ClinVar Genomic variation as it relates to human health

This missense variant replaces glutamine with arginine at codon 1909 of the SCN5A protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental electrophysiological studies using in vitro expression systems have shown this variant increases late sodium current (PMID: 25370050, 25757662, 25904541, 28087622, 28734073). However, clinical relevance of this observation is not clear. This variant has been reported in an individual affected with long QT syndrome (PMID: 19841300), in an individual affected with sudden infant death syndrome (PMID: 25757662), and in an individual referred for long QT syndrome genetic testing (PMID: 15840476). This variant has also been reported in an individual with normal QT interval (PMID: 26159999). 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.

This missense variant replaces glutamine with arginine at codon 1909 of the SCN5A protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental electrophysiological studies using in vitro expression systems have shown this variant increases late sodium current (PMID: 25370050, 25757662, 25904541, 28087622, 28734073). However, clinical relevance of this observation is not clear. This variant has been reported in an individual affected with long QT syndrome (PMID: 19841300), in an individual affected with sudden infant death syndrome (PMID: 25757662), and in an individual referred for long QT syndrome genetic testing (PMID: 15840476). This variant has also been reported in an individual with normal QT interval (PMID: 26159999). 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 c.5726A>G (p.Q1909R) alteration is located in exon 28 (coding exon 27) of the SCN5A gene. This alteration results from a A to G substitution at nucleotide position 5726, causing the glutamine (Q) at amino acid position 1909 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). One individual with a definite diagnosis of Long QT syndrome was observed to have this variant, and it was not detected in 1300 healthy controls (Kapa, 2009). This variant was also reported in a child with SIDS (Winkel, 2015). This amino acid position is highly conserved in available vertebrate species. While this variant occurs at the interface with Calmodulin, a protein central in regulation of heart rhythm, internal structural analysis indicates this variant may not be sufficiently destabilizing to suggest pathogenicity (Wang, 2012; Gabelli, 2014; Ambry internal data). In vitro functional data suggests that this variant may interfere with channel gating (Winkel, 2015). This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

p.Gln1909Arg (CAG>CGG): c.5726 A>G in exon 28 of the SCN5A gene (NM_198056.2) The Gln1909Arg mutation in the SCN5A gene has also been reported previously in one individual with LQTS, and this mutation was absent from 1,688 control alleles (Tester D et al., 2005). The NHLBI ESP Exome Variant Server reports Gln1909Arg was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Gln1909Arg results in a non-conservative amino acid substitution of a neutral, polar Glutamine with a positively charged Arginine at a residue that is conserved across species. In silico analysis predicts Gln1909Arg is probably damaging to the protein structure/function. In addition, a mutation in a nearby codon (Arg1913His) has also been reported in association with LQTS, supporting the functional importance of this region of the protein. In summary, Gln1909Arg in the SCN5A gene is interpreted as a disease-causing mutation. The variant is found in LQT panel(s).

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 1909 of the SCN5A protein (p.Gln1909Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with long QT syndrome (PMID: 19841300). ClinVar contains an entry for this variant (Variation ID: 68008). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SCN5A function (PMID: 25757662, 28087622, 28734073). 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 variant has been reported as associated with Long QT syndrome in the following publications (PMID:15840476;PMID:19841300). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.