	D
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

Other links and lift over

dbSNP: rs199473294; hg19: chr3-38592825; COSMIC: COSV61115988; COSMIC: COSV61115988;