chr3-38630342-G-A

Position:

• chr3-38630342-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001099404.2(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 Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 0.970

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]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a helix (size 7) in uniprot entity SCN5A_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) 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 chr3-38630341-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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, 0.991
• 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/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.361C>T	p.Arg121Trp	missense_variant	3/28	ENST00000413689.6
SCN5A	NM_000335.5	c.361C>T	p.Arg121Trp	missense_variant	3/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.361C>T	p.Arg121Trp	missense_variant	3/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.361C>T	p.Arg121Trp	missense_variant	3/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461190 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726930

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.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

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) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 02, 2023	For these reasons, this variant has been classified as Pathogenic. 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). -

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 24, 2017

- -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2017

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. 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	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	.;.;.;.;.;D;.;.;.;D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Pathogenic	1.0	.;D;D;D;D;D;D;.;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	.;M;.;.;.;M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.69	T
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	D
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

Other links and lift over

dbSNP: rs199473556; hg19: chr3-38671833; COSMIC: COSV60067309; COSMIC: COSV60067309;