rs137854612

Positions:

• chr3-38560170-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001099404.2(SCN5A):​c.4222G>A​(p.Gly1408Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/24 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 7.83

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 17 ACMG points.

• PM1: In a intramembrane_region Pore-forming (size 21) in uniprot entity SCN5A_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_001099404.2
• 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 4.7729 (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, 0.995
• PP5: Variant 3-38560170-C-T is Pathogenic according to our data. Variant chr3-38560170-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 9395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38560170-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.4222G>A	p.Gly1408Arg	missense_variant	23/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.4219G>A	p.Gly1407Arg	missense_variant	23/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.4222G>A	p.Gly1408Arg	missense_variant	23/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7	c.4219G>A	p.Gly1407Arg	missense_variant	23/28	1	NM_000335.5	ENSP00000398266	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460908 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726650

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 27, 2024	Published functional studies indicated mutant channels failed to produce inward sodium currents despite normal surface localization, suggesting a gating defect (PMID: 20539757); In silico analysis supports that this missense variant has a deleterious effect on 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.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27766308, 27381756, 28150151, 17368591, 26154754, 28018021, 28341781, 32569262, 31993492, 30147658, 34219138, 34436362, ONeill2021, 34649698, 34814702, 34147702, 33131149, 19251209, 30662450, 20031634, 30193851, 30203441, 37745129, 20129283, 20539757, 11748104, 14523039) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 22, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1408 of the SCN5A protein (p.Gly1408Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with first-degree heart block as a dominant trait and with sick sinus syndrome (SSS) as a recessive trait and Brugada syndrome (BrS) and isolated cardiac conduction disease in a large multigenerational family (PMID: 11748104, 14523039, 20129283). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9395). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	SCN5A: PM1, PM2, PS4:Moderate, PP1, PP3, PP4, PS3:Supporting -

Brugada syndrome Pathogenic:1 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:11748104;PMID:14523039;PMID:19251209;PMID:20129283;PMID:20539757). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Jan 13, 2017	- -

Brugada syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2003

- -

SUDDEN INFANT DEATH SYNDROME;C1832680:Dilated cardiomyopathy 1E;C1837845:Sick sinus syndrome 1;C1859062:Long QT syndrome 3;C1879286:Progressive familial heart block, type 1A;C2751898:Ventricular fibrillation, paroxysmal familial, type 1;C3151464:Atrial fibrillation, familial, 10;C4551804:Brugada syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 08, 2022

- -

Conduction system disorder Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2003

- -

Sick sinus syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2003

- -

Congenital long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Dec 07, 2023

The c.4222G>A (p.Gly1408Arg) variant in the SCN5A gene replaces glycine with arginine in codon 1408 of the SCN5A protein. This variant has been reported in individuals with Brugada syndrome and segregated with disease in members of a family (PMID: 11748104, 20129283, 36516610). Functional assays have shown disruptive impact of this variant on the protein (PMID: 11748104, 20539757). Computational models predict a deleterious impact of this variant on the translated protein. ClinVar contains an entry for this variant (Variation ID: 9395). This variant is absent in the population database (gnomAD). Based on the available evidence this variant is classified as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2023

The p.G1408R pathogenic mutation (also known as c.4222G>A), located in coding exon 22 of the SCN5A gene, results from a G to A substitution at nucleotide position 4222. The glycine at codon 1408 is replaced by arginine, an amino acid with dissimilar properties, and is located in the DIII-S5/S6 region. This variant (referred to as G1406R) has been reported to segregate either with Brugada syndrome (BrS) or cardiac conduction disease in one large family (Kyndt F et al. Circulation, 2001 Dec;104:3081-6). In another family, this variant segregated with sick sinus syndrome in three siblings with a second SCN5A variant, while individuals with only p.G1408R had heart block or normal ECGs (Benson DW et al. J. Clin. Invest., 2003 Oct;112:1019-28). This variant has also been detected in several unrelated individuals from a BrS cohort (Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46). In vitro assays have reported this variant to result in channels with low-to-no detectable current despite normal protein trafficking (Kyndt F et al. Circulation, 2001 Dec;104:3081-6; Benson DW et al. J. Clin. Invest., 2003 Oct;112:1019-28Gui J et al. PLoS ONE, 2010 Jun;5:e10985). In addition, this variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	.;.;.;.;.;D;.;.;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.7	.;.;.;.;.;H;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-7.8	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;D;D;.;.
Vest4		0.98
MutPred		0.98		Gain of methylation at G1408 (P = 0.0071);.;Gain of methylation at G1408 (P = 0.0071);Gain of methylation at G1408 (P = 0.0071);.;Gain of methylation at G1408 (P = 0.0071);.;.;.;
MVP		0.99
MPC		1.6
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.97
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.24		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs137854612; hg19: chr3-38601661; COSMIC: COSV104658845;