chr3-38575386-G-A

Position:

chr3-38575386-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM5PP2

The NM_001099404.2(SCN5A):c.3577C>T(p.Arg1193Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000317 in 1,609,246 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R1193Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

SCN5A
NM_001099404.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.28

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 Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-38575385-C-T is described in Lovd as [Pathogenic].

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2 linkuse as main transcript	c.3577C>T	p.Arg1193Trp	missense_variant	20/28	ENST00000413689.6
SCN5A	NM_000335.5 linkuse as main transcript	c.3574C>T	p.Arg1192Trp	missense_variant	20/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6 linkuse as main transcript	c.3577C>T	p.Arg1193Trp	missense_variant	20/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7 linkuse as main transcript	c.3574C>T	p.Arg1192Trp	missense_variant	20/28	1	NM_000335.5	A1	Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000746

AC:

AN:

241216

Hom.:

AF XY:

0.0000766

AC XY:

AN XY:

130560

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000595

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.000563

Gnomad SAS exome

AF:

0.0000682

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000276

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000295

AC:

AN:

1456928

Hom.:

Cov.:

AF XY:

0.0000331

AC XY:

AN XY:

724246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000680

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000253

Gnomad4 SAS exome

AF:

0.0000587

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000773

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000887

Hom.:

Bravo

AF:

0.0000567

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 17, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1193 of the SCN5A protein (p.Arg1193Trp). This variant is present in population databases (rs192379242, gnomAD 0.05%). This missense change has been observed in individual(s) with a sudden unexpected death in epilepsy (PMID: 31776209). ClinVar contains an entry for this variant (Variation ID: 201497). 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. 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, criteria provided, single submitter	clinical testing	GeneDx	Jan 31, 2017	The R1193W variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R1193W variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R1193W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is mostly conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense mutations in nearby residues (A1186T, R1195H, Y1199S) have been reported in association with arrhythmia, supporting the functional importance of this region of the protein. Nevertheless, the 1000 Genomes Project reports R1193W was observed in 0.5% (1 in 192) alleles from individuals of a sub-population of Asian background. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. -

Cardiac arrhythmia

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This missense variant replaces arginine with tryptophan at codon 1193 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with sudden unexpected death in epilepsy (PMID: 31776209). This variant has been identified in 18/241216 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 23, 2023	This missense variant replaces arginine with tryptophan at codon 1193 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with sudden unexpected death in epilepsy (PMID: 31776209). This variant has been identified in 18/241216 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Arrhythmogenic right ventricular cardiomyopathy

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Cardiac Research Department, West China Second University Hospital

Jun 14, 2022

- -

Brugada syndrome;C1859062:Long QT syndrome 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Sep 09, 2015

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 16, 2021

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

Benign

0.20

CardioboostCm

Benign

0.013

BayesDel_addAF

Benign

-0.083

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.84

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

Eigen

Benign

0.14

Eigen_PC

Benign

0.048

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.90

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

M_CAP

Pathogenic

0.34

MetaRNN

Uncertain

0.70

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

MetaSVM

Uncertain

0.35

MutationAssessor

Uncertain

2.3

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

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-4.0

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

REVEL

Pathogenic

0.65

Sift

Uncertain

0.0090

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

Sift4G

Uncertain

0.0070

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

Polyphen

0.99

D;P;.;D;.;P;D;.;.

Vest4

0.76

MVP

0.65

MPC

1.3

ClinPred

0.77

GERP RS

-0.11

Varity_R

0.33

gMVP

0.86

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