ClinVar Genomic variation as it relates to human health

The p.Ala993Thr variant in SCN5A has been reported in one individual with long Q T syndrome (Ortiz-Bonnin 2016). It was also identified in 0.004% (1/22694) of Af rican chromosomes by gnomAD (http://gnomad.broadinstitute.org), and has been rep orted as a variant of uncertain significance in ClinVar (Variation ID 463317). I n vitro functional studies provide some evidence that the variant may impact pro tein function (Ortiz-Bonnin 2016); however, these types of assays may not accura tely represent biological function. The alanine (Ala) residue at position 993 is poorly conserved, with multiple species carrying a threonine (Thr) at this posi tion. However, surrounding positions are also poorly conserved, suggesting that evolutionary conservation data may not be informative for position p.993. Comput ational prediction tools support that this variant may not impact the protein, t hough this information is not predictive enough to rule out pathogenicity. In su mmary, given the limited available evidence and the presence of conflicting data , the clinical significance of the p.Ala993Thr variant is uncertain. ACMG/AMP cr iteria applied: PM2_Supporting, BP4.

This missense variant replaces alanine with threonine at codon 993 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies support an impact of this variant on SCN5A activity, however the clinical relevance of this observation is not known (PMID: 27287068). This variant has been reported in one individual affected with long QT syndrome (PMID: 27287068). This variant has been identified in 3/270214 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 missense change has been observed in individual(s) with clinical features of long QT syndrome (PMID: 27287068). This variant is present in population databases (rs770088052, gnomAD 0.004%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 993 of the SCN5A protein (p.Ala993Thr). ClinVar contains an entry for this variant (Variation ID: 463317). 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. Experimental studies have shown that this missense change affects SCN5A function (PMID: 27287068). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function.

This missense variant replaces alanine with threonine at codon 993 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies support an impact of this variant on SCN5A activity, however the clinical relevance of this observation is not known (PMID: 27287068). This variant has been reported in one individual affected with long QT syndrome (PMID: 27287068). This variant has been identified in 3/270214 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.

The p.A993T variant (also known as c.2977G>A), located in coding exon 16 of the SCN5A gene, results from a G to A substitution at nucleotide position 2977. The alanine at codon 993 is replaced by threonine, an amino acid with similar properties. This variant was detected in an individual with prolonged QTc, as well as in her mother whose QTc value was in the upper range of normal (Ortiz-Bonnin B et al. Pflugers Arch, 2016 08;468:1375-87). This variant has also been reported in epilepsy and long QT syndrome cohorts with limited clinical details provided (Li X et al. Ann Hum Genet, 2020 03;84:161-168; Walsh R et al. Genet Med, 2021 01;23:47-58). Limited functional studies suggested some increase in peak current amplitude and slowed inactivation kinetics; however, the clinical consequences of these findings are uncertain (Ortiz-Bonnin B et al. Pflugers Arch, 2016 08;468:1375-87). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.