rs41311087

Positions:

chr3-38633255-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP2

The NM_000335.5(SCN5A):c.53G>A(p.Arg18Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000595 in 1,612,948 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R18W) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

SCN5A
NM_000335.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:2O:1

Conservation

PhyloP100: 0.272

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 Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 130) in uniprot entity SCN5A_HUMAN there are 19 pathogenic changes around while only 2 benign (90%) in NM_000335.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-38633256-G-A is described in Lovd as [Pathogenic].

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2 link	c.53G>A	p.Arg18Gln	missense_variant	2/28	ENST00000413689.6	NP_001092874.1	Q14524H9KVD2
SCN5A	NM_000335.5 link	c.53G>A	p.Arg18Gln	missense_variant	2/28	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.53G>A	p.Arg18Gln	missense_variant	2/28	5	NM_001099404.2	ENSP00000410257.1		H9KVD2
SCN5A	ENST00000423572.7 link	c.53G>A	p.Arg18Gln	missense_variant	2/28	1	NM_000335.5	ENSP00000398266.2		Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.0000724

AC:

AN:

248572

Hom.:

AF XY:

0.0000519

AC XY:

AN XY:

134962

show subpopulations

Gnomad AFR exome

AF:

0.0000649

Gnomad AMR exome

AF:

0.000290

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:

0.0000354

Gnomad OTH exome

AF:

0.000496

GnomAD4 exome

AF:

0.0000616

AC:

AN:

1460786

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

726724

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000585

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

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:

0.0000793

ExAC

AF:

0.0000248

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 10, 2018	proposed classification - variant undergoing re-assessment, contact laboratory -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 29, 2024	Variant summary: SCN5A c.53G>A (p.Arg18Gln) results in a conservative amino acid change in 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 7.2e-05 in 251172 control chromosomes, predominantly at a frequency of 0.00029 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.74 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Brugada Syndrome phenotype (0.00017), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.53G>A has been reported in the literature in individuals affected with features of Brugada Syndrome, Long QT Syndrome, or Torsades de Pointes without strong evidence of causality (e.g. Kapplinger_2009, 2010, Amit_2011, Kajiyama_2020). These reports do not provide unequivocal conclusions about association of the variant with Brugada Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Gutter_2013). These results showed no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 19716085, 20129283, 23805106, 21273195, 32153684). ClinVar contains an entry for this variant (Variation ID: 48306). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jul 03, 2017	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 07, 2025	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 18 of the SCN5A protein (p.Arg18Gln). This variant is present in population databases (rs41311087, gnomAD 0.03%). This missense change has been observed in individual(s) with sudden unexplained death, suspected or definite Brugada syndrome, or suspected Long QT syndrome (PMID: 19716085, 20129283, 21273195, 26164358, 32153684). ClinVar contains an entry for this variant (Variation ID: 48306). 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. Experimental studies have shown that this missense change does not substantially affect SCN5A function (PMID: 23805106). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 20, 2024	Identified in patients with Brugada, LQTS, short-coupled variant of Torsades de Pointes, and sudden unexplained death, but no segregation studies are available (PMID: 21273195, 20129283, 19716085, 32153684, 26164358); LQTS is caused by gain of function variants in the SCN5A channel (NaV1.5), while Brugada syndrome is caused by loss of function variants; as this variant has been identified in individuals with diseases that have different mechanisms of pathogenicity, its clinical significance is uncertain; Published functional studies demonstrated that the variant was comparable to wild-type with regards to whole-cell currents, steady state activation and inactivation, and recovery from inactivation, exhibiting no loss-of-function characteristics typically associated with Brugada syndrome pathogenic variants (PMID: 23805106); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24324440, 20129283, 22581653, 19716085, 33131149, 21273195, 32153684, 26164358, 23805106, 30203441, 29709244) -

Cardiac arrhythmia

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 20, 2024	This missense variant replaces arginine with glutamine at codon 18 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). A functional study has shown that this variant has no significant impact on channel function in transfected cells (PMID: 23805106). This variant has been reported in individuals affected with Brugada syndrome (PMID: 20129283, 21273195, 32893267), short coupled variant of Torsades de Pointes (ScTdP) (PMID: 32153684), peripartum cardiomyopathy (PMID: 33874732), or suspected of having long QT syndrome (PMID: 19716085), and Brugada syndrome (PMID: 26164358). This variant has been identified in 20/279956 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	Feb 23, 2023	This missense variant replaces arginine with glutamine at codon 18 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). A functional study has shown that this variant has no significant impact on channel function in transfected cells (PMID: 23805106). This variant has been reported in individuals affected with Brugada syndrome (PMID: 20129283, 21273195), short coupled variant of Torsades de Pointes (ScTdP) (PMID: 32153684), or suspected of having long QT syndrome (PMID: 19716085), and Brugada syndrome (PMID: 26164358). This variant has been identified in 20/279956 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;C4551804:Brugada syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Clinical Genomics Laboratory, Stanford Medicine

Aug 29, 2023

The p.Arg18Gln variant in the SCN5A gene has been previously reported in individuals with Brugada syndrome, long QT syndrome, and sudden unexplained death (Kapplinger et al., 2009; Kapplinger et al., 2010; Amin et al., 2011; Farrugia et al., 2015; Kajiyama et al., 2020; Walsh et al., 2021). This variant has been identified in 10/35,374 Latino/Admixed American chromosomes (20/279,956 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is present in ClinVar (Variation ID: 48306). Functional studies of the p.Arg18Gln variant demonstrated that this variant does not disrupt SCN5A protein function (Gütter et al., 2013). The arginine at position 18 is evolutionarily conserved. Computational tools predict that the p.Arg18Gln variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Arg18Gln variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: BS3_Supporting; PP3] -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 30, 2021

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. -

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

0.094

CardioboostCm

Benign

0.0021

BayesDel_addAF

Benign

-0.087

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.51

.;.;.;.;.;D;.;.;.;T;T

Eigen

Benign

0.19

Eigen_PC

Benign

0.15

FATHMM_MKL

Benign

0.67

LIST_S2

Uncertain

0.88

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

M_CAP

Pathogenic

0.34

MetaRNN

Uncertain

0.47

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

MetaSVM

Uncertain

0.41

MutationAssessor

Benign

1.9

.;L;.;.;.;L;.;.;.;.;.

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.3

N;N;N;N;N;N;N;N;N;.;N

REVEL

Pathogenic

0.66

Sift

Benign

0.13

T;T;T;T;T;T;T;T;T;.;T

Sift4G

Benign

0.15

T;T;T;T;T;T;T;T;T;T;.

Polyphen

0.79

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

Vest4

0.75

MutPred

0.59

Loss of methylation at R18 (P = 0.0463);Loss of methylation at R18 (P = 0.0463);Loss of methylation at R18 (P = 0.0463);Loss of methylation at R18 (P = 0.0463);Loss of methylation at R18 (P = 0.0463);Loss of methylation at R18 (P = 0.0463);Loss of methylation at R18 (P = 0.0463);Loss of methylation at R18 (P = 0.0463);Loss of methylation at R18 (P = 0.0463);Loss of methylation at R18 (P = 0.0463);Loss of methylation at R18 (P = 0.0463);

MVP

0.91

MPC

0.85

ClinPred

0.053

GERP RS

3.5

Varity_R

0.084

gMVP

0.55

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