ClinVar Genomic variation as it relates to human health

proposed classification - variant undergoing re-assessment, contact laboratory

This missense variant replaces arginine with cysteine at codon 1583 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved region of the transmembrane domain DIV. Rare nontruncating variants in this region (a.a. 1530 -1771) have been shown to be significantly overrepresented in individuals with Brugada syndrome (PMID: 32893267). A functional study has shown that this variant causes a reduction in channel peak current density in transfected cells (PMID: 32533946). This variant has been reported in several individuals affected with Brugada syndrome or suspected of having Brugada syndrome (PMID: 20129283, 25650408, 30193851, 32659924, 32893267). This variant has also been reported in an individual affected with an inherited arrhythmia (Mizusawa 2016, thesis, University of Amsterdam), as well as in another individual affected with sudden cardiac death, who also carried a pathogenic splicing variant in the LMNA gene (PMID: 31453232). This variant has been identified in 2/249188 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, Arg1583His, has also been reported in a few individuals affected with Brugada syndrome (PMID: 24136861, 25904541, 32893267, 34147702), indicating that arginine at this position is important for SCN5A protein function. Although there is a suspicion for a pathogenic role, the available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1583 of the SCN5A protein (p.Arg1583Cys). This variant is present in population databases (rs45514691, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of Brugada syndrome (PMID: 25650408, 30193851). ClinVar contains an entry for this variant (Variation ID: 67920). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on SCN5A function (PMID: 32533946). This variant disrupts the p.Arg1583 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been observed in individuals with SCN5A-related conditions (PMID: 30193851), which suggests that this may be a clinically significant amino acid residue. 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.

The c.4747C>T (p.R1583C) alteration is located in exon 27 (coding exon 26) of the SCN5A gene. This alteration results from a C to T substitution at nucleotide position 4747, causing the arginine (R) at amino acid position 1583 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

This variant has been reported as associated with Brugada syndrome in the following publications (PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.