3-38551513-G-A

Variant names:

• chr3-38551513-G-A
• rs199473282
• NM_001099404.2:c.4859C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_001099404.2(SCN5A):​c.4859C>T​(p.Thr1620Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 15/24 in silico tools predict a damaging 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. T1620K) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:2
• Conservation: PhyloP100: 8.13
• Publications: 74 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 16 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 uncertain in NM_001099404.2
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-38551513-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 67931.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 3-38551513-G-A is Pathogenic according to our data. Variant chr3-38551513-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 67932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001099404.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN5A	NM_001099404.2	MANE Plus Clinical	c.4859C>T	p.Thr1620Met	missense	Exon 28 of 28	NP_001092874.1
	SCN5A	NM_000335.5	MANE Select	c.4856C>T	p.Thr1619Met	missense	Exon 28 of 28	NP_000326.2
	SCN5A	NM_198056.3		c.4859C>T	p.Thr1620Met	missense	Exon 28 of 28	NP_932173.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCN5A	ENST00000413689.6	TSL:5 MANE Plus Clinical	c.4859C>T	p.Thr1620Met	missense	Exon 28 of 28	ENSP00000410257.1
	SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.4856C>T	p.Thr1619Met	missense	Exon 28 of 28	ENSP00000398266.2
	SCN5A	ENST00000333535.9	TSL:1	c.4859C>T	p.Thr1620Met	missense	Exon 28 of 28	ENSP00000328968.4

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152020 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250918 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461708 Hom.: 0 Cov.: 35 AF XY: 0.0000110 AC XY: 8 AN XY: 727136

African (AFR) AF: 0.00 AC: 0 AN: 33478

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1111872

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152020 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74246

African (AFR) AF: 0.00 AC: 0 AN: 41382

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Jun 03, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in association with Brugada syndrome, DCM, and unexplained sudden cardiac death (SCD) in published literature (PMID: 23785128, 15520322, 20129283, 34076677); Multiple studies have examined the functional effect of the p.(T1620M) variant, with the general conclusion that this variant impacts sodium ion channel function (PMID: 11827685, 9521325, 10532948, 10618304); 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: 11786529, 10618304, 11013131, 23785128, 29728395, 30662450, 30847666, 20129283, 10532948, 11029409, 11123251, 9521325, 34135346, 33131149, 11827685, 15520322, 38926839, 34076677, 30203441)

Jan 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1620 of the SCN5A protein (p.Thr1620Met). This variant is present in population databases (rs199473282, gnomAD 0.0009%). This missense change has been observed in individual(s) with Brugada syndrome and/or clinical features of SCN5A-related conditions (PMID: 9521325, 15520322, 20129283, 23785128, 29728395, 30847666, 34076677). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67932). 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: 9521325, 10532948, 10618304, 11029409, 11123251, 11827685). For these reasons, this variant has been classified as Pathogenic.

Brugada syndrome 1 Pathogenic:1 Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Jun 15, 2022

Institute of Human Genetics, Heidelberg University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

reported as secondary finding

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:9521325;PMID:20129283;PMID:10618304;PMID:15520322;PMID:11013131). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

Jun 09, 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 threonine with methionine at codon 1620 of the SCN5A protein. This variant is found within the highly conserved transmembrane domain DIV (a.a.1530-1771). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome(PMID: 32893267). Functional studies have generally shown that this variant alters the sodium channel function (PMID: 9521325, 10532948, 10618304, 11029409, 11123251, 11827685, 30050137). This variant has been reported in multiple unrelated individuals affected with Brugada syndrome (PMID: 15520322, 20129283, 25904541), as well as in an individual affected with fever-induced Brugada syndrome (PMID: 36516610). It has been shown that this segregates with disease in six relatives from a family (PMID: 9521325, 10662748, 15520322). This variant has been identified in 1/250918 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

SUDDEN INFANT DEATH SYNDROME;C1832680:Dilated cardiomyopathy 1E;C1837845:Sick sinus syndrome 1;C1859062:Long QT syndrome 3;C1879286:Progressive familial heart block, type 1A;C2751898:Ventricular fibrillation, paroxysmal familial, type 1;C3151464:Atrial fibrillation, familial, 10;C4551804:Brugada syndrome 1 Pathogenic:1

Jul 01, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiac arrhythmia Pathogenic:1

Apr 15, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with methionine at codon 1620 of the SCN5A protein. This variant is found within the highly conserved transmembrane domain DIV (a.a.1530-1771). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome(PMID: 32893267). Functional studies have generally shown that this variant alters the sodium channel function (PMID: 9521325, 10532948, 10618304, 11029409, 11123251, 11827685, 30050137). This variant has been reported in multiple unrelated individuals affected with Brugada syndrome (PMID: 15520322, 20129283, 25904541), as well as in an individual affected with fever-induced Brugada syndrome (PMID: 36516610). It has been shown that this segregates with disease in six relatives from a family (PMID: 9521325, 10662748, 15520322). This variant has been identified in 1/250918 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
CardioboostArm	Pathogenic	1.0
CardioboostCm	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		8.1
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.88
MutPred		0.94		Gain of MoRF binding (P = 0.0977)
MVP		0.99
MPC		1.3
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.85
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: rs199473282; hg19: chr3-38593004; COSMIC: COSV104413440; COSMIC: COSV104413440;