ClinVar Genomic variation as it relates to human health

The p.Arg1638X variant in SCN5A has been reported in at least 5 heterozygous individuals with Brugada syndrome (Meregali 2006, Kapplinger 2010). This variant was also reported by other clinical laboratories in ClinVar (Variation ID 523778) and has been identified in 0.002% (2/113722) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 1638. This alteration occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. While the effect on the protein is unknown, functional studies using patient cells provide some evidence that the p.Arg1623X variant causes a loss of function (Kosmidis 2016). Additionally, numerous nonsense and frameshift variants downstream of this variant have been reported in affected individuals. Heterozygous loss of function variants of the SCN5A gene have been previously reported for DCM (Olson 2005), Brugada syndrome (Kapplinger 2010), ventricular fibrillation (Chen 1998), and atrioventricular block and cardiac conduction defects (Baruteau 2012). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Brugada syndrome based upon low frequency in controls, presence in multiple affected individuals, functional evidence and predicted impact to the protein. ACMG/AMP Criteria applied: PVS1_Strong, PM2, PS4_Supporting.

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 380 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23333720, 19251209, 22373669, 20129283, 21273195, 28754655, 28721524, 16764707, 19843921, 27784737, 31737537, 33164571, 30662450)

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the SCN5A protein in which other variant(s) (p.Glu1867*) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 523778). This premature translational stop signal has been observed in individual(s) with clinical features of Brugada syndrome (PMID: 16764707, 20129283). This variant is present in population databases (rs761505217, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg1638*) in the SCN5A gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 379 amino acid(s) of the SCN5A protein.

The p.R1638* pathogenic mutation (also known as c.4912C>T), located in coding exon 27 of the SCN5A gene, results from a C to T substitution at nucleotide position 4912. This changes the amino acid from an arginine to a stop codon within coding exon 27. This alteration occurs at the 3' terminus of theSCN5A gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 10% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration has been reported in association with Brugada syndrome (Meregalli PG et al. J. Cardiovasc. Electrophysiol., 2006 Aug;17:857-64; Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46; Nannenberg EA et al. Circ Cardiovasc Genet, 2012 Apr;5:183-9). Cardiomyocytes derived from human induced pluripotent stem cells generated from a patient heterozygous for this mutation exhibit significantly reduced sodium current and altered action potential parameters (Kosmidis G et al. Circ Arrhythm Electrophysiol, 2016 Nov;9:e004227). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.