chr3-38603998-C-T

Position:

chr3-38603998-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_001099404.2(SCN5A):c.1604G>A(p.Arg535Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,613,594 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

SCN5A
NM_001099404.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.05

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 5 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 4.7729 (greater than threshold 3.09). GenCC has associacion of 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.872

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2 linkuse as main transcript	c.1604G>A	p.Arg535Gln	missense_variant	12/28	ENST00000413689.6
SCN5A	NM_000335.5 linkuse as main transcript	c.1604G>A	p.Arg535Gln	missense_variant	12/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6 linkuse as main transcript	c.1604G>A	p.Arg535Gln	missense_variant	12/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7 linkuse as main transcript	c.1604G>A	p.Arg535Gln	missense_variant	12/28	1	NM_000335.5	A1	Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000202

AC:

AN:

248026

Hom.:

AF XY:

0.0000223

AC XY:

AN XY:

134658

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000999

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000267

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1461412

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

726956

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.00

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

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000595

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain: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	GeneDx	Nov 06, 2020	Reported in association with Long QT syndrome and atrial fibrillation (Kapplinger et al., 2009; Gregers et al., 2017); Reported in ClinVar (ClinVar Variant ID# 67672; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26746457, 28549997, 28573431, 19716085, 24349418) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 27, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 535 of the SCN5A protein (p.Arg535Gln). This variant is present in population databases (rs199473121, gnomAD 0.01%). This missense change has been observed in individual(s) with SCN5A-related conditions (PMID: 24349418, 28549997). ClinVar contains an entry for this variant (Variation ID: 67672). 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 disruptive. Experimental studies have shown that this missense change affects SCN5A function (PMID: 24349418, 34843967). 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	Sep 20, 2023	This missense variant replaces arginine with glutamine at codon 535 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). Functional studies have shown that this variant has mild impact on sodium channel function without affecting cell surface expression (PMID: 24349418, 34843967). This variant has been reported in an individual affected with long QT syndrome (PMID 24349418), atrial fibrillation (PMID: 28549997), and individuals referred for long QT syndrome testing (PMID: 19716085). This variant has been identified in 5/248026 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	Oct 06, 2023	This missense variant replaces arginine with glutamine at codon 535 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). Functional studies have shown that this variant has mild impact on sodium channel function without affecting cell surface expression (PMID: 24349418, 34843967). This variant has been reported in an individual affected with long QT syndrome (PMID 24349418), atrial fibrillation (PMID: 28549997), and individuals referred for long QT syndrome testing (PMID: 19716085). This variant has been identified in 5/248026 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. -

Long QT syndrome 3

Pathogenic:1

Pathogenic, flagged submission

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Aug 03, 2016

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 28, 2019

Variant summary: SCN5A c.1604G>A (p.Arg535Gln) results in a conservative amino acid change located in the intracellular linker region between DI and DII in the alpha-subunit of a voltage-gated Na+ ion channel, cytoplasmic domain (IPR024583) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 248026 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.1604G>A, has been reported in the literature in individuals affected with long QT syndrome 3 or atrial fibrillation (Kapplinger_2009, Fatima_2013, Van Driest SL_2016, Gregers_2017). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Fatima_2013 reports that the variant of LQTS-3 CM have a defective sodium channel which takes longer time for inactivation leading to persistent sodium current and the tendency for prolongation of action potential duration. Two ClinVar submissions (evaluation after 2014) cite the variant once as pathogenic and once as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Brugada syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Primary dilated cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Genetics and Genomics Program, Sidra Medicine

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 08, 2021

The c.1604G>A (p.R535Q) alteration is located in exon 12 (coding exon 11) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 1604, causing the arginine (R) at amino acid position 535 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Congenital long QT 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 Long QT syndrome in the following publications (PMID:19716085). 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

0.095

CardioboostCm

Benign

0.050

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.31

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.66

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

Eigen

Uncertain

0.31

Eigen_PC

Benign

0.20

FATHMM_MKL

Benign

0.66

LIST_S2

Uncertain

0.90

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

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.87

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

MetaSVM

Pathogenic

0.87

MutationAssessor

Uncertain

2.0

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

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.41

PROVEAN

Benign

-2.0

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

REVEL

Pathogenic

0.66

Sift

Benign

0.057

T;T;T;T;D;T;T;D;D

Sift4G

Benign

0.36

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

Polyphen

1.0

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

Vest4

0.65

MutPred

0.73

Loss of MoRF binding (P = 0.0575);Loss of MoRF binding (P = 0.0575);Loss of MoRF binding (P = 0.0575);Loss of MoRF binding (P = 0.0575);Loss of MoRF binding (P = 0.0575);Loss of MoRF binding (P = 0.0575);Loss of MoRF binding (P = 0.0575);Loss of MoRF binding (P = 0.0575);Loss of MoRF binding (P = 0.0575);

MVP

0.96

MPC

1.2

ClinPred

0.48

GERP RS

4.3

Varity_R

0.16

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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