ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.3823G>A (p.Asp1275Asn) (rs137854618)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183045 SCV000235454 pathogenic not provided 2021-01-27 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Reported in ClinVar as pathogenic (ClinVar Variant ID 9401; 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 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)
Invitae RCV000058604 SCV000545069 pathogenic Brugada syndrome 2020-06-21 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 1275 of the SCN5A protein (p.Asp1275Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (rs137854618, ExAC no frequency). This variant has been reported to segregate with dilated cardiomyopathy and arrhythmia (PMID: 21596231) as well as atrial standstill (PMID: 12522116). In addition, this variant has been observed in isolated individuals with heart block (PMID: 22247482), sinus node dysfunction (PMID: 24762805, 26111534), and Brugada syndrome (PMID: 24136861). ClinVar contains an entry for this variant (Variation ID: 9401). Experimental studies have shown that this missense alters the trafficking of the protein to the cell membrane and the channel kinetics (PMID: 12522116, 21824921). Animal models also recapitulate the phenotype found in patients (PMID: 21824921, 23791817). In summary, this variant is not found in population databases, has been shown to segregate with disease, and has been shown to have a deleterious effect on protein function. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000617238 SCV000737080 pathogenic Cardiovascular phenotype 2016-03-26 criteria provided, single submitter clinical testing 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 alterationhas 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 alterationreported similar phenotype as observed in humans, andmouse cardiomyocytes expressing thisalterationshowed 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.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000656563 SCV000778608 pathogenic Long QT syndrome 3 2018-05-08 criteria provided, single submitter research
OMIM RCV000010003 SCV000030224 pathogenic Dilated cardiomyopathy 1E 2006-05-01 no assertion criteria provided literature only
OMIM RCV000022946 SCV000044237 pathogenic Atrial fibrillation, familial, 10 2006-05-01 no assertion criteria provided literature only
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058604 SCV000090124 not provided Brugada syndrome no assertion provided literature only 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.
OMIM RCV000114992 SCV000148901 pathogenic Atrial standstill 1, digenic 2006-05-01 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000183045 SCV000280475 pathogenic not provided 2014-02-24 no assertion criteria provided clinical testing 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 may already be included above.] This is a non-conservative amino acid change, resulting in the replacement of an aspartic acid (acidic) with an asparagine (polar). The aspartic acid at this location is highly conserved and is thought to be part of the voltage-sensing mechanism of the ion channel (Groenewegen et al. 2003). This residue is also highly conserved across paralog genes, according to This variant alters a transmembrane region of the SCN5A protein (segment 3, domain III); such variants are considered likely to be pathogenic (Kapa et al. 2009). In silico analysis with PolyPhen-2 ( predicts the variant to be “probably damaging” with a score of 1.0. Variation at nearby residues (Asn1269Ser, Trp1271Cys, Ile1278Asn, Val1279Ile, Val1281Phe, Leu1283Met) has been reported in HGMD in association with Brugada syndrome, atrial standstill, long QT syndrome, and DCM, supporting the functional importance of this region of the protein. Mice transgenic for human Asp1275Asn have slow cardiac conduction, heart block, atrial fibrillation, VT, and DCM (Watanabe et al. 2011). Transgenic zebrafish with Asp1275Asn expressed in their hearts show more bradycardia, conduction-system abnormalities (including sinus pauses and AV conduction block), and early death (Huttner et al. 2013). In vitro functional data is available, and shows that this variant may reduce sodium channel current (Groenewegen et al. 2003; Gui et al. 2010a+b; Watanabe et al. 2011). In total the variant has not been seen in ~2,315 controls and ~6,500 individuals from publicly available population datasets = 8,815 total. Groenewegen et al. (2003) 180 controls; Olson et al. (2005) 500 controls; McNair et al. (2004, 2011) 150 ethnically-matched controls; Laitinen-Forsblom et al. (2006) 185 controls; Kapa et al. (2009)/Kapplinger (2010) 1300 unrelated, ethnically diverse controls. There is no variation at this residue in the NHLBI Exome Sequencing Project dataset (, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. This variant is not listed in 1000 genomes ( Ancestry of our patient’s affected parent is from Italy and Ireland.
Clinical Genetics,Academic Medical Center RCV000183045 SCV001917116 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000183045 SCV001952892 pathogenic not provided no assertion criteria provided clinical testing

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