rs199473175

Positions:

• chr3-38585749-G-A
• chr3-38585749-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_001099404.2(SCN5A):​c.2729C>T​(p.Ser910Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,360 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1 O:1
• Conservation: PhyloP100: 8.04

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 10 ACMG points.

• PM1: In a repeat II (size 270) in uniprot entity SCN5A_HUMAN there are 47 pathogenic changes around while only 2 benign (96%) 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, 0.957
• PP5: Variant 3-38585749-G-A is Pathogenic according to our data. Variant chr3-38585749-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67753.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, not_provided=1, Uncertain_significance=1, Pathogenic=1}. Variant chr3-38585749-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.2729C>T	p.Ser910Leu	missense_variant	16/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.2729C>T	p.Ser910Leu	missense_variant	16/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.2729C>T	p.Ser910Leu	missense_variant	16/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7	c.2729C>T	p.Ser910Leu	missense_variant	16/28	1	NM_000335.5	ENSP00000398266	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250430 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135602

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461360 Hom.: 0 Cov.: 36 AF XY: 0.00000275 AC XY: 2 AN XY: 726958

Gnomad4 AFR exome AF: 0.0000299

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

Bravo AF: 0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Brugada syndrome Pathogenic:1 Uncertain: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:11901046;PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 04, 2024	proposed classification - variant undergoing re-assessment, contact laboratory -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 18, 2023	This missense variant replaces serine with leucine at codon 910 of the SCN5A protein. This variant is found within a highly conserved region of the transmembrane domain DII. Rare nontruncating variants in this region (a.a. 718 - 938) have been shown to be significantly overrepresented in individuals with Brugada syndrome (PMID: 32893267). A functional study has shown that this variant causes reduced cell surface expression of the SCN5A protein and decreased sodium current density compared to wild-type cells, indicating a trafficking deficit (PMID: 24768612). This variant has been reported in at least 6 unrelated individuals affected with or suspected of having Brugada syndrome (PMID: 11901046, 20129283, 24768612, 26173111, 28087566, 29574140, 32268277, 32893267), and several other individuals affected with sick sinus syndrome, atrial standstill, ventricular fibrillation, or dilated cardiomyopathy (PMID: 28104484, 31983221, 36147716, ClinVar SCV000741704.3). This variant has been identified in 1/250430 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 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 01, 2024	Reported in individuals with features consistent with or suggestive of Brugada syndrome and in individuals with sick sinus syndrome and DCM (PMID: 20129283, 11901046, 26173111, 28104484, 31983221); Reported in a child who experienced cardiac arrest with ventricular fibrillation and in her asymptomatic mother, both of whom had a positive ajmaline test (PMID: 24768612); Published in vitro analysis showed that S910L destroys channel peak current and has a dominant negative effect on current density (PMID: 24768612, 35305865); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30193851, 15655131, 14753626, 12650874, 24768612, 14961552, 31983221, 25904541, 32268277, 30662450, 20100972, 25274057, 22999724, 22840528, 22766342, 19251209, 18378609, 17210839, 16684018, 16453024, 15840476, 14523039, 12736279, 10940383, 10471492, 32533946, 28104484, 26173111, 33131149, 29574140, 11901046, 33164571, 34461752, 36147716, 30203441, 35130036, 20129283, 37652022, 35305865) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 23, 2022	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SCN5A function (PMID: 24768612). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 67753). This missense change has been observed in individuals with Brugada syndrome or sick sinus syndrome (PMID: 11901046, 24768612, 26173111, 28104484, 29574140; 20129283.). This variant is present in population databases (rs199473175, gnomAD 0.0009%). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 910 of the SCN5A protein (p.Ser910Leu). -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 30, 2023

The p.S910L variant (also known as c.2729C>T), located in coding exon 15 of the SCN5A gene, results from a C to T substitution at nucleotide position 2729. The serine at codon 910 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in Brugada syndrome cohorts and individuals reported to have Brugada syndrome, cardiac arrest, ventricular arrhythmia or atrial standstill; however, in some cases clinical details were limited and some cohorts may overlap (Priori SG et al. Circulation, 2002;105:1342-7, Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46; Pambrun T et al. Heart Rhythm, 2014;11:1393-400; Selga E et al. PLoS ONE, 2015;10:e0132888; Ishikawa T et al. Heart Rhythm, 2017 May;14:717-724; Sonoda K et al. Heart Rhythm, 2018 Aug;15:1179-1188; Berthome P et al. Heart Rhythm, 2019 Feb;16:260-267; Kato Y et al. HeartRhythm Case Rep, 2022 Sep;8:636-638). This variant has also been detected in a dilated cardiomyopathy cohort; however, details were limited (Mazzarotto F et al. Circulation, 2020 Feb;141:387-398). A functional study found no visible-gated sodium current at any potential in p.S910L transfected cells as well as reduced cell surface expression of p.S910L channels compared to wild type. In addition, co-expression of p.S910L and wild-type resulted in a significant decrease in fast sodium current density by 49% compared to wild-type alone, suggesting this alteration has a dominant negative effect (Pambrun T et al. Heart Rhythm, 2014;11:1393-400). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved through mammals, but not in all 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
CardioboostCm	Uncertain	0.18
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	.;.;.;.;.;D;.;.;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.97	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Uncertain	2.3	.;M;.;.;.;M;.;.;.
MutationTaster	Benign	0.79	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.6	D;D;D;D;N;D;D;N;N
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;D;P;.;.
Vest4		0.89
MutPred		0.85		Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);
MVP		0.95
MPC		0.93
ClinPred		0.97	D
GERP RS		4.2
Varity_R		0.41
gMVP		0.94

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

Other links and lift over

dbSNP: rs199473175; hg19: chr3-38627240; COSMIC: COSV100347038;