rs199473625

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3PP5

The NM_001099404.2(SCN5A):c.4978A>G(p.Ile1660Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000675 in 1,613,942 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 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. I1660T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000067 ( 1 hom. )

Consequence

SCN5A
NM_001099404.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:5O:1

Conservation

PhyloP100: 6.21

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_001099404.2

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, SCN5A

PP3

MetaRNN computational evidence supports a deleterious effect, 0.812

PP5

Variant 3-38551394-T-C is Pathogenic according to our data. Variant chr3-38551394-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67947.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Likely_pathogenic=2, Uncertain_significance=5}. Variant chr3-38551394-T-C is described in Lovd as [Pathogenic]. Variant chr3-38551394-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2 linkuse as main transcript	c.4978A>G	p.Ile1660Val	missense_variant	28/28	ENST00000413689.6
SCN5A	NM_000335.5 linkuse as main transcript	c.4975A>G	p.Ile1659Val	missense_variant	28/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6 linkuse as main transcript	c.4978A>G	p.Ile1660Val	missense_variant	28/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7 linkuse as main transcript	c.4975A>G	p.Ile1659Val	missense_variant	28/28	1	NM_000335.5	A1	Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152050

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251490

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000615

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000670

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000646

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000872

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152050

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74258

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000134

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:5Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:7Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1660 of the SCN5A protein (p.Ile1660Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with Brugada syndrome or dilated cardiomyopathy and/or SCN5A-related conditions (PMID: 16414944, 20812931, 26173111, 29709101, 29759671, 30847666; Invitae). ClinVar contains an entry for this variant (Variation ID: 67947). 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 affects SCN5A function (PMID: 17075016). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Apr 23, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 09, 2022	Reported in association with LQTS, Brugada syndrome, and cardiomyopathy, though several individuals harbored additional variants (Napolitano et al., 2005; Cordeiro et al., 2006; Kapplinger et al., 2010; Postema et al., 2011; van Waning et al., 2018; van Lint et al., 2019; Burstein et al., 2021); Identified in an individual with Brugada syndrome who also harbored another SCN5A missense variant in trans; however, neither variant presented with Brugada syndrome when inherited alone (Cordeiro et al., 2006); Reported in one individual with a severe phenotype of mixed LQTS/Brugada features who also harbored an SCN5A gain-of-function variant (Postema et al., 2011); Observed in multiple unrelated individuals referred for cardiac genetic testing at GeneDx; however, segregation data for these families are inconclusive and one individual harbored an additional variant in another arrhythmia-related gene; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26187847, 24136861, 20129283, 22581653, 19336922, 18616619, 18436145, 30203441, 33131149, 20812931, 16414944, 17075016, 29402340, 29759671, 29728395, 32268277, 29709101, 29447731, 32048431, 30291343, 30847666, 29709244, 32746448, 31677787, 32569262, 34697415, 34649698) -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 18, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Dilated cardiomyopathy 1E

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Provincial Medical Genetics Program of British Columbia, University of British Columbia

Jan 01, 2022

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 08, 2022

The p.I1660V variant (also known as c.4978A>G), located in coding exon 27 of the SCN5A gene, results from an A to G substitution at nucleotide position 4978. The isoleucine at codon 1660 is replaced by valine, an amino acid with highly similar properties. This alteration has been detected in long QT syndrome (LQTS), Brugada syndrome, and left ventricular non-compaction (LVNC) cohorts and a subject with hypertrophic cardiomyopathy (HCM); however, clinical details were limited, and some cases had additional cardiac variants detected (Napolitano C et al. JAMA. 2005;294:2975-80; Kapplinger JD et al. Heart Rhythm. 2010;7:33-46; Selga E et al. PLoS ONE, 2015 Jul;10:e0132888; van Waning JI et al. J. Am. Coll. Cardiol., 2018 02;71:711-722; Amin AS et al. Int J Cardiol, 2018 Sep;266:128-132; Burstein DS et al. Pediatr Res, 2021 05;89:1470-1476). This alteration was described in an individual reported to have Brugada syndrome, who carried another SCN5A variant on the second allele. The proband's father and daughter who had this alteration in isolation did not display ECG phenotypes diagnostic of Brugada syndrome (Cordeiro JM et al. Circulation. 2006;114:2026-33). This alteration has also been reported in a healthy Dutch cohort and as a secondary finding in a whole exome sequencing cohort (Haer-Wigman L et al. Eur J Hum Genet, 2019 02;27:325-330; Diebold I et al. Hum Mutat, 2020 05;41:1025-1032). This alteration was also reported in an individual who also carried a gain-of-function mutation in SCN5A, and displayed features of both LQTS and Brugada syndrome (Postema PG et al. J Cardiovasc Electrophysiol. 2011;22:590-3). In addition, in vitro studies in TSA201 cells suggested that this alteration changed intracellular protein localization and abolished channel current, indicating a possible trafficking defect (Cordeiro JM et al. Circulation. 2006;114:2026-33). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Cardiac arrhythmia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

This missense variant replaces isoleucine with valine at codon 1660 of the SCN5A protein. This variant is also known as p.Ile1659Val in the literature based on a different NM_000335 transcript. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved region of the transmembrane domain DIV. Rare nontruncating variants in this region are overrepresented in individuals with Brugada syndrome (PMID: 32893267). A functional study has shown that this variant causes a loss of sodium channel current and affects intracellular SCN5A protein trafficking (PMID: 17075016). This variant has been reported in at least seven unrelated individuals with Brugada syndrome (PMID: 17075016, 20812931, 26173111, 29709101, 32268277, 32893267, 34649698, 36516610, 37061847) and in a few individuals suspected of having Brugada syndrome (PMID: 20129283, 29759671, 30847666). One of the affected individuals carried an additional pathogenic variant in the SCN5A gene and exhibited severe ECG abnormalities with a mixed phenotypic expression of Brugada syndrome and long QT syndrome (PMID: 20812931). This variant has also been reported in individuals with long QT syndrome (PMID: 16414944, 32893267), dilated cardiomyopathy (PMID: 36178741), noncompaction cardiomyopathy (PMID: 29447731), in an individual with hypertrophic cardiomyopathy who also carried a pathogenic variant in the MYBPC3 gene (PMID: 32746448), and in individuals with ventricular arrhythmia or other SCN5A-related conditions (ClinVar SCV001220057.3; communication with an external lab; Color internal data). This variant has been identified in 9/282866 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, the available evidence is not sufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

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:16414944). 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

Uncertain

0.38

CardioboostArm

Pathogenic

0.99

CardioboostCm

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.47

Cadd

Uncertain

Dann

Pathogenic

1.0

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.98

M_CAP

Pathogenic

0.59

MetaRNN

Pathogenic

0.81

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

MetaSVM

Pathogenic

1.1

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.89

N;N;N;N;N;N;N;N;N

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0010

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

Polyphen

0.99

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

Vest4

0.88

MVP

0.92

MPC

1.3

ClinPred

0.40

GERP RS

4.7

Varity_R

0.73

gMVP

0.95

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