ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.1936del (p.Gln646fs) (rs727505158)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000156628 SCV000206349 pathogenic Brugada syndrome 2014-06-26 criteria provided, single submitter clinical testing The p.Gln646ArgfsX5 variant in SCN5A has been reported in 5 individuals with Bru gada syndrome (Kapplinger 2010, Kante 2012, Park 2012) and segregated with disea se in 21 affected relatives (clinical manifestations included arrhythmia, syncop e, cardiac arrest, or sudden death) from one family (Park 2012). This variant h as also been reported by other clinical laboratories in ClinVar (Variation ID:17 9829) and has been identified in 1/15412 European chromosomes in gnomAD (https:/ / This variant is predicted to cause a frameshift, w hich alters the protein?s amino acid sequence beginning at position 646 and lead s to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function varian ts in SCN5A are most commonly associated with Brugada syndrome although overlap presentations including other SCN5A-related phenotypes (Long QT syndrome) have b een described (Remme 2013). In summary, the p.Gln646ArgfsX5 variant meets our cr iteria to be classified as pathogenic for autosomal dominant Brugada syndrome ba sed upon the predicted impact to the protein, segregation with disease and very low frequency in the general population. ACMG/AMP Criteria applied: PVS1; PS4_Su pporting; PP1_Strong; PM2.
GeneDx RCV000183151 SCV000235567 pathogenic not provided 2018-07-23 criteria provided, single submitter clinical testing The c.1936delC pathogenic variant in the SCN5A gene has been previously reported in at least five unrelated individuals with Brugada syndrome (Kapplinger et al., 2010; Kanter et al., 2012; Park et al., 2012). Park et al. (2012) reported that the c.1936delC variant also co-segregated with disease in 21 affected family members (clinical manifestations included arrhythmia, syncope, cardiac arrest, or sudden death). The c.1936delC variant causes a frameshift starting with codon Glutamine 646, changes this amino acid to an Arginine residue, and creates a premature Stop codon at position 5 of the new reading frame, denoted p.Gln646ArgfsX5. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1936delC variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.1936delC as a pathogenic variant.
Invitae RCV000156628 SCV000291787 pathogenic Brugada syndrome 2019-10-23 criteria provided, single submitter clinical testing This sequence change deletes one nucleotide in exon 13 of the SCN5A mRNA (c.1936delC), causing a frameshift at codon 646. This creates a premature translational stop signal (p.Gln646Argfs*5) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in SCN5A are known to be pathogenic. This particular variant has been reported in the literature in individuals affected with Brugada syndrome and has been shown to segregate with disease in a large family (PMID: 20129283, 22090166, 22370247). For these reasons, this variant has been classified as Pathogenic.
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000156628 SCV000995249 pathogenic Brugada syndrome 2019-01-17 criteria provided, single submitter clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000853392 SCV000996270 pathogenic Brugada syndrome 1 2019-03-27 criteria provided, single submitter clinical testing This variant causes a frameshift at codon 646 which subsequently introduces a premature stop codon at position 5 and is therefore predicted to result in loss of normal protein function. Loss of function is a known mechanism of disease in the SCN5A gene. This variant has been previously reported as a heterozygous change in patients with Brugada Syndrome (PMID: 20129283, 22090166, 22370247). This variant was found to segregate with disease in a large affected family: 21/35 family members tested were found to harbor the p.Gln646ArgfsTer5 variant, all carriers had an abnormal ECG while other clinical manifestations ranged in severity but included arrhythmia, syncope, cardiac arrest, or sudden death (PMID: 22370247). This variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.003% (1/30926) and thus is presumed to be rare. Based on the available evidence, the c.1936del; p.Gln646ArgfsTer5 variant is classified as Pathogenic.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV001254734 SCV001430815 pathogenic Sinus node disease; Brugada syndrome; Sudden cardiac arrest 2019-09-18 no assertion criteria provided research This variant has been identified in 3 probands as part of our research program. The first proband had a diagnosis of Brugada Syndrome, the second proband survived a cardiac arrest but no diagnosis could be made and the third proband of European descent presented with sinus node disease. For further information please feel free to contact us.

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