3-38550512-C-T

Variant names:

• chr3-38550512-C-T
• rs397517956
• NM_001099404.2:c.5860G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001099404.2(SCN5A):​c.5860G>A​(p.Glu1954Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,610,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 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. E1954D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:1
• Conservation: PhyloP100: 1.85
• Publications: 3 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=0.21795249).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.5860G>A	p.Glu1954Lys	missense_variant	Exon 28 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.5857G>A	p.Glu1953Lys	missense_variant	Exon 28 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.5860G>A	p.Glu1954Lys	missense_variant	Exon 28 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.5857G>A	p.Glu1953Lys	missense_variant	Exon 28 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000434

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000244 AC: 6 AN: 246254 AF XY: 0.0000224

Gnomad AFR exome AF: 0.000260

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: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000892 AC: 13 AN: 1457918 Hom.: 0 Cov.: 31 AF XY: 0.00000552 AC XY: 4 AN XY: 724544

African (AFR) AF: 0.000239 AC: 8 AN: 33410

American (AMR) AF: 0.0000225 AC: 1 AN: 44520

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25968

East Asian (EAS) AF: 0.00 AC: 0 AN: 39586

South Asian (SAS) AF: 0.00 AC: 0 AN: 85990

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109230

Other (OTH) AF: 0.0000333 AC: 2 AN: 60150

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152234 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74374

African (AFR) AF: 0.000434 AC: 18 AN: 41476

American (AMR) AF: 0.00 AC: 0 AN: 15282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

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

Alfa AF: 0.0000783 Hom.: 0

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Apr 02, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in conjunction with a pathogenic variant in KCNQ1 in a child with LQTS (PMID: 23631430); In silico analysis indicates that this missense variant does not alter protein structure/function; Reported as a variant of uncertain significance in an individual with dilated cardiomyopathy (PMID: 29517769); This variant is associated with the following publications: (PMID: 30847666, 23631430, 29517769)

Aug 17, 2018

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1954 of the SCN5A protein (p.Glu1954Lys). This variant is present in population databases (rs397517956, gnomAD 0.04%). This missense change has been observed in individual(s) with SCN5A-related conditions (PMID: 23631430, 29517769, 30847666). ClinVar contains an entry for this variant (Variation ID: 48312). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 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.Glu1954Lys variant in SCN5A has not been reported in the literature nor previously identified by our laboratory. The affected amino acid (glutamic acid, Glu) is poorly conserved in evolution with at least one mammalian species carrying the variant amino acid. This suggests but does not prove that this change is tolerated. Additional studies are needed to fully assess its clinical significance.

Cardiac arrhythmia Uncertain:2

Dec 11, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glutamic acid with lysine at codon 1954 of the SCN5A protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a child affected with long QT syndrome, who also carried a pathogenic variant in the KCNQ1 gene that could explain the observed phenotype (PMID: 23631430). This variant has also been reported in two individuals affected with dilated cardiomyopathy (PMID: 29517769, 30847666). This variant has been identified in 11/277646 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.

Feb 05, 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 glutamic acid with lysine at codon 1954 of the SCN5A protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a child affected with long QT syndrome, who also carried a pathogenic variant in the KCNQ1 gene that could explain the observed phenotype (PMID: 23631430). This variant has also been reported in two individuals affected with dilated cardiomyopathy (PMID: 29517769, 30847666). This variant has been identified in 11/277646 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.

SCN5A-related disorder Uncertain:1

Jan 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SCN5A c.5860G>A variant is predicted to result in the amino acid substitution p.Glu1954Lys. This variant was reported in an individual with long QT syndrome who also had the variant KCNQ1 c.1615C>T (p.Arg539Trp) (Lieve et al. 2013. PubMed ID: 23631430). This variant was also reported in two individuals with dilated cardiomyopathy (Herkert et al. 2018. PubMed ID: 29517769; online supplementary file 2, van Lint et al. 2019. PubMed ID: 30847666). This variant is reported in 0.037% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Cardiovascular phenotype Uncertain:1

Feb 23, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E1954K variant (also known as c.5860G>A), located in coding exon 27 of the SCN5A gene, results from a G to A substitution at nucleotide position 5860. The glutamic acid at codon 1954 is replaced by lysine, an amino acid with similar properties. This variant has been detected in one individual diagnosed with long QT syndrome who was also reported to carry a second alteration in KCNQ1 (p.R539W) (Lieve KV et al., Genet Test Mol Biomarkers 2013 Jul; 17(7):553-61). This alteration was also reported in a pediatric dilated cardiomyopathy (DCM) cohort and a cardiomyopathy/arrhythmia genetic testing cohort; however, clinical details were limited (Herkert JC et al. Genet. Med., 2018 11;20:1374-1386; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

not specified Benign:1

Jun 23, 2025

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SCN5A c.5860G>A (p.Glu1954Lys) results in a conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 2e-05 in 1610152 control chromosomes, predominantly at a frequency of 0.00035 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2.1 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Brugada Syndrome phenotype (0.00017). c.5860G>A has been observed in at least 2 individuals with dilated cardiomyopathy (example: Herkert_2018, van Lint_2019) and at least 1 individual with long QT syndrome (example: Lieve_2013), without strong evidence of causality. These report(s) do not provide unequivocal conclusions about association of the variant with Brugada Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23631430, 30847666, 29517769). ClinVar contains an entry for this variant (Variation ID: 48312). Based on the evidence outlined above, the variant was classified as likely benign.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
CardioboostArm	Benign	0.0000033
CardioboostCm	Benign	0.0021
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;.;.;.;.;D;.;.;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.0	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	0.0	.;.;.;.;.;M;.;.;.
PhyloP100		1.9
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.9	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.26
Sift	Benign	0.11	T;T;T;T;D;T;T;D;D
Sift4G	Benign	0.38	T;T;T;T;T;T;T;T;T
Vest4		0.69
ClinPred		0.027	T
GERP RS		0.96
Varity_R		0.12
gMVP		0.48
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: rs397517956; hg19: chr3-38592003;