chr3-38554306-A-T

Position:

chr3-38554306-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP2PP3_Strong

The NM_000335.5(SCN5A):c.4783T>A(p.Phe1595Ile) 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. F1595F) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

SCN5A
NM_000335.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:15B:1O:1

Conservation

PhyloP100: 7.45

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:

SCN5A (HGNC:):

SCN5A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a helix (size 16) in uniprot entity SCN5A_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000335.5

PM2

Very rare variant in population databases, with high coverage;

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). 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.976

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2 linkuse as main transcript	c.4786T>A	p.Phe1596Ile	missense_variant	27/28	ENST00000413689.6	NP_001092874.1	Q14524H9KVD2
SCN5A	NM_000335.5 linkuse as main transcript	c.4783T>A	p.Phe1595Ile	missense_variant	27/28	ENST00000423572.7	NP_000326.2	Q14524-2Q86V90

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6 linkuse as main transcript	c.4786T>A	p.Phe1596Ile	missense_variant	27/28	5	NM_001099404.2	ENSP00000410257.1		H9KVD2
SCN5A	ENST00000423572.7 linkuse as main transcript	c.4783T>A	p.Phe1595Ile	missense_variant	27/28	1	NM_000335.5	ENSP00000398266.2		Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.000101

AC:

AN:

248326

Hom.:

AF XY:

0.000119

AC XY:

AN XY:

134822

show subpopulations

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 SAS 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.:

Cov.:

AF XY:

0.000176

AC XY:

128

AN XY:

725610

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000206

Gnomad4 NFE exome

AF:

0.000224

Gnomad4 OTH exome

AF:

0.0000830

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000363

Hom.:

Bravo

AF:

0.000117

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ExAC

AF:

0.0000661

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:15Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:7

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 03, 2022	BS3, PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2024	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) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	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. -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 20, 2016	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 -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 15, 2018	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 22, 2022	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

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 20, 2021

- -

SCN5A-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

The SCN5A c.4786T>A (p.Phe1596Ile) missense variant has been reported in five studies of individuals with various cardiac disorders (Kapplinger et al. 2009; Olesen et al. 2012; Christiansen et al. 2014; Boehringer et al. 2014; Hoshi et al. 2015) and described in a heterozygous state in six out of a total of 2814 individuals screened, giving an allele frequency of 0.00178. One of the six individuals also carried two variants in the KCNH2 gene. The variant was also detected in two unaffected individuals in a heterozygous state, one of whom, an unaffected sibling, carried the same additional two variants in the KCNH2 gene as her affected brother (Hoshi et al. 2015). The p.Phe1596Ile variant was absent from 3992 control alleles and is reported at a frequency of 0.00012 in the European (non-Finnish) population of the Exome Aggregation Consortium. The Phe1596 residue is conserved. The variant is described as having no electrophysiological consequence with patch-clamping experiments demonstrating no changes in activation / inactivation parameters or in peak current density compared to wild type (Olesen et al. 2014). Hoshi et al. (2015) confirmed a peak current density similar to wild type with however, a faster recovery from inactivation and increased persistent current compared to wild type. The functional data suggest the p.Phe1596Ile variant has a mild effect, however, due to the prevalence of the variant in cases compared to controls, the p.Phe1596Ile variant is classified as a variant of unknown significance but suspicious for pathogenicity for SCN5A-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Sick sinus syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 06, 2022

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). An experimental functional study has suggested that this variant may cause modest changes in the biophysical properties of the sodium channel but is insufficient to cause disease (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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2023

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;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

CardioboostCm

Uncertain

0.88

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.51

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.96

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

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.83

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

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.5

.;.;.;.;.;M;.;.

PrimateAI

Pathogenic

0.92

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

GERP RS

4.0

Varity_R

0.55

gMVP

0.99

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