rs199473278

Variant names:

• chr3-38554306-A-T
• rs199473278
• NM_001099404.2:c.4786T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PP3_Strong

The NM_001099404.2(SCN5A):​c.4786T>A​(p.Phe1596Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000174 in 1,611,818 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. F1596F) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:14 B:1 O:1
• Conservation: PhyloP100: 7.45
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• Brugada syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Brugada syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1E

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• sick sinus syndrome 1

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• progressive familial heart block, type 1A

  Inheritance: SD, AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp
• atrial standstill

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial sick sinus syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• paroxysmal familial ventricular fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• progressive familial heart block

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• short QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 19 uncertain in NM_001099404.2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.4786T>A	p.Phe1596Ile	missense_variant	Exon 27 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.4783T>A	p.Phe1595Ile	missense_variant	Exon 27 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.4786T>A	p.Phe1596Ile	missense_variant	Exon 27 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.4783T>A	p.Phe1595Ile	missense_variant	Exon 27 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152198 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000132

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000101 AC: 25 AN: 248326 AF XY: 0.000119

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.000187

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000184 AC: 268 AN: 1459620 Hom.: 0 Cov.: 32 AF XY: 0.000176 AC XY: 128 AN XY: 725610

African (AFR) AF: 0.0000598 AC: 2 AN: 33448

American (AMR) AF: 0.0000224 AC: 1 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.00 AC: 0 AN: 86216

European-Finnish (FIN) AF: 0.000206 AC: 11 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.000224 AC: 249 AN: 1110092

Other (OTH) AF: 0.0000830 AC: 5 AN: 60274

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152198 Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 9 AN XY: 74354

African (AFR) AF: 0.0000241 AC: 1 AN: 41450

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68040

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000363 Hom.: 0

Bravo AF: 0.000117

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ExAC AF: 0.0000661 AC: 8

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:14 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:7

-

Clinical Genetics, Academic Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1596 of the SCN5A protein (p.Phe1596Ile). This variant is present in population databases (rs199473278, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 9716085, 21051419, 25051102, 26213684, 30847666, 31737537, 31983221). ClinVar contains an entry for this variant (Variation ID: 67924). 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 does not substantially affect SCN5A function (PMID: 21051419, 26213684). 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. -

May 14, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has been reported in individuals referred for indications unrelated to cardiomyopathy/arrhythmia (PMID: 27153395, 26746457); Reported in association with LQTS and atrial fibrillation in the published literature (PMID: 19716085, 21051419, 22685113, 24144883, 24606995, 26213684); Functional studies suggest that this variant does not significantly affect sodium channel function (PMID: 21051419, 26213684); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24144883, 24606995, 22685113, 31983221, 21051419, 25051102, 22581653, 25649125, 28150151, 26746457, 26213684, 28988457, 31737537, 30847666, 34803699, 23631430, 25904541, 37652022, 19716085, 27153395) -

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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS3, PP3 -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Uncertain:3

Oct 20, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 5 papers in HGMD, 2 are functional studies that suggest no impact on protein function. Few probands and no apparent segregations; ClinVar: VUS by GeneDx -

Aug 15, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SCN5A c.4786T>A; p.Phe1596Ile variant (rs199473278), is reported in the literature in multiple individuals affected with long QT syndrome (Christiansen 2014, Hoshi 2015, Kapplinger 2009) or atrial fibrillation (Boehringer 2014, Olesen 2012, Olesen 2011), though these studies did not report if this variant cosegregates with disease. This variant is reported in ClinVar (Variation ID: 67924) and is found in the non-Finnish European population with an overall allele frequency of 0.02% (25/125810 alleles) in the Genome Aggregation Database. The phenylalanine at codon 1596 is highly conserved and occurs in a C-terminal region of SCN5A containing other missense variants identified in individuals with Long QT syndrome (Christiansen 2014, Kapplinger 2009); however, computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Further, while electrophysiology studies indicate the p.Phe1596Ile variant has modestly faster recovery from inactivation and slightly higher persistent current than wildtype protein, these defects are thought to be insufficient to cause disease (Hoshi 2015), and protein activity appears otherwise wildtype (Olesen 2011, Hoshi 2015). Due to limited information, the clinical significance of the p.Phe1596Ile variant is uncertain at this time. References: Boehringer T et al. SCN5A mutations and polymorphisms in patients with ventricular fibrillation during acute myocardial infarction. Mol Med Rep. 2014 Oct;10(4):2039-44. Christiansen M et al. Mutations in Danish patients with long QT syndrome and the identification of a large founder family with p.F29L in KCNH2. BMC Med Genet. 2014 Mar 7;15:31. Hoshi M et al. Polygenic Case of Long QT Syndrome Confirmed through Functional Characterization Informs the Interpretation of Genetic Screening Results. HeartRhythm Case Rep. 2015 Jul 1;1(4):201-205. Kapplinger JD et al. Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. Heart Rhythm. 2009 Sep;6(9):1297-303. Olesen MS et al. High prevalence of long QT syndrome-associated SCN5A variants in patients with early-onset lone atrial fibrillation. Circ Cardiovasc Genet. 2012 Aug 1;5(4):450-9. Olesen MS et al. Mutations in sodium channel beta-subunit SCN3B are associated with early-onset lone atrial fibrillation. Cardiovasc Res. 2011 Mar 1;89(4):786-93. -

Aug 22, 2022

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SCN5A c.4786T>A (p.Phe1596Ile) results in a non-conservative amino acid change located in the ion transport domain (IPR005821) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 248326 control chromosomes (gnomAD). This frequency is approximately equal to that expected for a pathogenic variant in SCN5A causing Arrhythmia (0.0001 vs 0.0001), allowing no conclusion about variant significance. c.4786T>A has been reported in the literature as a VUS in settings of multigene panel testing in individuals/cohorts affected with a variety of cardiac conditions such as Long QT syndrome, Atrial Fibrillation, arrhythmogenic disorders and DCM (example Kapplinger_2009, Olesen_2011-2014, Lieve_2013, Boehringer_2014, Hoshi_2015, Kaltman_2019, Marschall_2019, Mazzarotto_2020). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia/Long QT syndrome. At least two publications report experimental evidence evaluating an impact on protein function (example, Olesen_2011, Hoshi_2015). These results showed no damaging effect of this variant in current-voltage relationship, steady state inactivation and steady state activation properties relative to the WT control. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cardiomyopathy Uncertain:1

Oct 20, 2021

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sick sinus 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Cardiac arrhythmia Uncertain:1

Feb 13, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces phenylalanine with isoleucine at codon 1596 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant causes modest changes in the biophysical properties of the sodium channel (PMID: 26213684). This variant has been reported in several individuals affected with long QT syndrome (PMID: 19716085), early-onset lone atrial fibrillation (PMID: 21051419, 22685113, 24144883), or atrioventricular nodal reentrant tachycardia (PMID: 29396561). It has also been observed in unaffected related individuals (PMID: 26213684). This variant has been identified in 30/279712 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. -

Cardiovascular phenotype Benign:1

Sep 20, 2023

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

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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;PMID:21051419;PMID:22685113). 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	0.21
CardioboostArm	Pathogenic	1.0
CardioboostCm	Uncertain	0.88
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.51
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	.;.;.;.;.;D;.;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.83	.;T;T;T;T;T;.;T
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	.;.;.;.;.;M;.;.
PhyloP100		7.4
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-4.3	D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Benign	0.031	D;D;D;D;D;D;D;D
Sift4G	Benign	0.093	T;T;T;T;T;T;T;T
Polyphen		0.057	B;B;.;B;.;B;.;.
Vest4		0.92
MutPred		0.90		.;.;Gain of catalytic residue at L1601 (P = 0.0457);.;.;Gain of catalytic residue at L1601 (P = 0.0457);.;.;
MVP		0.95
MPC		1.5
ClinPred		0.80	D
GERP RS		4.0
Varity_R		0.55
gMVP		0.99
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs199473278; hg19: chr3-38595797;