chr3-38630342-G-A

Variant names:

Variant summary

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

The NM_000335.5(SCN5A):c.361C>T(p.Arg121Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,190 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. R121Q) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SCN5A
NM_000335.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6O:1

Conservation

PhyloP100: 0.970

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PM1

In a helix (size 7) in uniprot entity SCN5A_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000335.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-38630341-C-T is described in Lovd as [Pathogenic].

PP2

Missense variant in the SCN5A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 99 curated pathogenic missense variants (we use a threshold of 10). The gene has 60 curated benign missense variants. Gene score misZ: 2.7504 (below the threshold of 3.09). Trascript score misZ: 4.8279 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.991

PP5

Variant 3-38630342-G-A is Pathogenic according to our data. Variant chr3-38630342-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38630342-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2 link	c.361C>T	p.Arg121Trp	missense_variant	Exon 3 of 28	ENST00000413689.6	NP_001092874.1	Q14524H9KVD2
SCN5A	NM_000335.5 link	c.361C>T	p.Arg121Trp	missense_variant	Exon 3 of 28	ENST00000423572.7	NP_000326.2	Q14524-2Q86V90

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6 link	c.361C>T	p.Arg121Trp	missense_variant	Exon 3 of 28	5	NM_001099404.2	ENSP00000410257.1		H9KVD2
SCN5A	ENST00000423572.7 link	c.361C>T	p.Arg121Trp	missense_variant	Exon 3 of 28	1	NM_000335.5	ENSP00000398266.2		Q14524-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461190

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726930

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Brugada syndrome 1

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	Sep 24, 2024	Heterozygous variant NM_000335.5:c.361C>T (p.Arg121Trp) in the SCN5A gene was found on WES data in male proband (9 y.o., Caucasian) with Brugada syndrome. This genetic variant is in The Genome Aggregation Database (gnomAD) v4.1.0 with total MAF 0.000001859 (Date of access 23-09-2024). Clinvar contains an entry for this variant (Variation ID: 67807). This variant located in a mutational hot spot and/or critical and well-established functional domain (PM1_moderate according to Walsh R. et al. (PMID: 32893267). Most in silico predictors show pathogenic result of the protein change (varsome.com). Published functional studies demonstrate a significant reduction of sodium current and reduced amounts of sodium channels (Holst et al., 2010; Clatot et al., 2012). This variant is associated with the following publications: (PMID: 31737537, 26173111, 28449774, 20395683, 22739120, 23874304, 20129283, 25863800, 23123192, 19606473, 24136861, 25904541, 30662450). In accordance with ACMG (2015) criteria this variant is classified as Pathogenic with following criteria selected: PM2, PM5, PP3, PS3, PM1, PP5. -
Pathogenic, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	May 24, 2017	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 02, 2023	This variant disrupts the p.Arg121 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20129283, 24529773). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects SCN5A function (PMID: 20395683, 22739120). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 32533946) indicates that this missense variant is expected to disrupt SCN5A function. ClinVar contains an entry for this variant (Variation ID: 67807). This missense change has been observed in individuals with Brugada syndrome (PMID: 19606473, 20129283, 20395683, 24136861, 26173111, 28449774). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 121 of the SCN5A protein (p.Arg121Trp). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2020	Identified in at least two unrelated individuals with Brugada syndrome in published literature (Kapplinger et al., 2010; Selga et al., 2015); Identified in a patient with arrhythmia and was also identified in his father who had a milder phenotype (Holst et al., 2010); Identified in a patient with sudden arrhythmic death syndrome (SADS) who had no cardiac symptoms prior to death and was also identified in his mother and brother who showed Brugada pattern on electrocardiogram (Lahrouchi et al., 2017); Not observed in large population cohorts (Lek et al., 2016); Reported as pathogenic/likely pathogenic in ClinVar but additional evidence is not available (ClinVar Variant ID#67807; Landrum et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a significant reduction of sodium current and reduced amounts of sodium channels (Holst et al., 2010; Clatot et al., 2012); A different missense change at this residue (R121Q) has been reported as pathogenic in ClinVar (ClinVar SCV#67808; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31737537, 26173111, 28449774, 20395683, 22739120, 23874304, 20129283, 25863800, 23123192, 19606473, 24136861, 25904541, 30662450) -

Dilated cardiomyopathy 1E;C1859062:Long QT syndrome 3;C1879286:Progressive familial heart block, type 1A;C3151464:Atrial fibrillation, familial, 10;C4551804:Brugada syndrome 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

A heterozygous missense variant in exon 3 of the SCN5A gene that results in the amino acid substitution of Tryptophan for Arginine at codon 121 was detected. The observed variant c.361C>T (p.Arg121Trp) has not been reported in the 1000 genomes and gnomAD databases. The in silico prediction of the variant are damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 28, 2024

The p.R121W variant (also known as c.361C>T), located in coding exon 2 of the SCN5A gene, results from a C to T substitution at nucleotide position 361. The arginine at codon 121 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in association with Brugada syndrome (Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46; Hertz CL et al. Int. J. Legal Med., 2015 Jul;129:793-800; Leong KM et al. HeartRhythm Case Rep, 2017 Mar;3:167-171). This alteration was also reported in a proband and his father who both had cardiac conduction disease (Holst AG et al. Cardiology, 2010 Apr;115:311-6). In addition, functional studies demonstrate a reduction of sodium current and are consistent with a dominant negative effect through retention in the endoplasmic reticulum (Holst AG et al. Cardiology, 2010 Apr;115:311-6; Clatot J et al. Cardiovasc. Res., 2012 Oct;96:53-63). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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:19606473;PMID:20129283;PMID:20395683;PMID:22739120). 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

0.92

CardioboostCm

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

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

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.84

LIST_S2

Pathogenic

1.0

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

M_CAP

Pathogenic

0.60

MetaRNN

Pathogenic

0.99

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.5

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

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-7.6

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

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.99

MutPred

0.94

Loss of methylation at K126 (P = 0.046);Loss of methylation at K126 (P = 0.046);Loss of methylation at K126 (P = 0.046);Loss of methylation at K126 (P = 0.046);Loss of methylation at K126 (P = 0.046);Loss of methylation at K126 (P = 0.046);Loss of methylation at K126 (P = 0.046);Loss of methylation at K126 (P = 0.046);Loss of methylation at K126 (P = 0.046);Loss of methylation at K126 (P = 0.046);

MVP

0.98

MPC

1.1

ClinPred

0.99

GERP RS

4.2

Varity_R

0.92

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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

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