ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.2533del (p.Val845fs) (rs794728912)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183153 SCV000235569 likely pathogenic not provided 2020-12-31 criteria provided, single submitter clinical testing Reported in a patient referred for Brugada syndrome genetic testing (Kapplinger et al., 2010); Reported in ClinVar (ClinVar Variant ID# 201559; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 20129283, 30662450, 31447099)
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000614105 SCV000731766 likely pathogenic Brugada syndrome 2017-12-12 criteria provided, single submitter clinical testing The p.Val845fs variant in SCN5A has been reported in 1 individual with suspected Brugada syndrome (Kapplinger 2010) and has also been reported by other clinical laboratories in ClinVar (Variation ID: 201559). It was absent from large popula tion studies. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 845 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted t o lead to a truncated or absent protein. Loss of function variants in SCN5A are typically associated with Brugada syndrome although overlapping presentations in cluding other SCN5A related phenotypes (Long QT syndrome) have been described (R emme 2013). In summary, although additional studies are required to fully establ ish its clinical significance, the p.Val845fs variant is likely pathogenic. ACMG /AMP Criteria applied: PVS1, PM2 (Richards 2015).
Ambry Genetics RCV000621392 SCV000738104 pathogenic Cardiovascular phenotype 2017-03-23 criteria provided, single submitter clinical testing The c.2533delG pathogenic mutation, located in coding exon 15 of the SCN5A gene, results from a deletion of one nucleotide at nucleotide position 2533, causing a translational frameshift with a predicted alternate stop codon (p.V845Cfs*2). This alteration has been detected in a cohort of individuals with confirmed or suspected Brugada syndrome (Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000614105 SCV000760219 pathogenic Brugada syndrome 2019-01-07 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Val845Cysfs*2) in the SCN5A gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in an individual referred for Brugada syndrome testing (PMID: 20129283). ClinVar contains an entry for this variant (Variation ID: 201559). Loss-of-function variants in SCN5A are known to be pathogenic (PMID: 20129283, 22789973). For these reasons, this variant has been classified as Pathogenic.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000614105 SCV000914210 pathogenic Brugada syndrome 2015-04-29 no assertion criteria provided clinical testing

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