ClinVar Genomic variation as it relates to human health

The SCN5A Arg814Gln variant was identified in a family with Brugada syndrome. The proband is an 83 yo woman diagnosed with Brugada syndrome following a resuscitated cardiac arrest. The variant was also found in her affected son as well as 4 clinically unaffected family members (however some have not undergone drug challenge testing). It is present in low frequency (0.00001 MAF) in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) and in silico software (SIFT and MutationTaster) predict this variant to be disease causing. The SCN5A Arg814Gln variant has been previously reported by Frigo et al (2007) in one family. The proband was homozygous for the variant and had a clear diagnosis of Brugada syndrome and documented ventricular arrhythmias. Within the family, there were 2 family members with a diagnostic ECG carrying the variant in a heterozygous state, as well as 4 other family members carrying the variant (heterozygous) with no clinical evidence of disease. Due to unclear genotype-phenotype correlation in our family, as well as in the previously reported family by Frigo et al (2007) we have classified this variant as a "variant of uncertain significance".

The R814Q pathogenic variant in the SCN5A gene has been previously reported in multiple individuals in association with Brugada syndrome (Frigo et al., 2007; Sommariva et al., 2013; Yamagata et al., 2017). Frigo et al. (2007) identified this variant in a homozygous individual with Brugada syndrome, sustained monomorphic ventricular tachycardia, left bundle branch block, and right ventricular abnormalities suggestive of arrhythmogenic right ventricular cardiomyopathy. This individual's parents and all four siblings were heterozygous for the R814Q variant, and both the mother and one sibling had ECG abnormalities suggestive of Brugada syndrome which were characterized by ST-segment elevation with coved type aspect in right precordial leads (Frigo et al., 2007). Additionally, this variant was identified in one Italian individual with Brugada syndrome (Sommarvia et al., 2013), and one Japanese individual with Brugada syndrome who experienced aborted cardiac arrest (Yamagata et al., 2017). This variant has also been reported in three individuals from one family in association with LQTS (Itoh et al., 2016), however, no clinical details regarding the proband or the affected status of the two relatives were described.The R814Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs in the voltage-sensing transmembrane segment (S4) of domain II at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, functional studies in Xenopus oocytes showed that R814Q reduces the net positive charge of the S4 segment, significantly decreases the voltage dependence of activation, and causes alterations in the slopes and mid-points of steady-state inactivation, which indicates this variant impacts both activation and inactivation gating of the sodium channel (Chen et al., 1996). Moreover, a pathogenic missense variant at the same residue (R814W) has been reported in association with SCN5A-related disorders (Olson et al., 2005), supporting the functional importance of this residue. Finally, the R814Q variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).

proposed classification - variant undergoing re-assessment, contact laboratory

Criteria applied: PS3,PM5

This c.2441G>A (p.Arg814Gln) variant in exon 16 of the SCN5A gene results in an amino acid change at residue 814 of an arginine to a glutamine. This variant has been observed in patients with Brugada syndrome and long QT syndrome (PMID: 23321620, 28341781, 26669661) and has also been observe in a homozygous state in one family (PMID: 17442746). This variant is rarely observed in general population databases and functional studies have shown an effect on steady state inactivation (PMID: 8972392). Therefore, the c.2441G>A (p.Arg814Gln) variant in the SCN5A gene is classified as likely pathogenic.

This missense variant replaces arginine with glutamine at codon 814 of the SCN5A protein. This variant is found within the highly conserved transmembrane domain DII (a.a. 718-938). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with Brugada syndrome and long QT syndrome (PMID: 32893267). Functional studies have shown that this missense variant affects sodium channel function (PMID: 8972392, 32533946, doi:10.1161/circ.118.suppl_18.S_1485). This variant has been reported in eight unrelated individuals affected with Brugada syndrome (PMID: 17442746, 23321620, 28341781, 33221895, 34147702, 36291626, ClinVar SCV000256650.2, doi:10.1161/circ.118.suppl_18.S_1485). This variant has also been reported in individuals affected with ventricular fibrillation (PMID: 32389048), dilated cardiomyopathy (PMID: 26669661, 31983221, 32659924), noncompaction cardiomyopathy (PMID: 30847666), and in a survivor of sudden cardiac arrest (PMID: 30975432). This variant has been identified in 7/279186 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon (p.Arg814Trp) is associated with disease (ClinVar variation ID 67731), suggesting that arginine at this position is important for the protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 814 of the SCN5A protein (p.Arg814Gln). This variant is present in population databases (rs199473584, gnomAD 0.005%). This missense change has been observed in individuals with clinical features of autosomal dominant SCN5A-related conditions (PMID: 17442746, 23321620, 26669661, 30847666, 30975432, 31983221, 32659924, 34461752). ClinVar contains an entry for this variant (Variation ID: 67732). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 32533946) did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN5A function. Experimental studies have shown that this missense change affects SCN5A function (PMID: 32533946). This variant disrupts the p.Arg814 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15671429, 24815523, 26733869). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

The p.R814Q variant (also known as c.2441G>A), located in coding exon 15 of the SCN5A gene, results from a G to A substitution at nucleotide position 2441. The arginine at codon 814 is replaced by glutamine, an amino acid with highly similar properties. This alteration was reported in homozygous state in an individual with Brugada syndrome (BrS), and segregated with the disease in his affected mother and brother who were heterozygous for this alteration (Frigo G et al. Europace, 2007 Jun;9:391-7). This alteration has also described in cohorts with BrS (Sommariva E et al. Eur. J. Hum. Genet., 2013 Sep;21:911-7, Yamagata K et al. Circulation, 2017 Jun;135:2255-2270), long QT syndrome (Itoh H et al. Eur. J. Hum. Genet., 2016 Aug;24:1160-6), cardiac arrest/ventricular fibrillation (Asatryan B. Am J Cardiol. 2019 06;123(12):2031-2038; Hylind RJ. J Am Heart Assoc. 2020 05;9(10):e016322), and cardiomyopathy (van Lint FHM. Neth Heart J. 2019 Jun;27(6):304-309; Mazzarotto F. Circulation. 2020 02;141(5):387-398). Internal structural analysis revealed that this alteration is disruptive to the voltage sensor motif. Consistently, in vitro studies showed that this alteration would affect channel activity (Chen LQ et al. J. Gen. Physiol., 1996 Dec;108:549-56). In addition, another change affecting the same amino acid, R814W, occurred de novo in an individual with dilated cardiomyopathy (Olson TM et al. JAMA, 2005 Jan;293:447-54), and was also indicated to affect channel function by in vitro assays (Nguyen TP et al. Circ. Res., 2008 Feb;102:364-71). 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.

The SCN5A c.2441G>A variant is predicted to result in the amino acid substitution p.Arg814Gln. This variant has been reported in individuals with Brugada syndrome (Sommariva et al. 2013. PubMed ID: 23321620; Ciconte et al. 2020. PubMed ID: 33221895; Milman et al. 2021. PubMed ID: 34461752), long QT syndrome (Itoh et al. 2016. PubMed ID: 26669661), dilated cardiomyopathy (DCM) (Mazzarotto et al. 2020. PubMed ID: 31983221; Kolokotronis et al. 2020. PubMed ID: 32659924), noncompaction cardiomyopathy (van Lint et al. 2019. PubMed ID: 30847666), sudden cardiac arrest (Asatryan et al. 2019. PubMed ID: 30975432), and ventricular fibrillation (Hylind et al. 2020. PubMed ID: 32389048). It has also been observed in the homozygous state in an individual with Brugada syndrome, monomorphic ventricular tachycardia, and structural abnormalities of the right ventricle and in the heterozygous state in 2 family members with ECG abnormalities suggestive of Brugada syndrome (Frigo et al. 2007. PubMed ID: 17442746). In vitro experimental studies indicate that this variant significantly alters sodium channel function (Chen et al. 1996. PubMed ID: 8972392; Glazer et al. 2020. PubMed ID: 32533946). This variant is reported in 0.0050% of alleles in individuals of East Asian descent in gnomAD. Another missense variant at the same amino acid residue (p.Arg814Trp) has been reported to be disease-causing in individuals with cardiomyopathy and/or arrhythmia and has been shown to be functionally deleterious (Olson et al. 2005. PubMed ID: 15671429; Nguyen et al. 2008. PubMed ID: 18048769; Beckermann et al. 2014. PubMed ID: 24815523). Taken together, the p.Arg814Gln variant is interpreted as likely pathogenic.

This variant has been reported as associated with Brugada syndrome in the following publications (PMID:17442746). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.