3-38604907-G-C

Variant names:

• chr3-38604907-G-C
• rs199473113
• NM_001099404.2:c.1340C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4 BS1_Supporting

The NM_001099404.2(SCN5A):​c.1340C>G​(p.Ala447Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000348 in 1,610,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. 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. A447V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense, splice_region
• Scores: Splicing: ADA: 0.9334
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:3 O:1
• Conservation: PhyloP100: 6.03
• Publications: 5 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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.26980394).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000217 (33/152312) while in subpopulation AFR AF = 0.00077 (32/41570). AF 95% confidence interval is 0.000559. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.1340C>G	p.Ala447Gly	missense_variant, splice_region_variant	Exon 11 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.1340C>G	p.Ala447Gly	missense_variant, splice_region_variant	Exon 11 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.1340C>G	p.Ala447Gly	missense_variant, splice_region_variant	Exon 11 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.1340C>G	p.Ala447Gly	missense_variant, splice_region_variant	Exon 11 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000540 AC: 13 AN: 240728 AF XY: 0.0000230

Gnomad AFR exome AF: 0.000748

Gnomad AMR exome AF: 0.0000596

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000158 AC: 23 AN: 1457754 Hom.: 0 Cov.: 30 AF XY: 0.0000152 AC XY: 11 AN XY: 724668

African (AFR) AF: 0.000569 AC: 19 AN: 33418

American (AMR) AF: 0.0000680 AC: 3 AN: 44124

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26030

East Asian (EAS) AF: 0.00 AC: 0 AN: 39612

South Asian (SAS) AF: 0.00 AC: 0 AN: 85240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53210

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110120

Other (OTH) AF: 0.0000166 AC: 1 AN: 60238

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17 AN XY: 74466

African (AFR) AF: 0.000770 AC: 32 AN: 41570

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

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: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000242

ESP6500AA AF: 0.000753 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000579 AC: 7

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Other:1

Nov 24, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1 -

Dec 11, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant has not been reported in association with a SCN5A-related disorder, but has been reported in one African control sample (PMID: 15851227, 19841300, 20129283); 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: 20129283, 19841300, 22581653, 15851227) -

-

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 in the following publications (PMID:19841300;PMID:20129283). -

Dec 28, 2023

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 glycine, which is neutral and non-polar, at codon 447 of the SCN5A protein (p.Ala447Gly). This variant is present in population databases (rs199473113, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. ClinVar contains an entry for this variant (Variation ID: 67657). 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 tolerated. 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. -

Mar 09, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SCN5A c.1340C>G; p.Ala447Gly variant (rs199473113) is reported in the literature in individuals affected with hypertrophic cardiomyopathy (Lopes 2015). However, this variant has also been reported in healthy individuals (Kapa 2009, Kapplinger 2010, Kapplinger 2015). This variant is also reported in ClinVar (Variation ID: 67657) and is found in the African/African-American population with an allele frequency of 0.07% (17/23416 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.538). Given the lack of clinical and functional data, the significance of this variant is uncertain at this time. References: Kapa S et al. Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. Circulation. 2009 Nov 3;120(18):1752-60. PMID: 19841300. Kapplinger JD et al. An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing. Heart Rhythm. 2010 Jan;7(1):33-46. PMID: 20129283. Kapplinger JD et al. Enhanced Classification of Brugada Syndrome-Associated and Long-QT Syndrome-Associated Genetic Variants in the SCN5A-Encoded Na(v)1.5 Cardiac Sodium Channel. Circ Cardiovasc Genet. 2015 Aug;8(4):582-95. PMID: 25904541. Lopes LR et al. Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. Heart. 2015 Feb;101(4):294-301. Epub 2014 Oct 28. PMID: 25351510. -

not specified Uncertain:2 Benign:1

Apr 10, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 20, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SCN5A c.1340C>G (p.Ala447Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 7.2e-05 in 262936 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in SCN5A causing Arrhythmia (7.2e-05 vs 0.0001), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1340C>G in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Brugada syndrome 1 Uncertain:2

-

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, 3-38604907-G-C was evaluated for association with the loss-of-function condition Brugada Syndrome.This Variant had an AF of 0.000210258 in gnomAD v3The in silico predictor SpliceAI scored the variant as 0.01; normal <0.2, likely damaging >0.5.Using the functional RNA-splicing assay, ParSE-seq, the variant was evaluated to have an indeterminate impact on splicing following the Brnich et al. calibration framework (PMID: 31892348). In aggregate, we therefore classify this variant as VUS using these collective data. -

Aug 30, 2019

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Cardiac arrhythmia Uncertain:1 Benign:1

Apr 25, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 13, 2023

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 glycine at codon 447 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with SCN5A-related disorders in the literature. This variant has been identified in 19/272122 chromosomes 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. -

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

-

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SCN5A NM_198056.2 exon 11 p.Ala447Gly (c.1340C>G): This variant has not been reported in the literature, but it is present in 17/23260 African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs199473113). This variant is present in ClinVar (Variation ID:67657). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain -

Cardiovascular phenotype Benign:1

Aug 25, 2022

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
CardioboostArm	Benign	0.000076
CardioboostCm	Benign	0.020
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	.;.;.;.;.;D;.;.;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	.;T;T;T;T;T;T;.;T
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Benign	1.4	.;L;.;.;.;L;.;.;.
PhyloP100		6.0
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.5	N;N;N;N;D;N;N;D;D
REVEL	Uncertain	0.54
Sift	Benign	0.14	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.13	T;T;T;T;T;T;T;T;T
Polyphen		0.98	D;D;.;D;.;P;D;.;.
Vest4		0.62
MVP		0.78
MPC		1.1
ClinPred		0.11	T
GERP RS		5.1
Varity_R		0.21
gMVP		0.46
Mutation Taster		=16/84	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.93
dbscSNV1_RF	Pathogenic	0.83
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: rs199473113; hg19: chr3-38646398;