rs199473207

chr3-38566555-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate

The NM_001099404.2(SCN5A):c.3694C>T(p.Arg1232Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,594 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1232Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5 O:2
• Conservation: PhyloP100: 0.612

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 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_001099404.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-38566554-C-T is described in Lovd as [Pathogenic].
• PP2: Missense variant where missense usually causes diseases, SCN5A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.3694C>T	p.Arg1232Trp	missense_variant	21/28	ENST00000413689.6
SCN5A	NM_000335.5	c.3691C>T	p.Arg1231Trp	missense_variant	21/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.3694C>T	p.Arg1232Trp	missense_variant	21/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.3691C>T	p.Arg1231Trp	missense_variant	21/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461594 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727088

Gnomad4 AFR exome AF: 0.0000299

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.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 13, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 15, 2022	Identified in one family with idiopathic ventricular fibrillation, who also harbored the T1620M variant on the same SCN5A allele (in cis); functional studies suggested that T1620M is probably disease-causing and that R1232W is a possible rare polymorphism because it did not alter the current voltage activity of the sodium channel (Chen et al., 1998); Another functional study demonstrated that the presence of a positively charged amino acid at position 1232 was essential for the proper trafficking of the sodium channel protein to the cell surface, and that the double mutant (R1232W/T1620M) showed abnormal functional sodium channel expression (Baroudi et al., 2002); However, Makita et al. (2008) reported R1232W/T1620M did not affect protein trafficking in their expression studies, contradicting the functional effect reported by Baroudi et al. (2002); 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: 29728395, 12454206, 24136861, 25904541, 16864729, 14961552, 11417215, 11013131, 19251209, 20129283, 26173111, 11786529, 21321465, 30193851, 18503232, 9521325, 33131149) -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 18, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1232 of the SCN5A protein (p.Arg1232Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 9521325, 19251209, 20129283, 21321465, 26173111, 30193851). ClinVar contains an entry for this variant (Variation ID: 67813). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on SCN5A function (PMID: 9521325, 11013131, 11417215, 11786529, 18503232). 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 phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2018

The p.R1232W variant (also known as c.3694C>T), located in coding exon 20 of the SCN5A gene, results from a C to T substitution at nucleotide position 3694. The arginine at codon 1232 is replaced by tryptophan, an amino acid with dissimilar properties, and is located in the transmembrane-spanning DIII-S1/S2 domain. This variant was detected in an individual with ECG findings consistent with Brugada syndrome (BrS); testing in family members revealed three symptomatic carriers and one unaffected carrier, who was young at the time of cardiac evaluation (Selga E et al. PLoS ONE, 2015 Jul;10:e0132888). In addition, this variant was described in a BrS case with a p.R1232W SCN5A variant also detected (Nakajima T et al. Int Heart J, 2011;52:27-31). It has also been reported in cis with an SCN5A p.T1620M variant in multiple affected individuals from one family with idiopathic ventricular fibrillation; however, functional and localization studies in R1232W/T1620M cells have shown conflicting results (Chen Q et al. Nature, 1998 Mar;392:293-6; Wan X et al. J. Mol. Cell. Cardiol., 2000 Oct;32:1873-84; Baroudi G et al. Circ. Res., 2002 Jan;90:E11-6; Makita N et al. Circ. J., 2008 Jun;72:1018-9). An alternate amino acid substitution at this position, p.R1232Q, was also reported in Brugada syndrome cohorts where clinical details were limited (Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46; Conte G et al. J. Cardiovasc. Electrophysiol., 2014 May;25:514-519; Conte G et al. J. Am. Coll. Cardiol., 2014 Jun;63:2272-9). 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. -

Cardiac arrhythmia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 25, 2020

This missense variant replaces arginine with tryptophan at codon 1232 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). Functional studies have shown that this variant does not adversely affect protein trafficking and channel function (PMID: 9521325, 18503232). This variant has been reported in a family affected with idiopathic ventricular fibrillation (PMID: 9521325). All eight affected individuals from this family carried this variant and p.Thr1620Met in cis. This variant has been reported in an individual affected with cardiac conduction disease (PMID: 19251209) and two individuals affected with Brugada syndrome (PMID: 20129283, 21321465). This variant has not been identified 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 1 Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

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:9521325;PMID:19251209;PMID:20129283;PMID:21321465). 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	0.59
CardioboostArm	Pathogenic	1.0
CardioboostCm	Uncertain	0.79
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.82	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	0.98	A;A;A;A;A;A;A;A;A;A
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-7.1	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;D;D;.;.
Vest4		0.85
MutPred		0.65		Loss of methylation at K1236 (P = 0.032);.;Loss of methylation at K1236 (P = 0.032);Loss of methylation at K1236 (P = 0.032);.;Loss of methylation at K1236 (P = 0.032);.;.;.;
MVP		0.92
MPC		1.4
ClinPred		1.0	D
GERP RS		2.7
Varity_R		0.91
gMVP		0.91

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: rs199473207; hg19: chr3-38608046; COSMIC: COSV100346639;