Submissions for variant NM_000335.5(SCN5A):c.1936del (p.Gln646fs)

dbSNP: rs727505158

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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:/ /gnomad.broadinstitute.org/). 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	2024-05-24	criteria provided, single submitter	clinical testing	Previously reported in multiple unrelated individuals with Brugada syndrome (PMID: 20129283, 22090166, 22370247, 32533187); 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22995932, 31447099, 34649698, 28008009, 21980601, 29652902, 27153395, 22090166, 36007526, 33087929, 33164571, 32533187, 34135346, 34495297, 36136372, 36578016, 22370247, 20129283)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000183151	SCV000291787	pathogenic	not provided	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln646Argfs*5) in the SCN5A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SCN5A are known to be pathogenic (PMID: 20129283, 22789973). This variant is present in population databases (rs727505158, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with Brugada syndrome (PMID: 20129283, 22090166, 22370247). ClinVar contains an entry for this variant (Variation ID: 179829). 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.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000183151	SCV001468057	pathogenic	not provided	2020-10-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003298171	SCV003997297	pathogenic	Cardiovascular phenotype	2023-05-19	criteria provided, single submitter	clinical testing	The c.1936delC pathogenic mutation, located in coding exon 12 of the SCN5A gene, results from a deletion of one nucleotide at nucleotide position 1936, causing a translational frameshift with a predicted alternate stop codon (p.Q646Rfs*5). This variant has been reported in association with Brugada syndrome, sudden cardiac arrest/death, ventricular arrhythmias, and early repolarization (Kapplinger JD et al. Heart Rhythm, 2010 Jan;7:33-46; Kanter RJ et al. Circulation, 2012 Jan;125:14-22; Chatterjee D et al. Eur Heart J, 2020 Aug;41:2878-2890; Campuzano O et al. EBioMedicine, 2020 Apr;54:102732; Wijeyeratne YD et al. Circ Genom Precis Med, 2020 Dec;13:e002911; Zhang ZH et al. J Am Coll Cardiol, 2021 Oct;78:1603-1617). In one family, all twenty-one individuals with this variant had abnormal ECGs and manifested varying severities of dysrhythmia phenotypes (Park JK et al. Heart Rhythm, 2012 Jul;9:1090-6). 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000183151	SCV004226748	pathogenic	not provided	2019-03-17	criteria provided, single submitter	clinical testing	PP1_strong, PM2_supporting, PVS1
All of Us Research Program, National Institutes of Health	RCV000156628	SCV004843401	pathogenic	Brugada syndrome	2023-08-23	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 13 of the SCN5A gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with Brugada syndrome (PMID: 20129283, 22370247, 32268277, 32533187, 33164571), early repolarization disorder (PMID: 34649698), and ventricular fibrillation (PMID: 22090166). This variant has been identified in 1/31374 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of SCN5A function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV001254734	SCV001430815	pathogenic	Sinoatrial node disorder; 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.