ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.2989G>A (p.Ala997Thr) (rs137854609)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171570 SCV000050613 uncertain significance SUDDEN INFANT DEATH SYNDROME; Brugada syndrome 2018-04-05 criteria provided, single submitter research
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058541 SCV000090061 not provided Brugada syndrome no assertion provided literature only This variant has been reported as associated with Brugada syndrome in the following publications (PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
GeneDx RCV000766794 SCV000235301 uncertain significance not provided 2018-05-17 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN5A gene. The A997T variant has been reported in two individuals with a definitive or suspected diagnosis of Brugada syndrome (Krahn et al. 2009; Kapplinger et al., 2010; Conte et al., 2014). Ng et al. (2013) identified A997T as a secondary finding via exome sequencing of ClinSeq participants. The individual was subsequently found to have an abnormal EKG with sinus bradycardia and right atrial abnormality, and authors classified A997T as likely pathogenic (Ng et al. 2013). No segregation data have been published to our knowledge. The A997T variant has also been reported in one individual with irritable bowel syndrome (IBS) (Beyder et al., 2014). The A997T variant has been observed in 12/57,670 (0.02%) alleles in individuals of European background in large population cohorts (Lek et al., 2016). Additionally, this variant is classified in ClinVar as a variant of uncertain significance by three other clinical laboratories (SCV000200239.4, SCV000545040.2, SCV000747960.1; Landrum et al., 2016).Functional studies in HEK-293 cells expressing the A997T variant demonstrated a significant effect on channel function including a 98% reduction in peak channel current (Beyder et al., 2014). The loss of function phenotype was rescued by incubating the cells in mexiletine, an anti-arrhythmic drug shown previously to rescue SCN5A-related channel defects (Beyder et al., 2014). The A997T 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. Nevertheless, in silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.
Invitae RCV000058541 SCV000545040 uncertain significance Brugada syndrome 2018-11-07 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 997 of the SCN5A protein (p.Ala997Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs137854609, ExAC 0.02%). This variant has been reported in several individuals with suspected Brugada syndrome (PMID: 19597050, 20129283, 24681144) and an individual with irritable bowel syndrome (PMID: 24613995). ClinVar contains an entry for this variant (Variation ID: 67771). Experimental studies have shown that this missense change reduces SCN5A activity (PMID: 24613995). This variant identified in the SCN5A gene is located in the interdomain linker DII/DIII region of the resulting protein (PMID: 25348405). 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 also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000151787 SCV000200239 uncertain significance not specified 2014-02-27 criteria provided, single submitter clinical testing The Ala997Thr variant in SCN5A has been reported in 1 adult with Brugada syndrom e (Kapplinger 2010, Conte 2014). Another variant at this position (Ala997Ser) ha s been reported in 1 infant with SIDS (absence in a large number of controls and in vitro functional studies supported pathogenicity though, though these assays may not accurately represent biological function; Ackerman 2001). Data from lar ge population studies is insufficient to assess the frequency of this variant. Computational prediction tools and conservation analysis suggest that this varia nt may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, additional information is needed to fully assess the clinical significance of the Ala997Thr variant.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000058541 SCV000747960 uncertain significance Brugada syndrome 2016-08-03 criteria provided, single submitter clinical testing

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