ClinVar Genomic variation as it relates to human health

The SCN5A c.4535G>A; p.Arg1512Gln variant (rs368219299) is reported in the literature in an individual affected with irritable bowel syndrome (Beyder 2014), but is also found in healthy controls (Kapplinger 2015) and has not been associated with cardiac disease. This variant is reported in ClinVar (Variation ID: 643516), and is only observed on seven alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 1512 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, functional assays show no significant difference compared to the wild type protein (Beyder 2014). Due to limited information, the clinical significance of the p.Arg1512Gln variant is uncertain at this time. References: Beyder A et al. Loss-of-function of the voltage-gated sodium channel NaV1.5 (channelopathies) in patients with irritable bowel syndrome. Gastroenterology. 2014;146(7):1659-1668. Kapplinger JD et al. Enhanced Classification of Brugada Syndrome-Associated and Long-QT Syndrome-Associated Genetic Variants in the SCN5A-Encoded Na(v)1.5 Cardiac Sodium Channel. Circ Cardiovasc Genet. 2015;8(4):582-595.

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1512 of the SCN5A protein (p.Arg1512Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with irritable bowel syndrome (PMID: 24613995). ClinVar contains an entry for this variant (Variation ID: 643516). 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 have shown that this missense change does not substantially affect SCN5A function (PMID: 24613995). This variant disrupts the p.Arg1512 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10690282, 15851227, 20110800, 20486126, 22840528, 24529773, 25650408, 26111534). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

This missense variant replaces arginine with glutamine at codon 1512 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). A functional study has shown that this variant has no impact on channel function in transfected cells (PMID: 24613995). This variant has been reported in an individual affected with irritable bowel syndrome (PMID: 24613995). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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.

The p.R1512Q variant (also known as c.4535G>A), located in coding exon 25 of the SCN5A gene, results from a G to A substitution at nucleotide position 4535. The arginine at codon 1512 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in an irritable bowel syndrome cohort; however clinical details were not provided (Beyder A et al. Gastroenterology, 2014 Jun;146:1659-1668). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.