chr3-38606743-C-T

Position:

chr3-38606743-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_001099404.2(SCN5A):c.1066G>A(p.Asp356Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D356Y) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

SCN5A
NM_001099404.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5O:1

Conservation

PhyloP100: 7.91

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 Pathogenic. Variant got 19 ACMG points.

PM1

In a strand (size 2) in uniprot entity SCN5A_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001099404.2

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-38606743-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 637989.Status of the report is criteria_provided_single_submitter, 1 stars.

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

PP5

Variant 3-38606743-C-T is Pathogenic according to our data. Variant chr3-38606743-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38606743-C-T is described in Lovd as [Pathogenic]. Variant chr3-38606743-C-T 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.1066G>A	p.Asp356Asn	missense_variant	9/28	ENST00000413689.6
SCN5A	NM_000335.5 linkuse as main transcript	c.1066G>A	p.Asp356Asn	missense_variant	9/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6 linkuse as main transcript	c.1066G>A	p.Asp356Asn	missense_variant	9/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7 linkuse as main transcript	c.1066G>A	p.Asp356Asn	missense_variant	9/28	1	NM_000335.5	A1	Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152260

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

249040

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135134

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461564

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727060

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74386

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 01, 2023	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 356 of the SCN5A protein (p.Asp356Asn). 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 autosomal dominant Brugada syndrome, as well as several individuals referred for Brugada syndrome testing (PMID: 16325048, 20129283, 26173111, 29574140, 30193851, 31737537, 32931854, 33131149). ClinVar contains an entry for this variant (Variation ID: 67632). 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: 16325048, 21840964). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2023	Reported multiple times in association with Brugada syndrome in published literature (Makiyama et al., 2005; Hedley et al., 2009; Kapplinger et al., 2010; Kanter et al., 2012; Walsh et al., 2014; Selga et al., 2015; Sonoda et al., 2018; Berthome et al., 2019; Milman et al., 2021); Identified in a patient with sick sinus syndrome (SSS) and hypothyroidism in published literature (Yamane et al., 2022); Identified in a patient with early onset drug-resistant epilepsy who also harbored a de novo pathogenic variant in the SCN1A gene (Tsang et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In vitro functional studies have demonstrated that p.(D356N) creates a non-functional sodium channel (Makiyama et al., 2005; Shinlapawittayatorn et al., 2011); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25863800, 18616619, 19606473, 29574140, 24903439, 22090165, 19027780, 18436145, 26154754, 22885917, 17504259, 21840964, 25904541, 16325048, 26173111, 30662450, 24136861, 30193851, 31737537, 33131149, 20129283, 35650162, 30868116, 22090166, 34461752, 30203441, 32931854) -

Brugada syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

May 09, 2018

- -

Brugada syndrome (shorter-than-normal QT interval)

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Feb 20, 2017

Variant summary: The SCN5A c.1066G>A (p.Asp356Asn) variant involves the alteration of a conserved nucleotide, is predicted to be damaging by 4/5 in silico tools and is located in Ion transport domain/S5-S6 extracellular loop that constitutes the pore region ((InterPro, Kapplinger_2010, Shinlapawittayatorn_2011). This variant is absent in 123598 control chromosomes from ExAC. This variant has been reported in at least 10 individuals with clinical features of Brugada syndrome and Brugada syndrome plus cardiac conduction defect (Makiyama_2005, Kapplinger_2010, Kanter_2012, Chockalingam_2012, Selga_2015). This variant was found to be one of four recurrent mutations in an international compendium of mutations in the SCN5A in patients referred for Brugada syndrome genetic testing (Kapplinger_2010). In vitro functional assays in HEK293 cells show that this variant leads to defective sodium current (Makiyama_2005, Shinlapawittayatorn_2011). One clinical diagnostic laboratory has classified this variant as likely pathogenic. Missense variants around this region such as p.D349N, p.G351D, p.G351V, p.T353I, p.Y352C, p.R367C, p.R367H, p.R367L, etc. have been reported in patients with BrS and other cardiac diseases, highlighting the functional importance of this region/domian. Taken together, this variant is classified as Pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 17, 2024

The p.D356N variant (also known as c.1066G>A), located in coding exon 8 of the SCN5A gene, results from a G to A substitution at nucleotide position 1066. The aspartic acid at codon 356 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in multiple subjects with Brugada syndrome (Makiyama T, J. Am. Coll. Cardiol. 2005 Dec; 46(11):2100-6; Kapplinger JD, Heart Rhythm 2010 Jan; 7(1):33-46; Kanter RJ, Circulation 2012 Jan; 125(1):14-22; Mellor G et al. Circ Cardiovasc Genet, 2017 Jun;10). In addition, in vitro studies have indicated that this alteration has a functional impact on sodium current (Makiyama T, J. Am. Coll. Cardiol. 2005 Dec; 46(11):2100-6; Shinlapawittayatorn K, Circ Cardiovasc Genet 2011 Oct; 4(5):500-9; O'Neill MJ et al. Genet Med. 2022 Jun;24(6):1238-1248). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Brugada 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 Brugada syndrome in the following publications (PMID:16325048;PMID:20129283). 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

Pathogenic

0.90

CardioboostCm

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

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

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

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

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.99

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.0

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

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-4.9

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

REVEL

Pathogenic

0.96

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

1.0

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

Vest4

0.99

MutPred

0.95

Loss of phosphorylation at Y352 (P = 0.1019);Loss of phosphorylation at Y352 (P = 0.1019);Loss of phosphorylation at Y352 (P = 0.1019);Loss of phosphorylation at Y352 (P = 0.1019);Loss of phosphorylation at Y352 (P = 0.1019);Loss of phosphorylation at Y352 (P = 0.1019);Loss of phosphorylation at Y352 (P = 0.1019);Loss of phosphorylation at Y352 (P = 0.1019);Loss of phosphorylation at Y352 (P = 0.1019);

MVP

0.98

MPC

1.1

ClinPred

1.0

GERP RS

4.7

Varity_R

0.89

gMVP

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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