This missense variant replaces alanine with threonine at codon 110 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with or suspected of having long QT syndrome (PMID 23174487, 23631430, 26159999). This variant has been identified in 4/249516 chromosomes 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 sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 110 of the SCN5A protein (p.Ala110Thr). This variant is present in population databases (rs730880202, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of long QT syndrome (PMID: 23174487, 23631430, 26159999, 32048431). ClinVar contains an entry for this variant (Variation ID: 180510). 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. 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 alanine with threonine at codon 110 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with or suspected of having long QT syndrome (PMID 23174487, 23631430, 26159999). This variant has been identified in 4/249516 chromosomes 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.

A variant of uncertain significance has been identified in the SCN5A gene. The A110T variant has been reported in association with Long QT Syndrome (LQTS) in one patient who also harbored additional variants (Mullally et al., 2013). This variant has also been reported in one individual with a normal QT interval (Ghouse et al., 2015). Nevertheless, the A110T 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). The A110T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Finally, this substitution occurs at a position that is conserved across species and, in silico analysis predicts this variant is probably damaging to the protein structure/function.

Variant summary: SCN5A c.328G>A (p.Ala110Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 249516 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.328G>A has been reported in the literature in individuals affected with Long QT Syndrome (Mullally_2012, Lieve_2013, Ghouse_2015). These reports do not provide unequivocal conclusions about association of the variant with Long QT Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32048431, 26159999, 23631430, 23174487). ClinVar contains an entry for this variant (Variation ID: 180510). Based on the evidence outlined above, the variant was classified as uncertain significance.

The p.A110T variant (also known as c.328G>A), located in coding exon 2 of the SCN5A gene, results from a G to A substitution at nucleotide position 328. The alanine at codon 110 is replaced by threonine, an amino acid with similar properties. This variant has been detected in individuals from cohorts reported to have long QT syndrome (LQTS) or who were referred for LQTS genetic testing; however, in one instance, variants in other arrhythmia-associated gene(s) were also detected, and the reported cases may overlap (Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61; Mullally J et al. Heart Rhythm, 2013 Mar;10:378-82). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.