rs199473083

Variant names:

• chr3-38609823-C-T
• rs199473083
• NM_001099404.2:c.845G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM5 PP3_Strong PP5_Very_Strong

The NM_001099404.2(SCN5A):​c.845G>A​(p.Arg282His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,618 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R282C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:2
• Conservation: PhyloP100: 1.72
• Publications: 36 publications found

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 Gene-Disease associations (from GenCC):

• Brugada syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Brugada syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1E

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• sick sinus syndrome 1

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• progressive familial heart block, type 1A

  Inheritance: SD, AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp
• atrial standstill

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial sick sinus syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• paroxysmal familial ventricular fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• progressive familial heart block

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• short QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-38609824-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 68047.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96
• PP5: Variant 3-38609823-C-T is Pathogenic according to our data. Variant chr3-38609823-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 68048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.845G>A	p.Arg282His	missense_variant	Exon 7 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.845G>A	p.Arg282His	missense_variant	Exon 7 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.845G>A	p.Arg282His	missense_variant	Exon 7 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.845G>A	p.Arg282His	missense_variant	Exon 7 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 249398 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461618 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727098

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53230

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111944

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Jun 09, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 282 of the SCN5A protein (p.Arg282His). This variant is present in population databases (rs199473083, gnomAD 0.006%). This missense change has been observed in individuals with Brugada syndrome (PMID: 11901046, 15828879, 28341781). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 68048). 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 have shown that this missense change affects SCN5A function (PMID: 15828879, 16864729). For these reasons, this variant has been classified as Pathogenic. -

Jul 14, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect as this variant results in significant reduction of sodium current density in SCN5A channels (PMID: 15828879, 16864729, 21840964); 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: 27153395, 15828879, 21840964, 22581653, 28341781, 30662450, 20625312, 32893267, 29574140, 33131149, 30203441, 31440721, 35305865, 36516610, 36204818, 16864729, 11901046) -

Nov 27, 2020

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 02, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Brugada syndrome Pathogenic:1 Other:1

-

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:11901046;PMID:15828879;PMID:21840964). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

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 histidine at codon 282 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 causes a large reduction in sodium channel current due to the defect in trafficking to cell surface (PMID: 15828879, 16864729, 21840964, 35305865). This variant has been reported in at least nine unrelated individuals affected with Brugada syndrome (PMID: 11901046, 20625312, 28341781, 30662450, 32893267). This variant has been shown to segregate with disease in five individuals affected with Brugada syndrome in two families and also seen in one unaffected family member (PMID: 14607451, 15828879, 16864729). This variant has been identified in 4/249398 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Jan 20, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.845G>A (p.R282H) alteration is located in exon 7 (coding exon 6) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 845, causing the arginine (R) at amino acid position 282 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of 0.0016% (4/249398) total alleles studied. The highest observed frequency was 0.0056% (1/17976) of East Asian alleles. This alteration has been reported in several individuals with Brugada syndrome (Priori, 2002; Itoh, 2005; Poelzing, 2006; Pitzalis, 2003; Sonoda, 2018; Yamagata, 2017). Additionally, some studies have suggested co-occurrence with a different SCN5A alteration (H558R), a common polymorphism, may rescue the function of the mutant channel protein, which may partially account for the reduced penetrance observed for the variant in disease (Poelzing, 2006; Shinlapawittayatorn, 2011). This amino acid position is highly conserved in available vertebrate species. In vitro functional studies have demonstrated the alteration has a deleterious impact on sodium channel function (Itoh, 2005; Poelzing, 2006). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Cardiac arrhythmia Pathogenic:1

Dec 11, 2024

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 histidine at codon 282 of the SCN5A protein. This variant is found within the highly conserved pore-forming region of transmembrane domain DI (a.a. 277-389). 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). Functional studies have shown that this variant causes a large reduction in sodium channel current due to the defect in trafficking to cell surface (PMID: 15828879, 16864729, 21840964, 35305865). This variant has been reported in at least nine unrelated individuals affected with Brugada syndrome (PMID: 11901046, 20625312, 28341781, 30662450, 32893267). This variant has been shown to segregate with disease in five individuals affected with Brugada syndrome in two families and also seen in one unaffected family member (PMID: 14607451, 15828879, 16864729). This variant has also been reported in an individual affected with dilated cardiomyopathy (PMID: 29095814) and in another individual affected with fever-induced Brugada syndrome (PMID: 36516610). This variant has been identified in 4/249398 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Brugada syndrome 1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
CardioboostArm	Benign	0.013
CardioboostCm	Uncertain	0.16
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	.;.;.;.;.;D;.;.;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.5	.;L;.;.;.;L;.;.;.
PhyloP100		1.7
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.5	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0090	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.018	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;D;D;.;.
Vest4		0.87
MutPred		0.89		Gain of catalytic residue at N283 (P = 0.0428);Gain of catalytic residue at N283 (P = 0.0428);Gain of catalytic residue at N283 (P = 0.0428);Gain of catalytic residue at N283 (P = 0.0428);Gain of catalytic residue at N283 (P = 0.0428);Gain of catalytic residue at N283 (P = 0.0428);Gain of catalytic residue at N283 (P = 0.0428);Gain of catalytic residue at N283 (P = 0.0428);Gain of catalytic residue at N283 (P = 0.0428);
MVP		0.96
MPC		1.3
ClinPred		0.89	D
GERP RS		5.3
Varity_R		0.46
gMVP		0.95
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs199473083; hg19: chr3-38651314; COSMIC: COSV61118240; COSMIC: COSV61118240;