ClinVar Genomic variation as it relates to human health

This missense variant replaces phenylalanine with cysteine at codon 532 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). Functional studies have shown that this variant causes a reduction of sodium current density in transfected rat neonatal cardiomyocytes but no changes in channel function found in transfected human kidney cell line tsA-201 (PMID: 18596570, 34843967). This variant has been reported in three individuals affected with or suspected of having Brugada syndrome (PMID: 20129283, 28341781, 32893267), and in other individuals affected with arrhythmia (PMID: 15996170), sudden infant death syndrome (PMID: 18596570), or sudden unexpected death (PMID: 32449611). This variant has also been reported in 2 related individuals with normal electrocardiograms exhibiting no type 1 Brugada ECG pattern or any T-wave abnormalities (PMID: 29062695). This variant has been identified in 4/247568 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 variant replaces phenylalanine with cysteine at codon 532 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). Functional studies have shown that this variant causes a reduction of sodium current density in transfected rat neonatal cardiomyocytes but no changes in channel function found in transfected human kidney cell line tsA-201 (PMID: 18596570, 34843967). This variant has been reported in three individuals affected with or suspected of having Brugada syndrome (PMID: 20129283, 28341781, 32893267), and in other individuals affected with arrhythmia (PMID: 15996170), sudden infant death syndrome (PMID: 18596570), or sudden unexpected death (PMID: 32449611). This variant has also been reported in 2 related individuals with normal electrocardiograms exhibiting no type 1 Brugada ECG pattern or any T-wave abnormalities (PMID: 29062695). This variant has been identified in 4/247568 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.

Reported in individuals with various cardiac phenotypes, including paroxysmal atrial fibrillation and atrial tachycardia, sudden infant death syndrome, and incomplete right bundle branch block with overall normal EKGs (Maekawa et al., 2005; Otagiri et al., 2008; Warring et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31043699, 29728395, 15996170, 18596570, 30662450, 29062695, 28341781)

This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 532 of the SCN5A protein (p.Phe532Cys). This variant is present in population databases (rs199473573, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of Brugada syndrome (PMID: 15996170, 18596570, 20129283, 28341781). ClinVar contains an entry for this variant (Variation ID: 67671). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on SCN5A function (PMID: 18596570). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 Brugada syndrome in the following publications (PMID:15996170;PMID:18596570;PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.