ClinVar Genomic variation as it relates to human health

proposed classification - variant undergoing re-assessment, contact laboratory

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Identified in patients with Brugada, LQTS, short-coupled variant of Torsades de Pointes, and sudden unexplained death, but no segregation studies are available (PMID: 21273195, 20129283, 19716085, 32153684, 26164358); LQTS is caused by gain of function variants in the SCN5A channel (NaV1.5), while Brugada syndrome is caused by loss of function variants; as this variant has been identified in individuals with diseases that have different mechanisms of pathogenicity, its clinical significance is uncertain; Published functional studies demonstrated that the variant was comparable to wild-type with regards to whole-cell currents, steady state activation and inactivation, and recovery from inactivation, exhibiting no loss-of-function characteristics typically associated with Brugada syndrome pathogenic variants (PMID: 23805106); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24324440, 20129283, 22581653, 19716085, 33131149, 21273195, 32153684, 26164358, 23805106, 30203441, 29709244)

This missense variant replaces arginine with glutamine at codon 18 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant has no significant impact on channel function in transfected cells (PMID: 23805106). This variant has been reported in individuals affected with Brugada syndrome (PMID: 20129283, 21273195), short coupled variant of Torsades de Pointes (ScTdP) (PMID: 32153684), or suspected of having long QT syndrome (PMID: 19716085), and Brugada syndrome (PMID: 26164358). This variant has been identified in 20/279956 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 arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 18 of the SCN5A protein (p.Arg18Gln). This variant is present in population databases (rs41311087, gnomAD 0.03%). This missense change has been observed in individual(s) with sudden unexplained death, suspected or definite Brugada syndrome, or suspected Long QT syndrome (PMID: 19716085, 20129283, 21273195, 26164358, 32153684). ClinVar contains an entry for this variant (Variation ID: 48306). 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 tolerated. Experimental studies have shown that this missense change does not substantially affect SCN5A function (PMID: 23805106). 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 arginine with glutamine at codon 18 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant has no significant impact on channel function in transfected cells (PMID: 23805106). This variant has been reported in individuals affected with Brugada syndrome (PMID: 20129283, 21273195), short coupled variant of Torsades de Pointes (ScTdP) (PMID: 32153684), or suspected of having long QT syndrome (PMID: 19716085), and Brugada syndrome (PMID: 26164358). This variant has been identified in 20/279956 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.

Variant summary: SCN5A c.53G>A (p.Arg18Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 251172 control chromosomes, predominantly at a frequency of 0.00029 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.74 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Brugada Syndrome phenotype (0.00017), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.53G>A has been reported in the literature in individuals affected with features of Brugada Syndrome, Long QT Syndrome, or Torsades de Pointes without strong evidence of causality (e.g. Kapplinger_2009, 2010, Amit_2011, Kajiyama_2020). These reports do not provide unequivocal conclusions about association of the variant with Brugada Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Gutter_2013). These results showed no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 19716085, 20129283, 23805106, 21273195, 32153684). ClinVar contains an entry for this variant (Variation ID: 48306). Based on the evidence outlined above, the variant was classified as likely benign.

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.