rs199473086

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP3

The NM_001099404.2(SCN5A):c.880G>A(p.Val294Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

SCN5A
NM_001099404.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8O:1

Conservation

PhyloP100: 0.684

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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, SCN5A

PP3

MetaRNN computational evidence supports a deleterious effect, 0.822

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2 linkuse as main transcript	c.880G>A	p.Val294Met	missense_variant	7/28	ENST00000413689.6
SCN5A	NM_000335.5 linkuse as main transcript	c.880G>A	p.Val294Met	missense_variant	7/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6 linkuse as main transcript	c.880G>A	p.Val294Met	missense_variant	7/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7 linkuse as main transcript	c.880G>A	p.Val294Met	missense_variant	7/28	1	NM_000335.5	A1	Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152268

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000241

AC:

AN:

249038

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135082

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000355

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1461288

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726906

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000688

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jun 24, 2023	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. Experimental studies have shown that this missense change affects SCN5A function (PMID: 21840964, 25261036). 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. ClinVar contains an entry for this variant (Variation ID: 68054). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 11901046, 31737537). This variant is present in population databases (rs199473086, gnomAD 0.01%). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 294 of the SCN5A protein (p.Val294Met). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 01, 2021	Reported in association with arrhythmia (Priori et al., 2000; Marschall et al., 2019); however, detailed clinical information was not provided; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 68054; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate a small but significant reduction of sodium current density in V294M SCN5A channels, though, it is not known whether this finding is physiologically relevant in vivo (Shinlapawittayatorn et al., 2011); This variant is associated with the following publications: (PMID: 33221895, 11901046, 14961552, 11076825, 21840964, 14753626, 27711072, 30662450, 31737537) -

Cardiac arrhythmia

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This missense variant replaces valine with methionine at codon 294 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). Experimental studies have shown that this variant may cause reduced sodium channel currents (PMID: 21840964, 25261036). This variant has been reported in an individual affected with Brugada syndrome (PMID: 11901046), and in an individual suspected of having long QT syndrome (PMID: 31737537). This variant has been identified in 8/280450 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	Color Diagnostics, LLC DBA Color Health	Mar 02, 2023	This missense variant replaces valine with methionine at codon 294 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). Experimental studies have shown that this variant may cause reduced sodium channel currents (PMID: 21840964, 25261036). This variant has been reported in an individual affected with Brugada syndrome (PMID: 11901046), and in an individual suspected of having long QT syndrome (PMID: 31737537). This variant has been identified in 8/280450 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 20, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 BrS proband (PMID 11901046) and as secondary finding in a WES case. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Long QT syndrome 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Apr 25, 2018

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 19, 2020

The c.880G>A (p.V294M) alteration is located in exon 7 (coding exon 6) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 880, causing the valine (V) at amino acid position 294 to be replaced by a methionine (M). In silico prediction is conflicting:_x000D_ The p.V294M alteration is predicted to be possibly damaging by Polyphen and tolerated by SIFT in silico analyses. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Brugada syndrome

Other:1

not provided, no classification provided

literature only

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

This variant has been reported as associated with Brugada syndrome in the following publications (PMID:11901046;PMID:11076825). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

CardioboostArm

Benign

0.0031

CardioboostCm

Benign

0.013

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.14

Cadd

Benign

Dann

Uncertain

1.0

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.12

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.82

D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.0015

MutationTaster

Benign

0.95

N;N;N;N;N;N;N;N;N;N

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.10

N;N;N;N;N;N;N;N;N

REVEL

Uncertain

0.57

Sift

Benign

0.18

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

Sift4G

Benign

0.26

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

Polyphen

0.97

D;P;.;D;.;D;D;.;.

Vest4

0.81

MutPred

0.82

Gain of loop (P = 0.0195);Gain of loop (P = 0.0195);Gain of loop (P = 0.0195);Gain of loop (P = 0.0195);Gain of loop (P = 0.0195);Gain of loop (P = 0.0195);Gain of loop (P = 0.0195);Gain of loop (P = 0.0195);Gain of loop (P = 0.0195);

MVP

0.97

MPC

0.72

ClinPred

0.44

GERP RS

4.5

Varity_R

0.053

gMVP

0.90

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