3-38566426-C-T

Position:

• chr3-38566426-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001099404.2(SCN5A):​c.3823G>A​(p.Asp1275Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 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: 0.0000048 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• Conservation: PhyloP100: 7.91

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 15 ACMG points.

• 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 3-38566426-C-T is Pathogenic according to our data. Variant chr3-38566426-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 9401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38566426-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.3823G>A	p.Asp1275Asn	missense_variant	21/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.3820G>A	p.Asp1274Asn	missense_variant	21/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.3823G>A	p.Asp1275Asn	missense_variant	21/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7	c.3820G>A	p.Asp1274Asn	missense_variant	21/28	1	NM_000335.5	ENSP00000398266	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251372 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135858

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461378 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726966

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000615 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2022	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect on channel function (Gui et al., 2010; Watanabe et al., 2011; Hayano et al., 2017) and cardiac phenotypes in zebrafish and mouse models (Watanabe et al., 2011; Huttner et al., 2013); This variant is associated with the following publications: (PMID: 24573164, 23838598, 17368591, 23791817, 28018021, 27554632, 24136861, 20384651, 21167004, 18697752, 20129283, 26798387, 22749884, 24778431, 14523039, 22337857, 23178427, 24300601, 12522116, 24762805, 26111534, 21824921, 20539757, 22247482, 28637969, 28294644, 29579189, 15998690, 3953067, 19251209, 8567977, 25904541, 15671429, 15466643, 16684018, 21596231, 30662450, 31125670, 31514951, 30193851, 33131149, 33164571, 29709244) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Feb 24, 2014	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Asp1275Asn (D1275N; c.3823 G>A) in the SCN5A gene GeneDx classifies this as a published disease-causing mutation. We classify it as very likely disease causing as well, concluding that there is sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing in family members. When screening family members clinically, it is important to note this variant’s association with dilated cardiomyopathy (DCM) in addition to arrhythmias. Variants in the SCN5A gene have been reported in a variety of cardiac conditions including sick sinus syndrome, conduction system defects, dilated cardiomyopathy, Brugada syndrome, and long QT syndrome type 3. This particular variant has been reported multiple times in association with arrhythmias and dilated cardiomyopathy (DCM). There is strong segregation data available: It was found to co-segregate with disease in three unrelated families, specifically in 4, 6, and >15 affected relatives. There is also transgenic animal data in mice and zebrafish, discussed below. McNair et al. (2004) and Olson et al. (2005) detected Asp1275Asn in a large family of German and Swiss ancestry with dilated cardiomyopathy, conduction defects, and arrhythmias. It segregated with disease in >15 affected family members. The phenotype included sinus node dysfunction in adolescence, supraventricular tachyarrhythmia, and progressive AV and intraventricular conduction delay that led to permanent pacing in most cases. The phenotype was also characterized by a progression toward atrial dilation, frequently followed by right ventricular dilation and, in some cases, left ventricular dilation and dysfunction. McNair et al. reported a penetrance of around 75%. They checked for co-presence of the connexin-40 polymorphisms described below, and although present in some affected family members these did not always segregate with disease. In another family, Groenewegen et al. (2003, the Netherlands) reported that Asp1275Asn segregated with atrial standstill in 4 affected relatives, including 3 living affecteds and one deceased obligate carrier, but was coinherited with polymorphisms in regulatory regions of the atrial-specific gap junction channel protein connexin-40 (GJA5) in affected members of the family. The most distant relationship between affecteds was first cousin once removed. No member of this family had dilated cardiomyopathy, leading Groenewegen and Wilde (2005) to question whether the D1275N mutation was the primary cause of dilated cardiomyopathy as reported by McNair et al. (2004). Laitinen-Forsblom et al. (2006) identified Asp1275Asn in a large Finnish family with atrial fibrillation and conduction defects leading to pacemaker placement. It segregated with disease in all 6 affected family members. Echocardiography revealed an enlarged left ventricle with an increased left ventricular end-diastolic diameter (LVEDD) in 1 affected individual, and the right ventricle was slightly enlarged in 3 other affected individuals. Connexin-40 polymorphisms did not segregate with disease. Penetrance was 75% (but those not affected were still in their teens.) Other studies without segregation data exist as well: Watanabe et al. (2011) identified the variant in a 19-year-old Caucasian man with atrial flutter, atrial standstill, conduction disease, and sinus node dysfunction; the connexin-40 polymorphisms previously discussed were absent. Kapplinger et al, 2010, reported this variant in three unrelated individuals with Brugada syndrome, tested in France and at PGxHealth. [Meregalli et al. (2009) did a retrospective study involving 2 previously-identified individuals with this variant, who -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1275 of the SCN5A protein (p.Asp1275Asn). This variant is present in population databases (rs137854618, gnomAD 0.003%). This missense change has been observed in individuals with dilated cardiomyopathy and arrhythmia and heart block (PMID: 12522116, 21596231, 22247482, 24136861, 24762805, 26111534). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9401). 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. Experimental studies have shown that this missense change affects SCN5A function (PMID: 12522116, 21824921, 23791817). For these reasons, this variant has been classified as Pathogenic. -

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:12522116;PMID:15466643;PMID:16684018;PMID:19251209;PMID:20129283;PMID:20384651;PMID:20539757;PMID:21824921;PMID:22247482). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jun 08, 2023	This missense variant replaces aspartic acid with asparagine at codon 1275 in the transmembrane domain DIII of the SCN5A protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Multiple functional studies have shown that this variant affects sodium channel function (PMID: 12522116, 20539757, 21824921, 24573164) and results in reduced protein expression at the cell surface (PMID: 20539757, 28637969). Transgenic mice expressing the human SCN5A cDNA carrying this variant have exhibited slow conduction, heart block, atrial fibrillation, ventricular tachycardia, and dilated cardiomyopathy (PMID: 21824921). This variant has been reported in over 10 individuals affected with Brugada syndrome, cardiac conduction disorders, sick sinus syndrome, and sinus node dysfunction (PMID: 15466643, 16684018, 19251209, 21824921, 24762805, 25904541, 26111534, 26798387, 27707468, 28637969, 32893267, 35052356, 15671429). This variant has been shown to segregate with disease in multiple families (PMID: 12522116, 15466643, 15671429, 16684018, 24762805, 28637969, 32581083). In addition, this variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 15671429), atrial standstill (PMID: 12522116), progressive familial heart block (PMID: 22247482), and early-onset stroke (PMID: 29579189, 32581083). This variant has been identified in 2/251372 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Atrial standstill 1, digenic Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2006

- -

Atrial fibrillation, familial, 10 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2006

- -

Dilated cardiomyopathy 1E Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2006

- -

SCN5A-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 12, 2024

The SCN5A c.3823G>A variant is predicted to result in the amino acid substitution p.Asp1275Asn. This variant was reported in individuals with a wild phenotypic spectrum of SCN5A-associated disorders, including dilated cardiomyopathy, conduction disorder, and arrhythmia (Groenewegen et al. 2003. PubMed ID: 12522116; McNair et al. 2004. PubMed ID: 15466643; Table S1, Makita et al. 2012. PubMed ID: 22247482; Table S2, Berthome et al. 2019. PubMed ID: 30193851; Online Table 1, Gigli et al. 2019. PubMed ID: 31514951). In vivo mouse and zebrafish models recapitulated patient phenotypes, supporting the pathogenicity of this variant (Watanabe et al. 2011. PubMed ID: 21824921; Huttner et al. 2013. PubMed ID: 23791817). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 27, 2023

The p.D1275N pathogenic mutation (also known as c.3823G>A), located in coding exon 20 of the SCN5A gene, results from a G to A substitution at nucleotide position 3823. The aspartic acid at codon 1275 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in association with a range of cardiac phenotypes including atrial standstill, dilated cardiomyopathy, sinus node dysfunction, cardiac conduction disease, and other arrhythmias and has also been reported to segregate with disease in multiple families. The presence of additional alterations has also been suggested to impact disease expression (Groenewegen WA et al. Circ Res. 2003;92(1):14-22; McNair WP et al. Circulation. 2004; 110(15):2163-7; Laitinen-Forsblom PJ et al. J Cardiovasc Electrophysiol. 2006;17(5):480-5; Kapplinger JD et al. Heart Rhythm. 2010;7(1):33-46; Chiang DY et al. Circ Arrhythm Electrophysiol. 2015;8(5):1105-12). While some in vitro studies have reported varying results, studies of mice and zebrafish models expressing this alteration reported similar phenotype as observed in humans, and mouse cardiomyocytes expressing this alteration showed decreased channel function (Gui J et al. PLoS ONE. 2010;5(6):e10985; Watanabe H et al. Circulation. 2011;124(9):1001-11; Huttner IG et al. J Mol Cell Cardiol. 2013;61:123-32; Hoshi M et al. Circ Cardiovasc Genet. 2014;7(2):123-31). Based on the supporting evidence, p.D1275N is interpreted as a disease-causing mutation. -

Long QT syndrome 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

research

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

May 08, 2018

- -

Cardiac arrhythmia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 29, 2022

Variant summary: SCN5A c.3823G>A (p.Asp1275Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251372 control chromosomes (gnomAD). c.3823G>A has been reported in the literature in multiple individuals affected with a range of cardiac phenotypes, including various forms of arrhythmias and dilated cardiomyopathy, and the variant was reported to segregate with the disease phenotype in several families (e.g. McNair_2004, Groenewegen_2003, Olson_2005, McNair_2011, Abe_2014). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated no major difference in biophysical properties between wild-type and D1275N channels, however lower protein levels were also demonstrated, which correlated with reduced sodium channel function (Hayano_2017, Watanabe_2011). In addition, animal models (mouse and zebrafish) also recapitulated the phenotypes reported in patients (Watanabe_2011, Huttner_2013). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	.;.;.;.;.;D;.;.;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	1.0	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.5	.;.;.;.;.;H;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-4.9	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;D;D;.;.
Vest4		0.99
MutPred		0.97		Gain of MoRF binding (P = 0.0569);.;Gain of MoRF binding (P = 0.0569);Gain of MoRF binding (P = 0.0569);.;Gain of MoRF binding (P = 0.0569);.;.;.;
MVP		0.99
MPC		1.4
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.87
gMVP		0.99

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: rs137854618; hg19: chr3-38607917;