rs41311127

Variant names:

• chr3-38562500-A-G
• rs41311127
• NM_001099404.2:c.3878T>C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. PM2 PP2 BP4_Strong BS1

The NM_000335.5(SCN5A):​c.3875T>C​(p.Phe1292Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000345 in 1,613,890 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00033 (1 hom.)
• Consequence: SCN5A NM_000335.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:10 O:1
• Conservation: PhyloP100: 4.44

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_benign. Variant got -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.05141446).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00046 (70/152322) while in subpopulation AMR AF= 0.0017 (26/15308). AF 95% confidence interval is 0.00119. There are 0 homozygotes in gnomad4. There are 38 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.3878T>C	p.Phe1293Ser	missense_variant	Exon 22 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.3875T>C	p.Phe1292Ser	missense_variant	Exon 22 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.3878T>C	p.Phe1293Ser	missense_variant	Exon 22 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.3875T>C	p.Phe1292Ser	missense_variant	Exon 22 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 70 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000648 AC: 161 AN: 248636 Hom.: 0 AF XY: 0.000660 AC XY: 89 AN XY: 134920

Gnomad AFR exome AF: 0.0000647

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00906

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000222

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000333 AC: 486 AN: 1461568 Hom.: 1 Cov.: 31 AF XY: 0.000345 AC XY: 251 AN XY: 727062

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.00968

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000109

Gnomad4 OTH exome AF: 0.000861

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.000510 AC XY: 38 AN XY: 74484

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00807

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000718 Hom.: 1

Bravo AF: 0.000574

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000476 AC: 4

ExAC AF: 0.000389 AC: 47

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:10 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5 Other:1

May 30, 2017

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: The SCN5A c.3878T>C (p.Phe1293Ser) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 49/119844 control chromosomes including ExAC at a frequency of 0.0004089, which is approximately 2 times the estimated maximal expected allele frequency of a pathogenic SCN5A variant (0.0001667), suggesting this variant is likely a benign polymorphism. This variant has been reported in two Brugada syndrome (BrS) patients and one patient presenting with sodium channelopathy (cardiac symptoms, positive family history, and/or abnormal electrocardiogram) in literature (Priori_2002, Chockalingam_2012, and Sommariva_2013). In one BrS patient, another truncating variant c.3258-3261del4 (p.E1087PfsX57) was also present (Sommariva_2013), supporting benign outcome. It has been also reported as polymorphism from published sources (Kapa_2009, Kapplinger_2010) as it was found in healthy controls of European origin. In ClinVar while two clinical labs have classified this variant as VUS, one lab has classified as likely benign. Taken together, this variant is currently classified as likely benign. -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SCN5A: BS1 -

Jan 17, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

- -

-

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 in the following publications (PMID:11901046;PMID:15851227;PMID:19841300;PMID:20129283). -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 33083721, 30847666, 29167113, 27153395, 11901046, 22885917, 15851227, 20129283, 23414114) -

Jul 01, 2019

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Brugada syndrome Benign:2

Feb 07, 2024

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Cardiac arrhythmia Benign:2

Dec 17, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Jul 23, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Phe1293Ser variant in SCN5A has been reported in 2 individuals with Brugada syndrome (Priori 2002, Sommariva 2012), one of whom carried a frameshift variant in the other copy of SCN5A, but has also been identified in 1/590 Caucasian con trol chromosomes (Ackerman 2004) and in 4/8412 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/; dbSNP rs41311 127). This variant has also been identified by our laboratory in 1 Caucasian ind ividual with DCM, who had a pathogenic variant in a different gene. The affected amino acid is poorly conserved in evolution, raising the possibility that a cha nge at this position would be tolerated. Other computational prediction tools do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the Phe1293Ser variant is uncertain. -

Brugada syndrome 1 Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

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

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SCN5A NM_198056.3 exon 22 p.Phe1293Ser (c.3878T>C): This variant has been reported in the literature in at least two individuals with Brugada syndrome, one of whom also carried a truncating variant in SCN5A (Priori 2002 PMID:11901046, Sommariva 2012). However, this variant is present in 0.9% (93/10336) of Ashkenazi Jewish alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/3-38603991-A-G) and is present in ClinVar, with several labs classifying this variant as likely benign (Variation ID:67833). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Primary familial dilated cardiomyopathy Uncertain:1

-

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome Uncertain:1

Aug 01, 2016

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

Found in patient having exome sequencing for an unrelated indication. No known history of Long QT syndrome. -

Cardiovascular phenotype Benign:1

Mar 13, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
CardioboostCm	Benign	0.0066
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	.;.;.;.;.;D;.;.;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.58
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.85	.;T;T;T;T;T;T;.;T
M_CAP	Pathogenic	0.74	D
MetaRNN	Benign	0.051	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	-0.58	.;.;.;.;.;N;.;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-4.7	D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.10	T;T;T;T;T;T;T;T;T
Polyphen		0.39	B;B;.;B;.;P;P;.;.
Vest4		0.69
MVP		0.93
MPC		1.9
ClinPred		0.28	T
GERP RS		2.9
Varity_R		0.77
gMVP		0.98

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: rs41311127; hg19: chr3-38603991;