rs45627438

Positions:

chr3-38604025-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP2

The ENST00000423572.7(SCN5A):c.1577G>A(p.Arg526His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,611,038 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign 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. R526C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 1 hom. )

Consequence

SCN5A
ENST00000423572.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.955

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.

PM1

In a modified_residue Omega-N-methylarginine; alternate (size 0) in uniprot entity SCN5A_HUMAN

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2 linkuse as main transcript	c.1577G>A	p.Arg526His	missense_variant	12/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5 linkuse as main transcript	c.1577G>A	p.Arg526His	missense_variant	12/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6 linkuse as main transcript	c.1577G>A	p.Arg526His	missense_variant	12/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7 linkuse as main transcript	c.1577G>A	p.Arg526His	missense_variant	12/28	1	NM_000335.5	ENSP00000398266	A1	Q14524-2

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000577

AC:

AN:

242632

Hom.:

AF XY:

0.0000531

AC XY:

AN XY:

131710

show subpopulations

Gnomad AFR exome

AF:

0.000136

Gnomad AMR exome

AF:

0.0000296

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000235

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000365

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000288

AC:

AN:

1458774

Hom.:

Cov.:

AF XY:

0.0000262

AC XY:

AN XY:

725338

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000226

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000163

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.0000664

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152264

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000787

Hom.:

Bravo

AF:

0.0000604

ESP6500AA

AF:

0.000247

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.0000579

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 11, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 2024	Observed in individuals reported to have HCM, DCM, and/or Brugada syndrome (Hershberger et al., 2008; Kapplinger et al., 2010; Sommariva et al., 2013; Alba et al., 2014; Priganc et al., 2016; Miszalski-Jamka et al., 2017; Berthome et al., 2019; Kuhnisch et al., 2019); Published functional studies are conflicting: some studies demonstrated that this variant results in loss of PKA-mediated phosyphorylation and dysregulation of trafficking and signaling, while other studies show function similar to wild type (Aiba et al., 2014; Hoshi et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 24795344, 19412328, 32048431, 24573164, 23414114, 20129283, 21726068, 23732518, 27554632, 25172307, 31333075, 23321620, 30193851, 28798025, 31568572, 33131149, 30203441, 32268277, 35163304, 33969014, 35932045) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 526 of the SCN5A protein (p.Arg526His). 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 and/or dilated cardiomyopathy, hypertrophic cardiomyopathy, or left ventricular hypertrabeculation (PMID: 19412328, 20129283, 23321620, 24795344, 27554632, 28798025, 30193851, 31568572; Invitae). ClinVar contains an entry for this variant (Variation ID: 67668). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SCN5A function (PMID: 24573164, 24795344). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

Brugada syndrome 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	in vitro;research	Roden Lab, Vanderbilt University Medical Center	-	We classified this variant using data from the calibrated functional assay 'ParSE-seq' (PMID: 37732247), population data, and in silico data within the ACMG v3 framework (PMID: 25741868)The SCN5A variant, 3-38604025-C-T was evaluated for association with the loss-of-function condition Brugada Syndrome.This Variant had an AF of 0.0000526 in gnomAD v3The in silico predictor SpliceAI scored the variant as 0.2278; normal <0.2, likely damaging >0.5.Using the functional RNA-splicing assay, ParSE-seq, the variant was evaluated to have an indeterminate impact on splicing following the Brnich et al. calibration framework (PMID: 31892348). In aggregate, we therefore classify this variant as VUS using these collective data. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Cardiac arrhythmia

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 02, 2023	This missense variant replaces arginine with histidine at codon 526 of the SCN5A protein. Histidine residue is tolerated in over 15 mammalian species, suggesting that this variant may be tolerated for SCN5A function. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have provided conflicting information about the effect of this variant on the SCN5A sodium channel function, with one study reporting insignificant impact (PMID: 24573164) and another study reporting reduced basal sodium current densities and reduced protein expression at the cell surface (PMID: 24795344). This variant has been reported in four individuals affected with Brugada syndrome (PMID 23321620, 24795344, 30193851, 32268277, 32893267), two individuals suspected of having Brugada syndrome (PMID: 20129283), one individual with unspecified arrhythmia (Mizusawa 2016, dissertation, University of Amsterdam), six individuals with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 19412328, 27554632, 31568572), and one individual affected with left ventricular hypertrabeculation (PMID: 28798025). This variant has also been identified in 15/274016 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 23, 2024	This missense variant replaces arginine with histidine at codon 526 of the SCN5A protein. Histidine residue is tolerated in over 15 mammalian species, suggesting that this variant may be tolerated for SCN5A function. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that the variant does not cause a significant difference in recovery from inactivation and steady-state inactivation parameters (PMID: 24573164). However, the variant results in both reduced basal Na+ current densities, due to absence of phosphorylation and reduced cell surface channel expression, and absence of augmentation of current densities by beta-adrenergic stimulation (PMID: 24795344). Post-translational methylation of arginine at codon 526 has been proposed as a possible mechanism behind reduced sodium current in end-stage heart failure (PMID: 25172307). Clinical relevance of these functional observations is not known. This variant has been reported in a few individuals affected with Brugada syndrome (PMID: 24795344, 32268277, 32893267), two individuals suspected of having Brugada syndrome (PMID: 20129283), one individual with unspecified arrhythmia (Mizusawa 2016, dissertation, University of Amsterdam), four individuals with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 27554632, 31568572), and one individual affected with left ventricular hypertrabeculation (PMID: 28798025). This variant has not been identified 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. -

Primary familial hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Klaassen Lab, Charite University Medicine Berlin

Jul 03, 2019

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 27, 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. -

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: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

Benign

0.065

CardioboostCm

Benign

0.0015

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Uncertain

0.51

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

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.83

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

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.053

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.54

MutationAssessor

Benign

0.080

.;N;.;.;.;N;.;.;.

MutationTaster

Benign

0.96

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

PrimateAI

Benign

0.19

PROVEAN

Benign

-0.94

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

REVEL

Uncertain

0.48

Sift

Benign

0.46

T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.28

T;T;T;T;T;T;T;T;T

Polyphen

0.0

B;B;.;B;.;B;B;.;.

Vest4

0.17

MVP

0.92

MPC

0.43

ClinPred

0.014

GERP RS

1.7

Varity_R

0.032

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.22

Position offset: -25

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