rs199473624

chr3-38551447-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_001099404.2(SCN5A):c.4925G>A(p.Gly1642Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G1642G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4 O:1
• Conservation: PhyloP100: 7.89

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 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_001099404.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SCN5A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.4925G>A	p.Gly1642Glu	missense_variant	28/28	ENST00000413689.6
SCN5A	NM_000335.5	c.4922G>A	p.Gly1641Glu	missense_variant	28/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.4925G>A	p.Gly1642Glu	missense_variant	28/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.4922G>A	p.Gly1641Glu	missense_variant	28/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461878 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000166

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 14, 2023	Identified in patients with Brugada syndrome referred for genetic testing at GeneDx and in published literature (Kapplinger et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a significant reduction in current density and alteration of other electrophysiological parameters (Glazer et al., 2020); 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: 25904541, 30203441, 30662450, 20129283, 32533946) -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 10, 2023	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1642 of the SCN5A protein (p.Gly1642Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 20129283, 32533946, 36578016; Invitae). ClinVar contains an entry for this variant (Variation ID: 67940). Advanced modeling performed at Invitae incorporating data from internal and/or published 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. -

Sudden unexplained death Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Mar 07, 2018

SCN5A Gly1642Glu has been previously identified in 1 patient referred for Brugada Syndrome genetic testing (Kapplinger et al., 2010) and 1 sudden unexplained death in a teenager (Ambry, Pers. Comm.). We identified this variant in a patient who also suffered a sudden unexplained death and who has a family history of Brugada Syndrome. The variant was found to segregate with disease in our family (3 meiosis). SCN5A Gly1642Glu is absent in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). In silico tools PolyPhen2, SIFT and MutationTaster all predict that this variant is disease causing. In summary this variant is rare in the general population, has been observed in at least 1 other case of Brugada Syndrome and 1 case of SUD, and multiple in silico tools predict it to be deleterious, therefore we classify SCN5A Gly1642Glu as a variant of 'uncertain significance". -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2016

The p.G1642E variant (also known as c.4925G>A), located in coding exon 27 of the SCN5A gene, results from a G to A substitution at nucleotide position 4925. The glycine at codon 1642 is replaced by glutamic acid, an amino acid with similar properties, and is located in the DIV-S4 transmembrane region of the protein. In a study of Brugada syndrome clinical genetic testing, this alteration was detected with another SCN5A variant in one individual; however, clinical details were limited (Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Brugada syndrome Other:1

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:20129283). 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	0.99
CardioboostArm	Pathogenic	1.0
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-7.4	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.99
Sift	Uncertain	0.022	D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;D;D;.;.
Vest4		0.85
MutPred		0.95		.;.;Loss of MoRF binding (P = 0.0558);.;.;Loss of MoRF binding (P = 0.0558);.;.;.;
MVP		0.99
MPC		1.6
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.93
gMVP		1.0

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: rs199473624; hg19: chr3-38592938; COSMIC: COSV61123957; COSMIC: COSV61123957;