rs41315493

Positions:

• chr3-38550521-C-A
• chr3-38550521-C-G
• chr3-38550521-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001099404.2(SCN5A):​c.5851G>T​(p.Val1951Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.002 in 1,611,666 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1951M) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0041 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (46 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:27 O:1
• Conservation: PhyloP100: 0.927

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 Benign. Variant got -19 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0035488904).
• BP6: Variant 3-38550521-C-A is Benign according to our data. Variant chr3-38550521-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 36765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38550521-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00409 (623/152342) while in subpopulation AMR AF= 0.0273 (418/15306). AF 95% confidence interval is 0.0251. There are 7 homozygotes in gnomad4. There are 315 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.5851G>T	p.Val1951Leu	missense_variant	28/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.5848G>T	p.Val1950Leu	missense_variant	28/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.5851G>T	p.Val1951Leu	missense_variant	28/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7	c.5848G>T	p.Val1950Leu	missense_variant	28/28	1	NM_000335.5	ENSP00000398266	A1

Frequencies

GnomAD3 genomes AF: 0.00405 AC: 617 AN: 152224 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00347

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0270

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00328

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00662 AC: 1633 AN: 246710 Hom.: 26 AF XY: 0.00520 AC XY: 696 AN XY: 133972

Gnomad AFR exome AF: 0.00358

Gnomad AMR exome AF: 0.0405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00298

Gnomad SAS exome AF: 0.00181

Gnomad FIN exome AF: 0.000561

Gnomad NFE exome AF: 0.000376

Gnomad OTH exome AF: 0.00467

GnomAD4 exome AF: 0.00178 AC: 2598 AN: 1459324 Hom.: 46 Cov.: 31 AF XY: 0.00158 AC XY: 1145 AN XY: 725558

Gnomad4 AFR exome AF: 0.00281

Gnomad4 AMR exome AF: 0.0405

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00305

Gnomad4 SAS exome AF: 0.00163

Gnomad4 FIN exome AF: 0.000881

Gnomad4 NFE exome AF: 0.000204

Gnomad4 OTH exome AF: 0.00257

GnomAD4 genome AF: 0.00409 AC: 623 AN: 152342 Hom.: 7 Cov.: 33 AF XY: 0.00423 AC XY: 315 AN XY: 74486

Gnomad4 AFR AF: 0.00349

Gnomad4 AMR AF: 0.0273

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00328

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.000820 Hom.: 0

Bravo AF: 0.00595

ESP6500AA AF: 0.00457 AC: 19

ESP6500EA AF: 0.000596 AC: 5

ExAC AF: 0.00525 AC: 635

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:27 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1 Benign:8

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 05, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 01, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	p.Val1951Leu in Exon 28 of SCN5A: This variant is not expected to have clinical significance because it has been identified in 6.5% (6/92) of chromosomes from a population in the dbSNP database (http://www.ncbi.nlm.nih.gov/projects/SNP; rs4 1315493). -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Mar 26, 2015	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Val1951Leu (c.5851G>T) in the SCN5A gene. This variant has been reported in published literature. Priori et al (2004) reported the presence of the variant in one Caucasian individual who had a Brugada syndrome diagnosis. It was also reported in a case of SIDS (Arnestad et al 2007). In vitro studies have been conflicting, with some reporting an abnormal biophysical phenotype (Wang er al 2008) and others reporting normal function (Tan et al 2005). Arnestad et al commented that this variant could exhibit ethnic-dependent phenotype expression (2007). A nonpolar, neutral Valine is replaced with a nonpolar, neutral Leucine at position 1951 in the SCN5A gene. The change does not affect the net charge of the polypeptide. This codon is not well conserved across species. In 2004, Darbar et al sequenced the SCN5A coding region of 378 individuals with Atrial fibrillation (alone or in association with another cardiac condition), they identified one Caucasian individual with atrial fibrillation and HCM who harbored a variant in the same codon (p.Val1951Met). In this patient’s family the variant did co segregate with phenotype in the patient’s father, paternal grandmother and 2 siblings. Priori et al (2004) report this variant was not found in 400 Caucasian presumably healthy controls. Genedx did not find the variant in 200 Caucasian and African American controls. However, the p.Val1951Leu variant has been reported in 6.7% of normal Hispanics (Ackerman et al 2005). Darbar et al (2008) reported that the p.Val1951Leu variant was observed in 7 out of 720 presumably healthy controls of both Caucasian and African American descent. In addition, Kapplinger et al (2010) reported that the p.Val1951Leu variant is found in highest percentage in Hispanic controls, then Asian, African America and “other” presumably healthy controls. They classified this variant as a polymorphism. Given these data, the impact of this variant on arrhythmic risk is unclear. It is possible that it is a common variant (i.e. >5%) in several ancestral groups and that it was identified in the published cases of SIDS and Brugada because of its prevalence, not because of its pathogenicity. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:5 Other:1

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 25, 2023	- -
not provided, no classification provided	literature only	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	-	This variant has been reported in the following publications (PMID:10807545;PMID:11901046;PMID:15851227;PMID:16379539;PMID:17210839;PMID:18426444;PMID:19841300;PMID:21109022;PMID:20129283;PMID:15992732;PMID:17210841;PMID:22378279). -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 18, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Ventricular tachycardia;CN225662:Pulmonary valve stenosis (rare) Benign:1

Likely benign, no assertion criteria provided

clinical testing

Blueprint Genetics

Aug 15, 2014

- -

Brugada syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Feb 05, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Ventricular fibrillation, paroxysmal familial, type 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Feb 05, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Dec 13, 2021

- -

Brugada syndrome Benign:1

Likely benign, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Atrial fibrillation;C1142166:Brugada syndrome Benign:1

Likely benign, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

Dilated cardiomyopathy 1E Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Feb 05, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Sick sinus syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Feb 05, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Long QT syndrome;C0878544:Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Jun 11, 2019

- -

Progressive familial heart block, type 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Feb 05, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Long QT syndrome Benign:1

Benign, no assertion criteria provided

clinical testing

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

Jan 08, 2015

Variant Summary: c.5848G>T is a missense variant that occurrs at a non-conserved position, and 5/5 in silico tools predict benign outcome of this variant. The observed allele frequency in an ethnically diverse set of control chromosomes is 102/24,730 (1/242; 0.41%; 2 homozgotes reported); this frequency is significantly higher than the maximal expected allele frequency of 1/48,000 for a pathogenic SCN5A variant for LQTS/SCD or 1/6,000 for BrS. The ExAC population reports the variant in 477/11,174 (1/23; 4.27%) Latino chromosomes, with 6 homozygotes. These allele frequencies strongly suggest that the variant is benign. Further support of a benign outcome is a reported Korean family (Shin et al, 2003) where this variant did not cosegregate with disease, and a sudden cardiac death patient whom also carried another potentially pathogenic variant in the KCNE1 gene (Tester et al 2012). Functional studies results are in conflict, but suggest that the variant may have a modifying effect dependent upon the presence of other SCN5A variants. Most in vitro studies have shown that the variant has no significant effect on in vitro function when in isolation. V1951L did not exhibit an overt LQT3-like phenotype or an overt loss of function phenotype, therefore its involvement in the settings of either LQT3 or Brugada syndrome is not substantiated. Furthermore, although the authors reported other "significant functional disturbances" , the results and conclusions of these findings are not applicable to the mechanism of action, and physiologic consequences or presentation of disease (i.e., LQT3 or Brugada). Collectively, although this variant may play a role in the context of complex or oligogenic alleles, in isolation there is no evidence to suggest that it significantly impairs SCN5A function, several reputable sources classify the variant as benign, and the significantly higher oberseved allele frequency compared to the maximimal expected allele frequency of a pathogenic SCN5A variant indicate that the in vivo consequence of this variant is, indeed, benign. -

Long QT syndrome 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Feb 05, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 05, 2015

This alteration is classified as 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. -

Cardiac arrhythmia Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 19, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	0.98
DANN	Benign	0.85
DEOGEN2	Benign	0.34	.;.;.;.;.;T;.;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.88
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.72	.;T;T;T;T;T;T;.;T
MetaRNN	Benign	0.0035	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	-0.90	.;.;.;.;.;N;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.24	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.19	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.29	T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;B;.;B;.;B;B;.;.
Vest4		0.14
MutPred		0.76		.;.;Loss of helix (P = 0.0558);.;.;Loss of helix (P = 0.0558);.;.;.;
MVP		0.77
MPC		0.50
ClinPred		0.0027	T
GERP RS		-0.53
Varity_R		0.051
gMVP		0.18

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: rs41315493; hg19: chr3-38592012;