ClinVar Genomic variation as it relates to human health

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1680 of the SCN5A protein (p.Ala1680Thr). This variant is present in population databases (rs199473294, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 16712702, 18508782, 19564561, 20129283, 23631430, 23671135, 30254039, 32533946). ClinVar contains an entry for this variant (Variation ID: 67952). 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: 32533946). 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 1680 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in three individuals affected with Brugada syndrome (PMID: 19564561, 30254039, 34620408) and in two individuals affected with sudden death (PMID: 16712702, 18508782). In one of these families, it was stated that this variant did not segregate with the disease phenotype (PMID: 18508782). This variant has been reported in individuals suspected to be affected with Brugada syndrome (PMID: 20129283, 23631430, 23671135). This variant has been identified in 13/282862 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

The p.Ala1680Thr variant in SCN5A has been identified in 1 individual with sudden adult death syndrome (SADS) and 5 individuals with suspected or established Brugada syndrome (Hofman-Bang 2006, Behr 2008, Lambiase 2009, Kapplinger 2010, Lieve 2013) and by our laboratory in 1 individual with a complex presentation (biventricular cardiomyopathy, VT, Brugada/ARVC pattern EKG) who carried a second, likely pathogenic variant in the DSP gene. Both variants were present in a sib with reduced ejection fraction but also in the unaffected mother. This variant is also present in a relative with Afib palpations and syncope. The p.Ala1680Thr variant reportedly did not segregate with disease in one family though no data was provided (Behr 2008). Non-segregation with disease raises some concern on whether the variant can cause disease. It has been identified in 9/126710 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs199473294). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Ala1680Thr variant is uncertain.

The c.5038G>A (p.A1680T) alteration is located in coding exon 27 of the SCN5A gene results from a G to A substitution at nucleotide position 5038, causing the Alanine (A) at amino acid position 1680 to be replaced by a Threonine (T). This alteration has been described in several patients; however, the available clinical information in the literate is often limited. This alteration has been reported in heterozygous state in a patient with Sudden Adult Death Syndrome (SADS) (Hofman-Bang, 2006) as well as in two other unrelated patients with Brugada syndrome (Kapplinger, 2010) and in a patient with Long QT syndrome (Lieve, 2013). This variant is reported in the SNP Database as rs199473294. Based on data from ExAC, the c.5038G>A allele has an overall frequency of approximately 0.002% (3/121408). Based on data from the NHLBI Exome Sequencing Project (ESP), the SCN5A c.5038G>A alteration was not observed among 6503 individuals tested (0.0%). Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project. The p.A1680T amino acid is very well conserved in the available vertebrate species. In addition, this alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Based on the majority of available evidence to date, the c.5038G>A (p.A1680T) variant is likely to be pathogenic._x000D_ _x000D_ Hofman-Bang J, et al. (2006) Clin Genet 69: 504–511_x000D_ _x000D_ Kapplinger J, et al. (2010) Heart Rhythm7(1):33-46_x000D_ _x000D_ Lieve KV, et al. (2013) Genet Test Mol Biomarkers. 17(7):553-61 Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Reported in individuals with sudden adult death syndrome and in several individuals with definite or probable Brugada syndrome (Hofman-Bang et al., 2006; Kapplinger et al., 2010; Stefek et al., 2018; Bennett et al., 2019; Miles et al., 2021); Also reported in family members of individuals with sudden cardiac death (Behr et al., 2008; Lambiase et al., 2009; Papadakis et al., 2013); however, p.(A1680T) did not segregate with the disease phenotype in one publication, suggesting it could be a polymorphism (Behr et al., 2008); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional patch clamp studies found no damaging effect (Glazer et al., 2020; Pearman et al., 2020); This variant is associated with the following publications: (PMID: 23631430, 19564561, 20129283, 18508782, 31535183, 30254039, 33131149, 23671135, 34620408, 16712702, 32746448, 32533946)

SCN5A: PM2

This variant has been reported as associated with Brugada syndrome in the following publications (PMID:16712702;PMID:18508782;PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.