chr3-38633255-C-T

Variant names:

• chr3-38633255-C-T
• rs41311087
• NM_001099404.2:c.53G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:2 O:1
• Conservation: PhyloP100: 0.272

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]

ACMG classification

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 the SCN5A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 99 curated pathogenic missense variants (we use a threshold of 10). The gene has 60 curated benign missense variants. Gene score misZ: 2.7504 (below the threshold of 3.09). Trascript score misZ: 4.8279 (above the threshold of 3.09). GenCC associations: The gene is linked to 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 rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.53G>A	p.Arg18Gln	missense_variant	Exon 2 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.53G>A	p.Arg18Gln	missense_variant	Exon 2 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.53G>A	p.Arg18Gln	missense_variant	Exon 2 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.53G>A	p.Arg18Gln	missense_variant	Exon 2 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152162 Hom.: 0 Cov.: 32

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: 18 AN: 248572 Hom.: 0 AF XY: 0.0000519 AC XY: 7 AN XY: 134962

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: 90 AN: 1460786 Hom.: 0 Cov.: 34 AF XY: 0.0000468 AC XY: 34 AN XY: 726724

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: 6 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74334

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.: 0

Bravo AF: 0.0000793

ExAC AF: 0.0000248 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2 Benign:1

Apr 10, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Apr 29, 2024

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.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. -

Jul 03, 2017

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:2

Aug 20, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Cardiac arrhythmia Uncertain:2

Feb 23, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 20, 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 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. -

Long QT syndrome 3;C4551804:Brugada syndrome 1 Uncertain:1

Aug 29, 2023

Clinical Genomics Laboratory, Stanford Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 30, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

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

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	17
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	D
LIST_S2	Uncertain	0.88	.;D;D;D;D;D;D;.;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.47	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	1.9	.;L;.;.;.;L;.;.;.;.;.
PrimateAI	Benign	0.41	T
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	T
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

Other links and lift over

dbSNP: rs41311087; hg19: chr3-38674746;