ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.4978A>G (p.Ile1660Val) (rs199473625)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183093 SCV000235503 uncertain significance not provided 2018-05-03 criteria provided, single submitter clinical testing The I1660V variant in the SCN5A gene has gene has previously been reported in association with LQTS and/or Brugada syndrome (Napolitano et al., 2005; Cordeiro et al., 2006; Kapplinger et al., 2010; Postema et al., 2011). Cordeiro et al. (2006) identified I1660V in an individual with Brugada syndrome who also harbored another SCN5A missense variant in trans; however, neither variant presented with Brugada syndrome when inherited alone. Similarly, Postema et al. (2011) reported I1660V in one individual with a severe phenotype of mixed LQTS/Brugada features who also harbored a SCN5A gain-of-function variant. This individual's mother and son also carried the gain-of-function variant, but no other family members harbored I1660V (Postema et al., 2011). This variant has been observed in multiple unrelated individuals referred for cardiac genetic testing at GeneDx; however, segregation data for these families are inconclusive and one individual harbored an additional variant in another arrhythmia-related gene. The I1660V variant is observed in 7/111,720 alleles (0.006%) from individuals of non-Finnish European ancestry in large population cohorts (Lek et al., 2016). The I1660V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Moreover, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Nevertheless, functional studies by Cordeiro et al. (2006) demonstrated that I1660V results in loss of sodium channel current, and immunofluorescence studies showed abnormal channel trafficking.
Ambry Genetics RCV000618797 SCV000737347 uncertain significance Cardiovascular phenotype 2018-02-01 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000777477 SCV000913339 uncertain significance Arrhythmia 2019-12-16 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000183093 SCV000927647 likely pathogenic not provided 2018-04-23 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000183093 SCV001153858 likely pathogenic not provided 2017-03-01 criteria provided, single submitter clinical testing
Invitae RCV001055657 SCV001220057 uncertain significance Brugada syndrome 2019-06-11 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 1660 of the SCN5A protein (p.Ile1660Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs199473625, ExAC 0.004%). This variant has been observed in individuals affected with long QT or Brugada syndromes (PMID: 16414944, 20812931, 26173111). ClinVar contains an entry for this variant (Variation ID: 67947). Experimental studies have shown that this missense change causes a loss of channel current in vitro (PMID: 17075016). 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.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058732 SCV000090252 not provided Congenital long QT syndrome no assertion provided literature only This variant has been reported as associated with Long QT syndrome in the following publications (PMID:16414944). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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