ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.5035G>A (p.Ala1679Thr) (rs199473294)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000621882 SCV000737526 uncertain significance Cardiovascular phenotype 2018-03-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171771 SCV000050782 likely benign Sudden cardiac death 2013-06-24 criteria provided, single submitter research
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058737 SCV000090257 not provided Brugada syndrome no assertion provided literature only 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.
Color RCV000777753 SCV000913716 uncertain significance Arrhythmia 2018-09-06 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the transmembrane domain DIV of the SCN5A protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an individual affected with Brugada syndrome (PMID: 19564561) and two individuals who died suddenly (PMID: 16712702, 18508782). In one of these families, it was stated that this variant did not segregate with disease phenotype (PMID: 18508782). This variant has been reported in three individuals referred for Brugada syndrome testing (PMID: 20129283, 23671135). This variant has also been identified in 13/277198 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 study is necessary to determine the pathogenicity of this variant conclusively.
GeneDx RCV000766807 SCV000235508 uncertain significance not provided 2018-07-12 criteria provided, single submitter clinical testing The A1680T variant of uncertain significance in the SCN5A gene has been published previously in an individual with sudden adult death syndrome, and in two individuals with definite or probable Brugada syndrome (Hofman-Bang et al., 2006; Kapplinger et al., 2010). In addition, the A1680T variant has been reported in family members of individuals with sudden cardiac death (Behr et al., 2008; Lambiase et al., 2009; Papadakis et al., 2013); however, A1680T did not segregate with the disease phenotype in one publication, suggesting it could be a polymorphism (Behr et al., 2008). This variant has also been identified independently and/or in conjunction with additional cardiogenetic variants in individuals referred for arrhythmia genetic testing at GeneDx. So far, segregation data is limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members. The A1680T 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Nevertheless, A1680T was observed in 13/277,198 (0.005%) alleles from individuals of varying ethnic backgrounds in large population cohorts (Lek et al., 2016). Furthermore, no pathogenic missense variants in nearby residues have been reported in the Human Gene Mutation Database (Stenson et al., 2014).
Invitae RCV000058737 SCV000545049 uncertain significance Brugada syndrome 2017-07-07 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1680 of the SCN5A protein (p.Ala1680Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs199473294, ExAC 0.01%). This variant has been reported in one individual with Brugada syndrome (PMID: 19564561), two individuals who died suddenly (PMID: 16712702, 23671135), two individuals referred for long QT syndrome testing (PMID: 23631430), and two individuals referred for Brugada syndrome testing (PMID: 20129283). It has also been observed in an additional individual who died suddenly but this variant did not segregate with the phenotype in the family (PMID: 18508782). ClinVar contains an entry for this variant (Variation ID: 67952). This variant identified in the SCN5A gene is located in the transmembrane DIV-S5 region of the resulting protein (PMID: 25348405), but it is unclear how this variant impacts the function of this protein. 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, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. While it is rare in the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000183098 SCV000711268 uncertain significance not specified 2017-05-25 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Ala1680Th r variant in SCN5A has been identified in 1 individual with sudden adult death s yndrome (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 cardi omyopathy, 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 eject ion 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 c an cause disease. It has been identified in 9/126710 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs 199473294). Computational prediction tools and conservation analysis suggest tha t this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion fo r a pathogenic role, the clinical significance of the p.Ala1680Thr variant is un certain.

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