rs762012668

Variant names:

• chr3-38613791-G-A
• rs762012668
• NM_000335.5:c.655C>T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP2 PP3_Strong PP5

The NM_000335.5(SCN5A):​c.655C>T​(p.Arg219Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,458,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R219H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: SCN5A NM_000335.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:4
• Conservation: PhyloP100: 1.73

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 Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-38613790-C-T is described in Lovd as [Likely_pathogenic].
• 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, 0.993
• PP5: Variant 3-38613791-G-A is Pathogenic according to our data. Variant chr3-38613791-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 432157.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_000335.5	c.655C>T	p.Arg219Cys	missense_variant	Exon 6 of 28	ENST00000423572.7	NP_000326.2
SCN5A	NM_001099404.2	c.703+184C>T		intron_variant	Intron 6 of 27	ENST00000413689.6	NP_001092874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000423572.7	c.655C>T	p.Arg219Cys	missense_variant	Exon 6 of 28	1	NM_000335.5	ENSP00000398266.2
SCN5A	ENST00000413689.6	c.703+184C>T		intron_variant	Intron 6 of 27	5	NM_001099404.2	ENSP00000410257.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000164 AC: 4 AN: 244058 Hom.: 0 AF XY: 0.0000227 AC XY: 3 AN XY: 132234

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000294

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: 0.0000271

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1458552 Hom.: 0 Cov.: 30 AF XY: 0.0000165 AC XY: 12 AN XY: 725194

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000226

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: 0.0000171

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000189

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:2

Nov 05, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 14, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 30193851, 34461752, 33221895) -

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 219 of the SCN5A protein (p.Arg219Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Brugada syndrome and/or sick sinus syndrome (PMID: 26828384, 30193851, 33221895, 34147702, 34461752). ClinVar contains an entry for this variant (Variation ID: 432157). 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. This variant disrupts the p.Arg219 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22675453, 24762805, 26304136). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 Pathogenic:2

Aug 01, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in SCN5A is predicted to replace arginine with cysteine at codon 219, p.(Arg219Cys). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the transmembrane voltage sensing S4 region, amino acids 132-410, which is defined as a mutational hotspot and critical functional domain (PMID: 32893267). There is a large physicochemical difference between arginine and cysteine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.003% (3/110,678 alleles) in the European (non-Finnish) population. The prevalence of the variant in individuals with Brugada syndrome is significantly increased compared with the prevalence in the population (Odds ratio 15.4 95% CI: 2.6 to 92; PMID: 32893267 vs European non-Finnish gnomAD v2.1). This variant has been detected homozygous in at least two individuals, one with a diagnosis of sick sinus syndrome and in a child with Brugada syndrome (PMID: 26828384, 34147702). The heterozygous parents and sibling of one of these probands screened negative for cardiovascular disease, suggesting incomplete penetrance for the variant (PMID: 26828384). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.924). Another missense variant c.656G>A, p.(Arg219His) in the same codon with a smaller physicochemical difference has been classified as likely pathogenic and has been reported in individuals with SCN5A-related disorders (ClinVar ID: 242206). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM1, PM3, PP3, PS4_Supporting. -

Sep 27, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with cysteine at codon 219 of the SCN5A protein. This variant is found within a highly conserved region in the S4 segment of transmembrane domain DI (a.a. 132-410). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome and long QT syndrome (PMID: 32893267). A functional study has shown that this variant causes a slight inward current in Xenopus oocytes but the study was not done in great detail (PMID: 22675453). This variant has been reported in homozygosity in an individual affected with juvenile-onset sick sinus syndrome (PMID: 26828384) and in another young individual affected with Brugada syndrome (PMID: 34147702). This variant has also been reported in heterozygous state in a few other individuals affected with or suspected of having Brudaga syndrome (PMID: 29325976, 30193851, 32893267, 33221895), epilepsy (PMID: 31696929), or bradycardia (communication with an external laboratory; ClinVar SCV000589845.4). This variant has been identified in 4/244058 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg219His, is reported to be disease-causing (ClinVar variation ID: 242206), indicating that arginine at this position is important for SCN5A protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -

Cardiac arrhythmia Pathogenic:1

Nov 16, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with cysteine at codon 219 of the SCN5A protein. This variant is found within a highly conserved region in the S4 segment of transmembrane domain DI (a.a. 132-410). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome and long QT syndrome (PMID: 32893267). A functional study has shown that this variant causes a slight inward current in Xenopus oocytes but the study was not done in great detail (PMID: 22675453). This variant has been reported in homozygosity in an individual affected with juvenile-onset sick sinus syndrome (PMID: 26828384) and in another young individual affected with Brugada syndrome (PMID: 34147702). This variant has also been reported in heterozygous state in a few other individuals affected with or suspected of having Brudaga syndrome (PMID: 29325976, 30193851, 32893267, 33221895), epilepsy (PMID: 31696929), or bradycardia (communication with an external laboratory; ClinVar SCV000589845.4). This variant has been identified in 4/244058 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg219His, is reported to be disease-causing (ClinVar variation ID: 242206), indicating that arginine at this position is important for SCN5A protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -

Brugada syndrome 1 Uncertain:1

-

Roden Lab, Vanderbilt University Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: in vitro;research

We classified this variant using data from the calibrated functional assay 'ParSE-seq' (PMID: 37732247), population data, and in silico data within the ACMG v3 framework (PMID: 25741868)The SCN5A variant, 3-38613791-G-A was evaluated for association with the loss-of-function condition Brugada Syndrome.This Variant had an AF of 0 in gnomAD v3The in silico predictor SpliceAI scored the variant as 0.3443; normal <0.2, likely damaging >0.5.Using the functional RNA-splicing assay, ParSE-seq, the variant was evaluated to have a strong negative impact on splicing (PS3_strong) following the Brnich et al. calibration framework (PMID: 31892348). In aggregate, we therefore classify this variant as VUS using these collective data. -

Cardiovascular phenotype Uncertain:1

Nov 18, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R219C variant (also known as c.655C>T), located in coding exon 5 of the SCN5A gene, results from a C to T substitution at nucleotide position 655. The arginine at codon 219 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the transmembrane DI-S4 region. This variant has been detected in the homozygous state in an individual with sick sinus syndrome, and in the heterozygous state in three unaffected relatives (De Regibus V et al. Int J Cardiol, 2016 Apr;208:67-9). This variant has also been detected in an individual reported to have Brugada syndrome; however, details were limited (Berthome P et al. Heart Rhythm, 2019 02;16:260-267). A different variant affecting this codon (p.R219H c.656G>A) has been reported in association with SCN5A-related arrhythmia and cardiomyopathy (Gosselin-Badaroudine P et al. PLoS ONE. 2012;7:e38331; Abe K et al. Circ Arrhythm Electrophysiol. 2014;7:511-7; Robles C et al. Rev Esp Cardiol (Engl Ed). 2015;68:904-6). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
CardioboostCm	Uncertain	0.82
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	.;D;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.4	H;H;.
PROVEAN	Pathogenic	-7.8	D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.97
MutPred		0.89		Loss of MoRF binding (P = 0.0262);Loss of MoRF binding (P = 0.0262);Loss of MoRF binding (P = 0.0262);
MVP		0.99
ClinPred		0.98	D
GERP RS		4.3
Varity_R		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs762012668; hg19: chr3-38655282; COSMIC: COSV61116418; COSMIC: COSV61116418;