ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.2441G>A (p.Arg814Gln) (rs199473584)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000058501 SCV000256650 uncertain significance Brugada syndrome 2015-04-15 criteria provided, single submitter research 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".
Ambry Genetics RCV000620361 SCV000736449 likely pathogenic Cardiovascular phenotype 2017-11-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Structural Evidence
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058501 SCV000090021 not provided Brugada syndrome no assertion provided literature only 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.
GeneDx RCV000497380 SCV000589534 pathogenic not provided 2017-05-08 criteria provided, single submitter clinical testing 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).
Invitae RCV000058501 SCV000545082 uncertain significance Brugada syndrome 2018-06-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 814 of the SCN5A protein (p.Arg814Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs199473584, ExAC 0.01%). ClinVar contains an entry for this variant (Variation ID: 67732). This variant has been reported in an individual and a family affected with Brugada syndrome that included a homozygous individual and several unaffected carriers (PMID: 17442746, 23321620), and was reported in individuals affected with long QT syndrome (PMID:26669661). ClinVar contains an entry for this variant (Variation ID: 67732). This variant identified in the SCN5A gene is located in the transmembrane DII-S4 region of the resulting protein (PMID: 25348405). For more information about the location of this variant, please visit www.invitae.com/SCN5A-topology. It is unclear how this variant impacts the function of this protein. A different missense substitution at this codon (p.Arg814Trp) has been determined to be pathogenic (PMID: 15671429, 26733869, 24815523). This suggests that the arginine residue is critical for SCN5A protein function and that other missense substitutions at this position may also be pathogenic. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000824760 SCV000272411 uncertain significance not specified 2018-04-12 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg814Gln variant in SCN5A has been reported in the heterozygous state in at least 3 indi viduals with SNC5A associated disorders (1 with Brugada syndrome, 1 with Long QT syndrome, 1 with DCM; Itoh 2016, Yamagata 2017, LMM Data). In addition, this va riant has been reported in a family with autosomal dominant inheritance of Bruga da syndrome (proband with BrS and monomorphic ventricular tachycardia, mother an d one brother with features suggestive of BrS; Frigo 2007). The variant was pres ent in the homozygous state in the proband and in the heterozygous state in his brother and mother but also in 7 unaffected family members, raising concern as t o whether it can cause disease. It has been identified in 1/18854 East Asian chr omosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitut e.org/; dbSNP rs199473584) and is reported by other clinical laboratories in Cli nVar (Variation ID: 67732). In vitro functional studies provide some evidence t hat the p.Arg814Gln variant may impact protein function (Chen 1996). A disease-c ausing change at the same position (p.Arg814Trp) was reported as de novo in 1 in dividual with DCM (Olson 2005) and in vitro functional studies showed that the i t altered the SCN5A channel's kinetics (Nguyen 2008, Beckermann 2014, Moreau 201 5), suggesting that a change at this position may not be tolerated. Computationa l prediction tools and conservation analysis suggest that the p.Arg814Gln varian t may impact the protein, though this information is not predictive enough to de termine pathogenicity. In summary, while there is some suspicion for a pathogen ic role, the clinical significance of thep.Arg814Gln variant is uncertain. ACMG/ AMP Criteria applied: PM2, PM5, PP3, PS3_Supporting, PS4_Supporting.

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