3-38581170-C-T

Variant names:

• chr3-38581170-C-T
• rs137854609
• NM_001099404.2:c.2989G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM5 BP4_Strong

The NM_001099404.2(SCN5A):​c.2989G>A​(p.Ala997Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000739 in 1,611,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign 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. A997S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:17 B:1 O:1
• Conservation: PhyloP100: -3.52
• Publications: 25 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: Likely_benign. The variant received -2 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-38581170-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 9388.
• BP4: Computational evidence support a benign effect (MetaRNN=0.05895406).

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.2989G>A	p.Ala997Thr	missense	Exon 17 of 28	NP_001092874.1
	SCN5A	NM_000335.5	MANE Select	c.2989G>A	p.Ala997Thr	missense	Exon 17 of 28	NP_000326.2
	SCN5A	NM_198056.3		c.2989G>A	p.Ala997Thr	missense	Exon 17 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.2989G>A	p.Ala997Thr	missense	Exon 17 of 28	ENSP00000410257.1
	SCN5A	ENST00000423572.7	TSL:1 MANE Select	c.2989G>A	p.Ala997Thr	missense	Exon 17 of 28	ENSP00000398266.2
	SCN5A	ENST00000333535.9	TSL:1	c.2989G>A	p.Ala997Thr	missense	Exon 17 of 28	ENSP00000328968.4

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152018 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.000250

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000792 AC: 19 AN: 239824 AF XY: 0.000107

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000590

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000149

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000665 AC: 97 AN: 1459124 Hom.: 0 Cov.: 36 AF XY: 0.0000730 AC XY: 53 AN XY: 725724

African (AFR) AF: 0.0000299 AC: 1 AN: 33466

American (AMR) AF: 0.0000675 AC: 3 AN: 44416

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85970

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52838

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.0000783 AC: 87 AN: 1110772

Other (OTH) AF: 0.0000830 AC: 5 AN: 60220

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152018 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74260

African (AFR) AF: 0.0000242 AC: 1 AN: 41392

American (AMR) AF: 0.000262 AC: 4 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000869

ExAC AF: 0.000108 AC: 13

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:17 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:5

Mar 29, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ala997Thr variant in SCN5A has been reported in 1 adult with Brugada syndrome (Kapplinger 2010, Conte 2014). Another variant at this position (Ala997Ser) has been reported in 1 infant with SIDS (absence in a large number of controls and in vitro functional studies supported pathogenicity though, though these assays may not accurately represent biological function; Ackerman 2001). Data from large population studies is insufficient to assess the frequency of this variant. Computational prediction tools and conservation analysis suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, additional information is needed to fully assess the clinical significance of the Ala997Thr variant.

Aug 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SCN5A: PM5:Supporting, BP4

May 17, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A variant of uncertain significance has been identified in the SCN5A gene. The A997T variant has been reported in two individuals with a definitive or suspected diagnosis of Brugada syndrome (Krahn et al. 2009; Kapplinger et al., 2010; Conte et al., 2014). Ng et al. (2013) identified A997T as a secondary finding via exome sequencing of ClinSeq participants. The individual was subsequently found to have an abnormal EKG with sinus bradycardia and right atrial abnormality, and authors classified A997T as likely pathogenic (Ng et al. 2013). No segregation data have been published to our knowledge. The A997T variant has also been reported in one individual with irritable bowel syndrome (IBS) (Beyder et al., 2014). The A997T variant has been observed in 12/57,670 (0.02%) alleles in individuals of European background in large population cohorts (Lek et al., 2016). Additionally, this variant is classified in ClinVar as a variant of uncertain significance by three other clinical laboratories (SCV000200239.4, SCV000545040.2, SCV000747960.1; Landrum et al., 2016).Functional studies in HEK-293 cells expressing the A997T variant demonstrated a significant effect on channel function including a 98% reduction in peak channel current (Beyder et al., 2014). The loss of function phenotype was rescued by incubating the cells in mexiletine, an anti-arrhythmic drug shown previously to rescue SCN5A-related channel defects (Beyder et al., 2014). The A997T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Nevertheless, in silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.

Sep 29, 2023

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) This variant is statistically more frequent in individuals with Brugada syndrome than in the general population. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 24613995)

Jul 20, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 997 of the SCN5A protein (p.Ala997Thr). This variant is present in population databases (rs137854609, gnomAD 0.02%). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 19597050, 20129283, 24400668, 24681144, 29728395). ClinVar contains an entry for this variant (Variation ID: 67771). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects SCN5A function (PMID: 24613995). 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.

Sick sinus syndrome 1 Uncertain:2

Aug 20, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PS3,PP5,BP4.

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Cardiac arrhythmia Uncertain:2

Jan 13, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces alanine with threonine at codon 997 of the SCN5A protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. A functional study has shown that this variant results in a decreased sodium channel current in (PMID: 24613995). This variant has been reported in individuals affected with or suspected of having Brugada syndrome (PMID: 19597050, 20129283, 24400668), long QT syndrome (PMID: 26743238), irritable bowel syndrome (PMID: 24613995) and limb-girdle muscular dystrophy (PMID: 29970176). This variant has also been observed in multiple individuals who lack the personal history of SCN5A-related disorders (Color data). This variant has been identified in 23/271150 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and occurs at an appreciable frequency in the Non-Finnish European population (20/122914 chromosomes). 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.

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces alanine with threonine at codon 997 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant causes a reduction of peak channel current in HEK-293 cells (PMID: 24613995), although clinical relevance of this observation is not clear. This variant has been reported in individuals affected with or suspected of having Brugada syndrome (PMID: 19597050, 20129283, 24400668), long QT syndrome (PMID: 26743238), irritable bowel syndrome (PMID: 24613995) and limb-girdle muscular dystrophy (PMID: 29970176). This variant has also been observed in multiple individuals who lack the personal history of SCN5A-related disorders (Color data). This variant has been identified in 23/271150 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and occurs at an appreciable frequency in the Non-Finnish European population (20/122914 chromosomes). 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 Uncertain: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:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

Aug 03, 2016

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dilated cardiomyopathy 1E Uncertain:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Ventricular fibrillation, paroxysmal familial, type 1 Uncertain:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Cardiomyopathy Uncertain:1

Mar 14, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 Uncertain:1

Apr 20, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Progressive familial heart block, type 1A Uncertain:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Long QT syndrome 3 Uncertain:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

SUDDEN INFANT DEATH SYNDROME;C1142166:Brugada syndrome Uncertain:1

Apr 05, 2018

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Cardiovascular phenotype Benign:1

Jun 10, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
CardioboostArm	Benign	0.0000015
CardioboostCm	Benign	0.0023
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	0.017
DANN	Benign	0.67
DEOGEN2	Benign	0.38	T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	-0.080	N
PhyloP100		-3.5
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.57	N
REVEL	Uncertain	0.48
Sift	Benign	0.53	T
Sift4G	Benign	0.68	T
Polyphen		0.0010	B
Vest4		0.095
MVP		0.98
MPC		0.029
ClinPred		0.018	T
GERP RS		-11
Varity_R		0.022
gMVP		0.46
Mutation Taster		=0/100	disease causing

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: rs137854609; hg19: chr3-38622661;