rs199473083

Positions:

chr3-38609823-C-T

Variant summary

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

The ENST00000423572.7(SCN5A):c.845G>A(p.Arg282His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,618 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R282C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

SCN5A
ENST00000423572.7 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8O:2

Conservation

PhyloP100: 1.72

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 3) in uniprot entity SCN5A_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in ENST00000423572.7

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-38609824-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 68047.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Pathogenic=1, Uncertain_significance=3, not_provided=1}.

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, 0.96

PP5

Variant 3-38609823-C-T is Pathogenic according to our data. Variant chr3-38609823-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38609823-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2 linkuse as main transcript	c.845G>A	p.Arg282His	missense_variant	7/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5 linkuse as main transcript	c.845G>A	p.Arg282His	missense_variant	7/28	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.845G>A	p.Arg282His	missense_variant	7/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7 linkuse as main transcript	c.845G>A	p.Arg282His	missense_variant	7/28	1	NM_000335.5	ENSP00000398266	A1	Q14524-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

249398

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135288

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:

0.0000464

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461618

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727098

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jun 09, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 27, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 01, 2024	Published functional studies demonstrate a damaging effect as this variant results in significant reduction of sodium current density in SCN5A channels (PMID: 15828879, 16864729, 21840964); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27153395, 15828879, 21840964, 22581653, 28341781, 30662450, 20625312, 32893267, 11901046, 29574140, 36204818, 36516610, 33131149, 30203441, 31440721, 35305865, 16864729) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Oct 02, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2023	ClinVar contains an entry for this variant (Variation ID: 68048). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SCN5A function (PMID: 15828879, 16864729). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This missense change has been observed in individuals with Brugada syndrome (PMID: 11901046, 15828879, 28341781). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs199473083, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 282 of the SCN5A protein (p.Arg282His). -

Brugada syndrome

Pathogenic:1Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 27, 2024	This missense variant replaces arginine with histidine at codon 282 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). Functional studies have shown that this variant causes a large reduction in sodium channel current due to the defect in trafficking to cell surface (PMID: 15828879, 16864729, 21840964, 35305865). This variant has been reported in at least nine unrelated individuals affected with Brugada syndrome (PMID: 11901046, 20625312, 28341781, 30662450, 32893267). This variant has been shown to segregate with disease in five individuals affected with Brugada syndrome in two families and also seen in one unaffected family member (PMID: 14607451, 15828879, 16864729). This variant has been identified in 4/249398 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
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:11901046;PMID:15828879;PMID:21840964). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 20, 2022

The c.845G>A (p.R282H) alteration is located in exon 7 (coding exon 6) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 845, causing the arginine (R) at amino acid position 282 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of 0.0016% (4/249398) total alleles studied. The highest observed frequency was 0.0056% (1/17976) of East Asian alleles. This alteration has been reported in several individuals with Brugada syndrome (Priori, 2002; Itoh, 2005; Poelzing, 2006; Pitzalis, 2003; Sonoda, 2018; Yamagata, 2017). Additionally, some studies have suggested co-occurrence with a different SCN5A alteration (H558R), a common polymorphism, may rescue the function of the mutant channel protein, which may partially account for the reduced penetrance observed for the variant in disease (Poelzing, 2006; Shinlapawittayatorn, 2011). This amino acid position is highly conserved in available vertebrate species. In vitro functional studies have demonstrated the alteration has a deleterious impact on sodium channel function (Itoh, 2005; Poelzing, 2006). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Cardiac arrhythmia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 05, 2023

This missense variant replaces arginine with histidine at codon 282 of the SCN5A protein. This variant is found within the highly conserved pore-forming region of transmembrane domain DI (a.a. 277-389). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome and long QT syndrome (PMID: 32893267). Functional studies have shown that this variant causes a large reduction in sodium channel current due to the defect in trafficking to cell surface (PMID: 15828879, 16864729, 21840964, 35305865). This variant has been reported in at least nine unrelated individuals affected with Brugada syndrome (PMID: 11901046, 20625312, 28341781, 30662450, 32893267). This variant has been shown to segregate with disease in five individuals affected with Brugada syndrome in two families and also seen in one unaffected family member (PMID: 14607451, 15828879, 16864729). This variant has also been reported in an individual affected with dilated cardiomyopathy (PMID: 29095814) and in another individual affected with fever-induced Brugada syndrome (PMID: 36516610). This variant has been identified in 4/249398 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Brugada syndrome 1

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

CardioboostCm

Uncertain

0.16

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

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

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.96

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

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.96

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.5

.;L;.;.;.;L;.;.;.

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-2.5

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

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0090

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

Sift4G

Uncertain

0.018

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

Polyphen

1.0

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

Vest4

0.87

MutPred

0.89

Gain of catalytic residue at N283 (P = 0.0428);Gain of catalytic residue at N283 (P = 0.0428);Gain of catalytic residue at N283 (P = 0.0428);Gain of catalytic residue at N283 (P = 0.0428);Gain of catalytic residue at N283 (P = 0.0428);Gain of catalytic residue at N283 (P = 0.0428);Gain of catalytic residue at N283 (P = 0.0428);Gain of catalytic residue at N283 (P = 0.0428);Gain of catalytic residue at N283 (P = 0.0428);

MVP

0.96

MPC

1.3

ClinPred

0.89

GERP RS

5.3

Varity_R

0.46

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