3-38550512-C-T

Position:

chr3-38550512-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_000335.5(SCN5A):c.5857G>A(p.Glu1953Lys) 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. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. E1953E) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

SCN5A
NM_000335.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 1.85

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN5A. . Gene score misZ: 2.7504 (greater than the threshold 3.09). Trascript score misZ: 4.8279 (greater than threshold 3.09). The gene has 99 curated pathogenic missense variants (we use a threshold of 10). The gene has 60 curated benign missense variants. GenCC has associacion of the gene with progressive familial heart block, type 1A, Brugada syndrome, familial sick sinus syndrome, short QT syndrome, paroxysmal familial ventricular fibrillation, progressive familial heart block, long QT syndrome 3, familial atrial fibrillation, catecholaminergic polymorphic ventricular tachycardia, dilated cardiomyopathy, dilated cardiomyopathy 1E, arrhythmogenic right ventricular cardiomyopathy, Brugada syndrome 1, atrial standstill, familial isolated dilated cardiomyopathy, familial long QT syndrome, sick sinus syndrome 1.

BP4

Computational evidence support a benign effect (MetaRNN=0.21795249).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2 link	c.5860G>A	p.Glu1954Lys	missense_variant	28/28	ENST00000413689.6	NP_001092874.1	Q14524H9KVD2
SCN5A	NM_000335.5 link	c.5857G>A	p.Glu1953Lys	missense_variant	28/28	ENST00000423572.7	NP_000326.2	Q14524-2Q86V90

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6 link	c.5860G>A	p.Glu1954Lys	missense_variant	28/28	5	NM_001099404.2	ENSP00000410257.1		H9KVD2
SCN5A	ENST00000423572.7 link	c.5857G>A	p.Glu1953Lys	missense_variant	28/28	1	NM_000335.5	ENSP00000398266.2		Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0000244

AC:

AN:

246254

Hom.:

AF XY:

0.0000224

AC XY:

AN XY:

133648

show subpopulations

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 SAS 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:

AN:

1457918

Hom.:

Cov.:

AF XY:

0.00000552

AC XY:

AN XY:

724544

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.0000225

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000333

GnomAD4 genome

AF:

0.000125

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.000434

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000225

Hom.:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2019	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 17, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2023	Reported in conjunction with a pathogenic variant in KCNQ1 in a child with LQTS (PMID: 23631430); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30847666, 29517769, 23631430) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2025	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. -

Cardiac arrhythmia

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 11, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	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

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 06, 2024

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 23, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

CardioboostCm

Benign

0.0021

BayesDel_addAF

Benign

-0.097

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

.;.;.;.;.;D;.;.;.

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.69

LIST_S2

Uncertain

0.89

.;D;D;D;D;D;D;.;D

M_CAP

Pathogenic

0.68

MetaRNN

Benign

0.22

T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.16

MutationAssessor

Uncertain

2.1

.;.;.;.;.;M;.;.;.

PrimateAI

Benign

0.47

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

Polyphen

0.023

B;B;.;B;.;B;B;.;.

Vest4

0.69

MVP

0.65

MPC

0.64

ClinPred

0.027

GERP RS

0.96

Varity_R

0.12

gMVP

0.48

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over